Frequently asked questions about XARELTO®

Reducing stroke risk in NVAF

In ROCKET AF, NVAF was defined as atrial fibrillation in the absence of hemodynamically significant mitral valve stenosis or a prosthetic heart valve. However, patients with mitral valve repair, such as annuloplasty with or without prosthetic ring, commissurotomy, and/or valvuloplasty, were permitted.1 

In ROCKET AF, the ITT population included all patients who underwent randomization and were followed for events during treatment or after premature discontinuation. The randomized population included 14,264 patients (7131 in the XARELTO® group and 7133 in the warfarin group). However, the ITT population that was analyzed for efficacy included a total of 14,171 patients (7081 in the XARELTO® group and 7090 in the warfarin group) because patients from 1 site were excluded from the efficacy analysis (50 from the XARELTO® group and 43 in the warfarin group) due to violation of good clinical practice.2 

The per-protocol population included every patient who underwent randomization in the trial and who received at least 1 dose of XARELTO®, did not have a major protocol violation, and was followed for events while receiving XARELTO® or within 2 days after discontinuation (on-treatment).2

In ROCKET AF, the per-protocol population included 13,962 patients (6958 patients in the XARELTO® group and 7004 patients in the warfarin group).2

The safety, as-treated, or safety, on-treatment, population included patients who received at least 1 dose of XARELTO® and were followed for events, regardless of adherence to the protocol, while they were receiving XARELTO® or within 2 days after discontinuation.2

In ROCKET AF, the safety, as-treated population included 14,143 patients (7061 patients in the XARELTO® group and 7082 patients in the warfarin group). The randomized ITT population included 14,264 patients, but because of violations of good clinical practice at 1 site, 93 patients (50 in the XARELTO® group and 43 in the warfarin group) were excluded from all efficacy analyses before unblinding and 28 patients (20 in the XARELTO® group and 8 in the warfarin group) were excluded because they did not receive the first dose of the study drug.1,2

Phase 1 data showed that once-daily XARELTO® demonstrated FXa inhibition through 24 hours.3  This was the basis for the once-daily dosing schedule in ROCKET AF, which demonstrated the efficacy and safety of XARELTO® in reducing the risk of stroke in more than 14,000 patients. XARELTO® should be taken once daily with the evening meal for patients with NVAF. For other indications, see the prescribing information.4

The clinical significance of pharmacokinetics and pharmacodynamics has not been established. 

ROCKET AF was a large, double-blind, double-dummy study evaluating XARELTO® versus dose-adjusted warfarin in more than 14,000 patients.2 The study population had prior stroke or multiple comorbidities, including CHF, hypertension, aged ≥75 years, diabetes, and prior stroke or TIA, reflecting an increased risk for stroke. With a 3.5 mean CHADS2 score, ROCKET AF patients were at moderate to high risk for stroke and candidates for anticoagulation prophylaxis. 

In ROCKET AF, 21% (n=2950) of the study population had moderate renal impairment (CrCl 30 to 49 mL/min) at the time of enrollment.4  The dose of XARELTO® in these patients was 15 mg once daily, taken with the evening meal. The findings in these patients were consistent with those who had better renal function (CrCl ≥50 mL/min) and with the overall ROCKET AF trial results. These patients had a median age of 79 years; a mean CHADS2 score of 3.7, reflecting an increased risk for stroke; and a higher prevalence of heart failure, peripheral vascular disease, and prior MI than those with better renal function.4 

Efficacy and safety results in patients with moderate renal impairment (CrCl 30 to 49 mL/min) receiving XARELTO® 15 mg once daily were generally consistent with those with better renal function (CrCl ≥50 mL/min) given XARELTO®  20 mg once daily, and consistent with the overall trial.4

Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in patients with AF. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. 

