Summary

• Please refer to the XARELTO® (rivaroxaban) full Prescribing Information including BOXED WARNING available at https://www.janssen.com/us/our-products or contact Johnson and Johnson Innovative Medicine Medical Information at (1-800-526-7736).¹
  • Premature discontinuation of XARELTO increases the risk of thrombotic events.
  • Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture.
  • 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.
  • 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.
• There are several guidelines and expert consensus decision pathways available on XARELTO periprocedural management from various organizations.^2-5
• Perioperative antithrombotic therapy management data from clinical studies is available.^6-18
• Bridging with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH), as commonly seen with patients on vitamin K antagonists (VKAs), is not necessary in patients treated with direct acting anticoagulants (DOACs). The predictable nature of DOACs allows for short-term cessation and reinitiation of therapy before and after surgery, without the need for bridging.¹¹
• A hemostatic safety threshold for periprocedural DOAC concentration for XARELTO has not been established.¹⁹
• Additional references identified during literature search are included in the REFERENCES section for your review.^{10-13,16,20-30}

Organizational guidelines

American College of Chest Physicians (ACCP), 2022

• Stop XARELTO 1 day before low/moderate bleed risk procedures, and 2 days before high-bleed risk procedures. This management may be applied irrespective of whether patients are receiving XARELTO for atrial fibrillation (AF) or venous thromboembolism (VTE).²
• Resume NOACs at least 24 hours after low-to-moderate-bleed-risk procedures and 48-72 hours after high-bleed-risk.
• Bridging with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) is not recommended.

American College of Cardiology/American Heart Association (ACC/AHA), 2014

• In patients with normal renal function undergoing elective procedures where hemostatic control is essential (such as major surgery, spine surgery, and epidural catheterization), discontinuation of factor Xa inhibitors for ≥48 hours is recommended.³

European Heart Rhythm Association and the European Society of Cardiology, 2021

• The European Heart Rhythm Association and the European Society of Cardiology recommend discontinuing DOACs 24 hours before procedures with a minor bleeding risk in patients with a normal kidney function, and 48 hours before procedures with a major bleeding (MB) risk, regardless of the specific drug.⁵

The 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation (NVAF) provides guidance specific to patients who are maintained on chronic anticoagulation therapy for NVAF. This decision pathway provides guidance of when to interrupt therapy with a DOAC, such as XARELTO, guidance for the durations for withholding XARELTO, and guidance on how to restart an anticoagulant after a procedure. Guidance differs depending on the patient bleed risk, the bleeding risk of the procedure (low vs uncertain, intermediate, or high bleed risk) and patient renal function,⁴ see Table: Guidance on Duration for Withholding XARELTO Based on Procedural Bleed Risk and Estimated CrCl When There Are No Increased Patient Bleed Risk Factors

MONITORING PARAMETERS

The ACC/AHA guidelines additionally suggest that monitoring prothrombin time (PT) for XARELTO and apixaban in the periprocedural setting may be helpful. A PT consistent with control levels suggests a low serum concentration of the anticoagulant.³ Proposals from the Working Group on Perioperative Thrombosis and Hemostasis (GIHP) state that an activated partial thromboplastin time (aPTT) ratio ≤1.2 indicates a XARELTO plasma concentration less than 30 ng/mL. An aPTT ratio between 1.2 and 1.5 corresponds to plasma concentrations between 30-200 ng/mL, and in these cases, delaying the procedure by 12 hours is recommended. An aPTT ratio greater than 1.5 corresponds to concentrations greater than 200 ng/mL, and a minimum of 24 hours is suggested to reach the hemostatic threshold of 30 ng/mL.¹⁹

CLINICAL STUDIES

ROCKET-AF

ROCKET AF⁶ (Rivaroxaban, Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) was a phase 3, randomized, double-blind, multicenter, noninferiority study designed to evaluate the efficacy and safety of oral XARELTO 20 mg once daily (QD); 15 mg for patients with creatinine clearance [CrCl] 30-49 mL/min) and warfarin (target international normalized ratio [INR]: 2.0-3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk of stroke.