The label provides guidance if therapy with XARELTO® must be interrupted or temporarily stopped for surgery or other interventions (see section 2.4 of the Prescribing Information). If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO® should be stopped at least 24 hours before the procedure to reduce the risk of bleeding. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO®, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO® should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short. If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

Update to: ESRD (<15 mL/min)5

  • Clinical efficacy and safety studies with XARELTO® did not enroll patients with ESRD on dialysis
  • In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO® 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study
  • It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF 

CAD/PAD 

When the COMPASS trial was published in 2017, the ACC/AHA had issued guidelines for the secondary prevention of cardiovascular events in CAD and chronic PAD patients. Both guidelines recommended aspirin as the antiplatelet therapy for secondary prevention of major cardiovascular events based on outcomes from long-term studies.6,7

For patients with CCD,* the 2023 ACC/AHA guideline recommends low-dose aspirin 81 mg (75-100 mg).8

For patients with symptomatic PAD, the 2024 ACC/AHA guideline recommends an aspirin dose between 75 mg and 325 mg daily.9 

*CCD is defined as a group of conditions that includes CAD, IHD diagnosed only by diagnostic testing, and chronic angina syndromes.8

The COMPASS trial studied patients with stable CAD and PAD.10

Aspirin was chosen as the comparator for the COMPASS trials because it was the only Level 1A recommended antithrombotic in the ACC/AHA guideline for both CAD and PAD at the time the trial was being planned.6,7

DAPT (clopidogrel with aspirin, 75 mg to 100 mg) referenced in the 2016 ACC/AHA guideline was only recommended as a reasonable alternative (2b level of evidence) to aspirin in certain conditions or patient types with limited data.7,11

The average time since an acute cardiovascular event in the COMPASS trial was 7 years.10 Given this and 2016 guideline-based recommendations, patients on DAPT were excluded from the COMPASS trial.10,12 

*Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

The COMPASS trial evaluated 27,395 patients with stable CAD and/or PAD on 3 different study arms including XARELTO® 2.5 mg twice daily in combination with aspirin 100 mg once daily.10 XARELTO® is also indicated for other conditions requiring different dosage strengths and dosing regimens (once daily or twice daily) based on the specific trial designs for VTE and stroke risk reduction in NVAF.

Rationale for the Low-dose XARELTO® 2.5 mg regimen* was supported by ATLAS TIMI-51, a phase 3 trial that evaluated the twice-daily 2.5 mg dose in addition to either aspirin alone or dual antiplatelet therapy in patients with acute coronary syndrome (ACS).13

While this indication was not FDA approved, outcomes prompted continuing the clinical evaluation of rivaroxaban 2.5 mg twice daily in combination with aspirin that led to the COMPASS trial rationale and study design.12

XARELTO® provides condition-specific dosing across a broad range of thrombotic risk.

*Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

Participants in the VOYAGER trial were either endovascular or surgical LER patients.14 A majority (about two thirds [65%]) had been treated with an endovascular procedure, and a little more than one third (35%) had been treated surgically.15 Among endovascular procedures, the most common procedures were balloon angioplasty, bare-metal stent, and drug-coated balloon.14

Both patient types were studied using the Low-dose XARELTO® 2.5 mg regimen* with relative risk reduction proven among both populations.14

Procedural Characteristics14
CharacteristicsXARELTO® 2.5 mg twice daily + aspirin 100 mg†
(n=3286)		Placebo
+ aspirin 100 mg†
(n=3278)
Median time from revascularization to randomization (IQR) - days5 (2-7)5 (2-7)
Qualifying revascularization - no. (%)
Endovascular2153 (65.5)2140 (65.3)
Balloon angioplasty1267 (38.6)1328 (40.5)
Drug-coated balloon533 (16.2)555 (16.9)
Bare-metal stent725 (22.1)742 (22.6)
Covered stent71 (2.2)53 (1.6)
Drug-coated stent140 (4.3)158 (4.8)
Atherectomy155 (4.7)156 (4.8)
Hybrid163 (5.0)125 (3.8)
Surgical1133 (34.5)1138 (34.7)

*Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

†Treatment schedule: XARELTO® 2.5 mg twice daily versus placebo; all patients received aspirin 100 mg once daily as background therapy.

The median age of PAD patients was 67 years and 26% of the patient population were women.14

Primary comorbidities included14:

  • 40% of patients had diabetes mellitus
  • 20% had an eGFR less than 60 mL per minute per 1.73 m2 of body-surface area
  • 35% were active smokers at randomization
  • 31% had known coronary disease
  • 11% had previous myocardial infarction
Common medications at baseline included14:
  • 79% were taking statin therapy
  • 63% were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs)
  • 51% of patients were taking clopidogrel
Values are approximate.

Primary efficacy outcome14,16: 

Composite of:

  • Acute limb ischemia
  • Major amputation of vascular etiology
  • MI
  • Ischemic stroke
  • CV death
Secondary efficacy outcomes15,16:
  • ALI, major amputation of a vascular etiology, MI, ischemic stroke, or CHD death
  • Unplanned index limb revascularizations for recurrent limb ischemia
  • Vascular hospitalizations for a peripheral or coronary event of a thrombotic nature
  • ALI, major amputation of a vascular etiology, MI, ischemic stroke, or all-cause mortality
  • ALI, major amputation of a vascular etiology, MI, all stroke, or CV death
  • Death from any cause
  • VTE
Principal safety outcome15:
  • TIMI major bleeding*
Secondary safety outcomes15,16:
  • ISTH major bleeding†
  • BARC major bleeding‡

*TIMI major bleeding is defined as fatal bleeding, intracranial hemorrhage, a decrease in hemoglobin level of ≥5 g/dL, or a decrease in hematocrit of ≥15%.

†ISTH major bleeding is defined as fatal bleeding, bleeding into a critical site, a decrease in hemoglobin level of ≥2 g/dL, or transfusion of at least 2 units of packed red cells or whole blood.

‡BARC major bleeding is defined as grade 3b or higher.

Patients in the VOYAGER trial received treatment with the Low-dose XARELTO® 2.5 mg regimen* within an average of 5 days post LER, with some receiving treatment as early as 2 days after successful LER.14

*Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

The median follow-up period in the VOYAGER trial was 28 months (interquartile range, 22 to 34 months).14

*Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

Patients should stay on the Low-dose XARELTO® 2.5 mg regimen* for the duration of treatment per the physician’s discretion. Patients in the VOYAGER trial were studied up to 36 months post treatment.14

*Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

Over 50% of the randomized patients (3313/6564) received clopidogrel for a median duration of 29.0 days. Although there is no recommended length of use for clopidogrel, it was to be administered for up to 6 months after revascularization at the discretion of the VOYAGER investigators.14,17*

The Low-dose XARELTO® 2.5 mg regimen† reduced the relative risk of adverse cardiovascular and limb events‡ with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of the Low-dose XARELTO® 2.5 mg regimen† was similar with or without the use of clopidogrel, but there was a trend for more ISTH major bleeding when clopidogrel was used for 30 days or more. The evidence shows a reduction of risk when XARELTO® is added to aspirin after LER regardless of concomitant clopidogrel; the evidence also shows that a shorter course of clopidogrel (<30 days) may result in less bleeding.17

*Clopidogrel use was not a randomized therapy and was associated with a different patient profile of CV risk, bleeding risk, and burden of concomitant CVD between the groups; direct comparisons of the efficacy and safety of clopidogrel in this setting are confounded, particularly without adjustment.

†Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

‡A composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or CV death.

More than 50% of the randomized patients (3313/6564) received clopidogrel for a median duration of 29.0 days.17

Efficacy:

Over 3 years, the hazard ratio for the primary outcome (composite of acute limb ischemia, major amputation of vascular etiology, MI, ischemic stroke, or CV death) of the Low-dose XARELTO® (2.5 mg) regimen* versus placebo† was HR = 0.85 (95% CI: 0.71-1.01) with clopidogrel and HR = 0.86 (95% CI: 0.73-1.01) without clopidogrel (P=0.92). The Low-dose XARELTO® (2.5 mg) regimen* resulted in an early apparent clinical difference in acute limb ischemia within 30 days (HR = 0.45 [95% CI: 0.14-1.46] with clopidogrel; HR = 0.48 [95% CI: 0.22-1.01] without clopidogrel [P=0.93]).17