Periprocedural Management

• For elective procedures, XARELTO was stopped 2 days prior to the procedure.⁷
• For semi-urgent procedures, XARELTO was stopped and the procedure was delayed by 24 hours from the last dose, if possible.
• For emergency procedures, all patients were managed as if they were taking warfarin. For some procedures (eg, urgent percutaneous coronary intervention), study drug was continued without interruption.
• In all cases, anticoagulant therapy was resumed when hemostasis was achieved and when the treating physician considered oral anticoagulant therapy was appropriate.

Temporary Interruption

Sherwood et al (2014)⁸ conducted a subanalysis of patients in ROCKET AF to determine reasons for temporary interruption (TI) and the relationship between anticoagulant and outcomes among patients with TI.

• TI was defined as discontinuation of study drug for ≥3 days, with resumption of therapy within 30 days (blinding was maintained).
• The TI study population consisted of 4692/14,236 patients (33%), and the median duration of TI was 5 days.
• More than 40% of TI patients (2130) experienced TI for a surgical or invasive procedure.
• The risk of stroke or noncentral nervous system systemic embolism during any “at-risk” period of TI for a surgical or invasive procedure was not significantly different in XARELTO-treated patients vs warfarin-treated patients.
• TI was associated with a 30-day stroke/systemic embolism rate of 0.36% and MB rate of 0.88%, and was similar in XARELTO- and warfarin-treated patients.

VENTURE-AF

VENTURE-AF⁹ was a prospective, randomized, open-label study that compared the safety of uninterrupted XARELTO 20 mg QD to uninterrupted vitamin K antagonists (uVKAs) in 248 patients undergoing catheter ablation for NVAF.

• Patients were required to receive continuous oral anticoagulation for at least 3 weeks prior to ablation (1-7 days prior to the ablation was permitted if the assessments verified an absence of an intracardiac thrombus).
• On the day of the ablation, XARELTO was continued and intravenous UFH was titrated to achieve an activated clotting time of 300-400 seconds.
• The first postprocedure dose of study medication was administered on the same day with the evening meal, at least 6 hours after homeostasis was established.
• Study drug was continued for 30±5 days following ablation.
• XARELTO patients had a similar incidence of periprocedural MB (0 with XARELTO vs 1 with VKA) and thromboembolic events (0 with XARELTO vs 2 with VKA).
• The number of serious adverse events (AEs) leading to hospitalization was comparable between XARELTO and VKA (11 vs 7, respectively).

Kawabata et al

Kawabata et al (2016)¹⁴ conducted a multicenter, prospective study to assess the safety of XARELTO as periprocedural anticoagulation therapy in 74 Japanese patients undergoing paroxysmal NVAF ablation.

• XARELTO 15 mg (CrCl ≥50 mL/min) or 10 mg (CrCl ≥30 and <50 mL/minute) QD was initiated ≥4 weeks prior to AF ablation, discontinued on the day of ablation, resumed within 24 hours following ablation (at the same prior dosage), and continued for ≥3 months thereafter.
• Bridging UFH therapy was administered during the time of XARELTO interruption.
• The mean duration of follow-up was 108 days.
• Outcomes assessed during the periprocedural period included: death, stroke, systemic thromboemboli, and cardiac events; bleeding complications; and other AEs.
• XARELTO dosage was 15 mg and 10 mg in 59 and 15 patients, respectively.
• Patients had a mean CHADS₂ (congestive heart failure, hypertension, age ≥75, diabetes, stroke [doubled]) and CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥75 [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 and sex category [female]) score of 0.6±0.7 and 1.2±1.0, respectively, and a mean HAS-BLED (hypertension, abnormal liver/renal function, stroke history, bleeding history or predisposition, labile INR, elderly, drug/alcohol usage) score of 1.0±0.8.
• During the periprocedural period, MB events and thromboembolic events were not observed, with the exception of a case of bleeding secondary to gastric cancer. Minor bleeding events occurred in 2 patients.
• Mean PT and mean aPTT were mildly prolonged and maintained during XARELTO therapy.
• XARELTO was discontinued in 5 (6.8%) patients due to MB from gastric cancer, cardiac tamponade following AF ablation, hepatic and renal dysfunction, and bleeding secondary to palpebral conjunctiva.