Safety:

Compared with aspirin, the Low-dose XARELTO® 2.5 mg regimen* had similar TIMI major bleeding regardless of clopidogrel use (P=0.71). With clopidogrel use >30 days, the Low-dose XARELTO® 2.5 mg regimen* was associated with more ISTH major bleeding within 365 days (HR = 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel.17

*Low-dose XARELTO® (2.5 mg) regimen = XARELTO® 2.5 mg twice daily plus aspirin (75 mg to 100 mg) once daily. Dosing of XARELTO® varies by indication. 2.5 mg is the lowest tablet strength of XARELTO® and is only approved for the CAD and PAD indications.

†Patients on placebo received aspirin 100 mg once daily.

ARR18RRR18
Definition

The ARR is the arithmetical difference between the event rates in the 2 groups.

This varies depending on the underlying event rate, becoming smaller when the event rate is low and larger when the event rate is high.

The RRR is the difference in event rates between 2 groups, expressed as a proportion of the event rate in the untreated group.

Calculation

ARR = Risk (placebo) - Risk (experimental)

RRR = (1 - HR) × 100

RR = Risk (experimental)/ Risk (placebo)

TIMI Bleeding Criteria19

Major

  • Hemoglobin drop of ≥5 g/dL, intracranial hemorrhage, or fatal bleed*

Minor

  • Hemoglobin drop of 3 to <5 g/dL

Minimal

  • Overt bleed† that does not meet the criteria for minor or major 
ISTH Bleeding Criteria19

Major

  • Hemoglobin drop of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells, symptomatic bleed in a critical area, or fatal bleed*

CRNM (Clinically Relevant Non-Major)

  • Requires or prolongs hospitalization or results in laboratory testing, imaging, compression, a procedure, interruption of the study medication, or a change in concomitant therapies

Minor

  • Overt bleed† that does not meet criteria for CRNM or major
BARC Bleeding Criteria19‡

BARC 5

  • Fatal bleed*

BARC 3c

  • Intracranial hemorrhage or intraocular bleed compromising vision

BARC 3b

  • Hemoglobin drop of ≥5 g/dL, tamponade, or requiring surgery or vasopressors

BARC 3a

  • Hemoglobin drop of 3 to <5 g/dL or transfusion with overt bleeding 

BARC 2

  • Actionable bleed prompting evaluation, requiring nonsurgical intervention, or leading to or prolonging hospitalization 

BARC 1

  • Bleed that does not result in medical evaluation or consultation but may include self-discontinuation of medicine 

*A bleeding event that directly leads to death within 7 days.

†Bleeding that is visible to the eye or detectable on an imaging study.

‡BARC 4 bleeding was not examined because coronary artery bypass surgeries were rare during trial follow-up.

In the VOYAGER clinical trial, death from any cause or from cardiovascular reasons was a secondary outcome that was tested in a hierarchical fashion. However, these mortality endpoints did not meet a statistically significant difference between experimental and control arms.14

DVT and PE treatment and reduction of recurrence

There is no need to bridge with heparin or LMWH for the DVT and PE treatment indications. XARELTO® can be used as a single, oral agent at the time of diagnosis; it can also be used following initial treatment with heparin or LMWH.20,21

Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.15

Recurrent VTE is more likely to occur in the first 3 weeks following an initial event.22 A dose of 15 mg twice daily is given at the beginning of treatment to ensure adequate anticoagulation during the highest risk period for recurrence. After 21 days, the risk of recurrence is lower, so the dosage of XARELTO® is reduced to 20 mg once daily. Dose selections were based on two phase 2 studies plus analysis of historical data with other anticoagulants.23-27

The EINSTEIN-DVT and EINSTEIN-PE trials had nearly identical designs, inclusion and exclusion criteria, and outcome measures. This allowed the safety data to be pooled and evaluated across a much larger population of more than 8200 patients.28

In EINSTEIN-DVT and EINSTEIN-PE, the enrolling physician determined treatment duration at the time of randomization based on the patient’s profile and local treatment preferences.29,30

For the DVT study, approximately 63% of all patients were allocated to 6 months of treatment, while 25% were allocated to 12 months of treatment.21 In the PE study, approximately 57% and 37% of all patients were allocated to 6 months and 12 months of treatment, respectively.20 

The criteria for a diagnosis of DVT were the presence of (1) a new noncompressible venous segment, (2) a substantial increase (≥4 mm) in the diameter of the thrombus during full compression in a previously abnormal segment on ultrasonography, or (3) a new intraluminal filling defect on venography.31

The criteria for a diagnosis of PE were (1) a new intraluminal filling defect on spiral computed tomography or pulmonary angiography, (2) a cutoff of a vessel of >2.5 mm in diameter on pulmonary angiography, (3) a new perfusion defect of at least 75% of a segment with corresponding normal ventilation (high probability), or (4) a new non–high-probability perfusion defect associated with DVT, as documented by ultrasonography or venography.31

Fatal PE was diagnosed based on objective diagnostic testing, autopsy, or death, which could not be attributed to a documented cause and for which PE could not be ruled out (unexplained death).31

DVT prophylaxis following hip or knee replacement surgery

The efficacy and safety profiles of XARELTO® taken once daily were demonstrated in large, randomized, multicenter clinical trials for DVT prophylaxis in patients following knee or hip replacement surgery.31-34

XARELTO® was studied in 3 randomized, controlled clinical trials—RECORD1, RECORD2, and RECORD3—that included more than 9000 patients undergoing elective knee or hip replacement surgery.

General questions

Extremes in body weight (≤50 kg or ≥120 kg) did not influence XARELTO® exposure. Therefore, XARELTO® dosing does not need to be adjusted.

XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO® in patients with active pathological hemorrhage. XARELTO® has a half-life of approximately 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in elderly subjects aged 60 to 76 years. 

An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable. Use or procoagulant agents, such as prothrombin  complex concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies.

Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended

This is not intended to replace clinical judgment or determine individual patient care.

XARELTO® is a selective inhibitor of FXa. It does not require a cofactor (such as anti-thrombin III) for activity. XARELTO® inhibits free FXa and prothrombinase activity. XARELTO® has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, XARELTO® decreases thrombin generation. 

Once a decision has been made to prescribe XARELTO® (rivaroxaban), XARELTO withMe is a personalized experience that connects your patients to educational support and cost support options.

XARELTO withMe is designed to help patients throughout their treatment journey:

  • Access helpful tips and educational content about their condition and treatment
  • Find options for both commercially and government-insured patients that may help lower out-of-pocket costs for XARELTO®
  • Stay on track with refill notifications

Only patients can sign up at XARELTOwithMe.com or by calling 888-XARELTO (888-927-3586),
Monday–Friday, 8:00 AM–8:00 PM ET.

If you have any questions or need support, call 888-XARELTO (888-927-3586),
Monday–Friday, 8:00 AM–8:00 PM ET.

For additional HCP access and affordability resources, visit JanssenCarePath.com

Discontinue warfarin and start XARELTO® as soon as the INR is below 3.0 in adults and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.

Start XARELTO® 0 to 2 hours prior to the next scheduled administration of the drug (eg, low-molecular-weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start XARELTO® at the same time.

Adults

  • For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5-mg XARELTO® dose as recommended at the next scheduled time
  • For patients receiving 15 mg twice daily: The patient should take XARELTO® immediately to ensure intake of 30 mg XARELTO® per day. Two 15-mg tablets may be taken at once
  • For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed XARELTO® dose immediately. The dose should not be doubled within the same day to make up for a missed dose

Pediatric Patients

  • If XARELTO® is taken once a day, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose
  • If XARELTO® is taken two times a day, the patient should take the missed morning dose as soon as possible once it is noticed. A missed morning dose may be taken together with the evening dose. A missed evening dose can only be taken in the same evening
  • If XARELTO® is taken three times a day, if a dose is missed, the patient should skip the missed dose and go back to the regular dosing schedule at the usual time without compensating for the missed dose

On the following day, the patient should continue with their regular regimen.