PAUSE

The PAUSE¹⁷ (Perioperative Anticoagulant Use for Surgery Evaluation) trial was a nonrandomized, prospective cohort study involving 3007 DOAC-treated patients with AF who required anticoagulant therapy interruption for an elective surgery or procedure. Patients were separated into 3 cohorts based on the DOAC used (apixaban, dabigatran, or XARELTO), of which, XARELTO accounted for 1082 (36.0%) of the patients enrolled.

• Consecutive patients were enrolled on the following eligibility criteria: adults (aged >18 years) with AF who were long-term users of apixaban (5 or 2.5 mg twice daily), dabigatran etexilate (150 mg or 110 mg twice daily), or XARELTO (20 mg or 15 mg daily), and were scheduled to have an elective surgery or procedure that required interruption of the anticoagulant regimen. Patients in each arm would be excluded if their CrCl was <30 mL/min for the dabigatran- and XARELTO-treated patients or <25 mL/min for apixaban-treated patients.
• Before the procedure patients were categorized as having a high- or low-bleeding risk procedure which informed the patient of the timing of DOAC therapy interruption and resumption, with a goal of having at least one-third of patients classified as high-bleeding risk. DOAC therapy would be omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. DOAC therapy would be resumed 1 day after a lower-bleeding-risk procedure and 2 to 3 days after a high-risk-bleeding procedure, provided hemostasis was achieved.
• The primary efficacy outcomes were MB and arterial thromboembolism (ischemic stroke, transient ischemic attack, and systemic embolism). For each DOAC cohort, the PAUSE management would be associated with a 1% rate of MB (with the upper limit of the 1-sided 95% confidence interval [CI] to exclude a 2% rate) and a 0.5% rate of arterial thromboembolism (with the upper limit of the 1-sided 95% CI to exclude a 1.5% rate). Secondary outcomes included clinically relevant nonmajor bleeding (CRNMB), minor bleeding, death, myocardial infarction, deep vein thrombosis, pulmonary embolism (PE), and catheter-associated venous or arterial thrombosis.
• Of the 1082 patients in the XARELTO-arm, 709 patients were classified as low-bleeding risk and 373 were classified as high-bleeding risk. MB occurred in 20 patients (1.85%) in the XARELTO-arm (1-sided 95% CI, 0-2.65; P=0.36). Arterial thromboembolism occurred in 4 patients (0.37%) in the XARELTO-arm (1-sided 95% CI, 0-0.82; P=0.001). No instances of myocardial infarction, deep vein thrombosis, or arterial catheter-associated thrombosis occurred in the XARELTO-arm. CRNMB occurred in 26 patients (2.4%) in the XARELTO-arm and minor bleeding occurred in 62 patients (5.73%).

Tafur et al (2020)³¹ conducted a prespecified subanalysis of the PAUSE study to evaluate predictors of perioperative bleeding. The primary outcome was the composite of CRNMB and MB or MB alone. The incidence of CRNMB and MB was 4.16% (1-sided 95% CI, 0-5.28), 3.02% (1-sided 95% CI, 0-3.92), and 2.84% (1 sided 95% CI, 0-4.11) for XARELTO, apixaban, and dabigatran, respectively. The rate of MB was 1.85% (1-sided 95% CI, 0-2.65), 1.35% (1-sided 95% CI, 0-2), and 0.9% (1-sided 95% CI, 0-1.73) for XARELTO, apixaban, and dabigatran, respectively. Predictors of perioperative MB included surgery bleeding risk (high vs low; odds ratio [OR], 2.76; 95% CI, 1.51-5.06), hypertension (OR, 3.33; 95% CI, 1.19-9.32), and high-bleed-risk surgery (OR, 2.76; 95% CI, 1.51-5.06).

EINSTEIN-Jr

EINSTEIN-Jr³² was an open-label, phase 3, randomized, multicentre study which compared the efficacy and safety of XARELTO with standard anticoagulants in pediatric patients (017 years old) with VTE.

Sánchez van Kammen et al (2022)³³ conducted a subgroup analysis of the EINSTEIN-Jr study evaluating therapeutic anticoagulation strategies and their outcomes in pediatric patients with cerebral venous thrombosis (CVT) and an associated head or neck infection.