XARELTO® requires no routine coagulation monitoring with treatment due to predictable PK/PD.2,3,15,20,21 The INR is not recommended because it is only calibrated and validated for VKAs.35

XARELTO® is contraindicated in patients with active major bleeding or patients with hypersensitivity to XARELTO®. Use of XARELTO® is not recommended in patients who have had transcatheter aortic valve replacement (TAVR), based on the results of the GALILEO study, which reported higher rates of death and bleeding in patients randomized to XARELTO® compared to those randomized to an antiplatelet regimen. The safety and efficacy of XARELTO® have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO® is not recommended in patients with prosthetic heart valves.

Direct-acting oral anticoagulants (DOACs), including XARELTO®, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis [see Boxed Warning]. 

To reduce the potential risk of bleeding associated with the concurrent use of XARELTO® and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO® [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO® is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO®. The next XARELTO® dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO® for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. 

Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. 

Pregnancy: The limited available data on XARELTO® in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO® for the mother and possible risks to the fetus when prescribing XARELTO® to a pregnant woman

Fetal/Neonatal adverse reactions: Based on the pharmacologic activity of FXa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO® in this setting.

There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage

Reducing stroke risk in NVAF

For patients with CrCl ≤50 mL/min, the dose of XARELTO® should be reduced to 15 mg once daily with the evening meal.

Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO® in patients who develop acute renal failure while taking XARELTO®. 

VTE prophylaxis in acutely ill medical patients

Avoid using XARELTO® in patients with CrCl <15 mL/min. Patients who develop acute renal failure while taking XARELTO® should discontinue the treatment.

Treatment of DVT and PE and reducing risk of recurrence

Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid using XARELTO® in patients with CrCl <15 mL/min. Patients who develop acute renal failure while taking XARELTO® should discontinue the treatment.

DVT prophylaxis after knee or hip replacement surgery

Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid using XARELTO® in patients with CrCl <15 mL/min.

Patients who develop acute renal failure while taking XARELTO® should discontinue the treatment.

Reducing risk of major cardiovascular events in CAD 

For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15 to 30 mL/min. Clinical efficacy and safety studies with XARELTO® did not enroll patients with end-stage renal disease (ESRD) on dialysis. 

No dose adjustment needed based on CrCl.

Reducing risk of major thrombotic vascular events in PAD 

For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15 to 30 mL/min. Clinical efficacy and safety studies with XARELTO® did not enroll patients with end-stage renal disease (ESRD) on dialysis. 

No dose adjustment needed based on CrCl.

Pediatric use

No dosage adjustment is required in patients 1 year of age or older with mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73 m2). There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment
(eGFR <50 mL/min/1.73 m2); therefore, avoid the use of XARELTO® in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO® in these patients [see Dosage and Administration (2.2)].

No clinical data are available for patients with severe hepatic impairment. XARELTO® use should be avoided in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

Avoid concurrent use of XARELTO® with other anticoagulants because of increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

In a single-dose drug interaction study, there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO®. However, aspirin and other NSAIDs are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

Approximately 1/3 (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces.

The clinical significance of pharmacokinetics and pharmacodynamics has not been established.

ACC = American College of Cardiology;  AF = atrial fibrillation;  AHA = American Heart Association;  ALI = acute limb ischemia;  aPCC = activated prothrombin complex concentrate;  ARR = absolute risk reduction;  BARC = Bleeding Academic Research Consortium;  CAD = coronary artery disease;  CHD = coronary heart disease;  CHF = congestive heart failure;  CrCl = creatinine clearance;  CV = cardiovascular;  CVD = cardiovascular disease;  DOAC = direct oral anticoagulant;  DVT = deep vein thrombosis;  eGFR = estimated glomerular filtration rate;  ESRD = end-stage renal disease;  FXa = Factor Xa;  INR = international normalized ratio;  IQR = interquartile range;  ISTH = International Society on Thrombosis and Haemostasis;  ITT = intent-to-treat;  LE = lower extremity;  LER = lower extremity revascularization;  LMWH = low-molecular-weight heparin;  MI = myocardial infarction;  NSAID = nonsteroidal anti-inflammatory drug;  NVAF = nonvalvular atrial fibrillation;  PAD = peripheral artery disease;  PCC = prothrombin complex concentrate;  PD = pharmacodynamics;  PE = pulmonary embolism;  PK = pharmacokinetics;  rFVIIa = recombinant factor VIIa;  RR = relative risk;  RRR = relative risk reduction;  TIA = transient ischemic attack;  TIMI = Thrombolysis in Myocardial Infarction;  U = unit;  VKA = vitamin K antagonist;  VTE = venous thromboembolism.

REFERENCES: 1. Online supplement to: Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. Accessed July 9, 2024. http://
www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf 2. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 3. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412-421. 4. Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32(19):2387-2394. 5. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43(4):229-236. 6. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACC/AHA/ACP/AATS/PCNA/SCAl/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):2564-2603. 7. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135:e726-e779. 8. Virani SS, Newby LK, Arnold SV, et al; Writing Committee Members. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA. Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2023;82(9):833-946. 9. Gornik HL, Aronow HD, Goodney PP, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83(24):2497-2607. 10. Eikelboom JW, Connolly SJ, Bosch J, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. 11. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. Circulation. 2016;134(10):e123-e155. 12. Bosch J, Eikelboom JW, Connolly SJ, et al. Rationale, design and baseline characteristics of participants in the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) trial. Can J Cardiol. 2017;33(8):1027-1035. 13. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19. 14. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization [article and supplementary appendix]. N Engl J Med. 2020;382(21):1994-2004. 15. XARELTO® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 16. Capell WH, Bonaca MP, Nehler MR, et al. Rationale and design for the vascular outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD). Am Heart J. 2018;199:83-91. 17. Hiatt WR, Bonaca MP, Patel MR, et al. Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: impact of concomitant clopidogrel on efficacy and safety. Circulation. 2020;142(23):2219-2230. 18. Schechtman E. Odds ratio, relative risk, absolute risk reduction, and the number needed to treat—which of these should we use? Value Health. 2002;5(5):431-436. 19. Bergmark BA, Kamphuisen PW, Wiviott SD, et al. Comparison of events across bleeding scales in the ENGAGE AF-TIMI 48 trial. Circulation. 2019;140:1792-1801. 20. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. 21. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. 22. Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med. 2000;160(22):3431-3436. 23. Limone BL, Hernandez AV, Michalak D, Bookhart BK, Coleman CI. Timing of recurrent venous thromboembolism early after the index event: a meta-analysis of randomized controlled trials. Thromb Res. 2013;132(4):420-426. 24. Buller HR, Lensing AWA, Prins MH, et al; EINSTEIN-DVT Dose-Ranging Study Investigators. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT Dose-Ranging Study. Blood. 2008;112(6):2242-2247. 25. Agnelli G, Gallus A, Goldhaber SZ, et al; ODIXa-DVT Study Investigators. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation. 2007;116(2):180-187. 26. The van Gogh Investigators. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med. 2007;357(11):1094-1104. 27. Fiessinger J-N, Huisman MV, Davidson BL, et al; THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA. 2005;293(6):681-689. 28. Prins MH, Lensing AWA, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21. 29. Online supplement to: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. Supplementary Protocol. N Engl J Med. 2010;363(26):2499-2510. Accessed July 9, 2024. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1007903/suppl_file/nejmoa1007903_protocol.pdf 30. Online supplement to: The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. Supplementary Protocol. N Engl J Med. 2012;366:1287-1297. Accessed July 9, 2024.http://www.nejm.org/doi/suppl/10.1056/NEJMoa1113572/suppl_file/nejmoa1113572_protocol.pdf 31. Online supplement to: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510. Accessed July 9, 2024. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1007903/suppl_file/nejmoa1007903_appendix.pdf 32. Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. 33. Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39. 34. Eriksson BI, Borris LC, Dahl OE, et al; ODIXa-HIP Study Investigators. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006;114(22):2374-2381. 35. Mueck W, Eriksson BI, Bauer KA. Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47(3):203-216.