Methods

• Following 5-9 days of initial heparin therapy, patients were randomized 2:1 to receive therapeutic anticoagulation with either LMWH (with or without subsequent VKAs) or XARELTO.
• The duration of treatment was 3 months, during which the patients were followed up for the occurrence of recurrent symptomatic venous thrombosis and bleeding.

Results

• A total of 74 patients received antibiotics and anticoagulants, of which 45 (61%) received XARELTO treatment.
• Of the 41 (55%) patients that underwent surgery, 38 (93%) had ear, nose, or throat surgery for the acute infection, combined with drainage of an intracranial abscess or empyema in 3 (4%) patients, whereas the remaining 3 patients underwent the first surgical procedure after the acute management of the head or neck infection.
• In 34 (83%) patients, CVT was diagnosed preoperatively. Prior to surgical intervention, anticoagulation was started in 12 of these patients, either as prophylactic (8%) or therapeutic (92%) therapy, and anticoagulation was interrupted one day before surgery (50%) or on the day of surgery (50%). Postoperatively, after a median of 1 day (interquartile range [IQR], 0-1), anticoagulation was started or restarted in all 34 patients in prophylactic (6%) or therapeutic (94%) doses.
• Among patients who underwent a surgical procedure, the time from CVT diagnosis to the initiation of anticoagulation was a median of 1 day (IQR, 0-2).
• None of the 41 patients (0%; 95% CI, 0-9) who had a surgical intervention had recurrent thrombosis, asymptomatic deterioration on repeat brain imaging, or MB or CRNMB complications during the 3-month study period.
• Overall, 1 of 74 patients (1%; 95% CI, 0-7) had recurrent symptomatic thrombosis, and 2 of 74 patients (3%; 95% CI, 1-10) had a clinically relevant bleeding complication (1 patient each experienced a subdural hematoma and epistaxis). Five of 74 (7%) patients had headaches, and 0 of 74 patients had seizures.
• At 3-months of treatment, no cases of mortality or new focal edema or ICH on repeat imaging were reported. Two (3%) patients required increased help in activities of daily living compared with before CVT, 3 (4%) had focal neurologic deficits, 2 (3%) had impaired vision, and 5 (15%) had hearing impairment.

Li et al

Li et al (2023)³⁴ conducted a prospective, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of the combined application of tranexamic acid (TXA) and XARELTO in 657 patients undergoing posterior/transforaminal lumbar interbody fusion (PLIF/TLIF) and explore relevant factors related to blood loss and VTE.

Methods

• Eligible patients (aged ≥18 years) with an Autar score of ≤10 were randomly assigned to group A (n=232) or B (n=220). Patients with an Autar score of >10 were assigned to group C (n=223).
• Patients received the following treatments:
  • Group A (control group, n=227): 0.9% NaCl solution intravenously.
  • Group B (n=212): 2 g TXA injected intravenously and 1 g TXA (1g TXA dissolved in 10 mL 0.9% NaCl solution) injected locally intraoperatively.
  • Group C (n=218): The same treatment as group B intraoperatively and XARELTO 10 mg QD postoperatively for 35 days.
• The primary outcomes included intraoperative blood loss, postoperative drainage, obvious total blood loss (TBL), the ultrasound results of the veins of both lower limbs postoperatively, and number of patients receiving blood transfusions.
• Hemoglobin (Hb) levels, hematocrit (HCT) levels, aPTT, PT, liver and kidney function, C-reactive protein (CRP), and D-dimer were tested preoperatively and on postoperative day (POD) 1, POD3, and POD5.

Results

• No significant differences in sex, age, body mass index (BMI), mean arterial pressure (MAP) or hematological parameters were detected among the 3 groups.
• Intraoperative blood loss and postoperative drainage in group A was significantly greater than that in group B (P<0.05) and no such difference was observed between groups B and C.
• The levels of HCT and Hb in group B were significantly higher than those in group A (P<0.05). No significant difference was detected in postoperative hematological parameters between groups B and C, see Table: Primary Outcomes-I.
• No significant differences in the CRP or D-dimer levels were observed preoperatively among all groups.
• After surgery, the CRP and D-dimer levels increased in all groups.
  • D-dimer levels on POD1, POD3, and POD5 were lower for group C (mean±standard deviation [SD], 0.81±0.50, 1.01±0.27, and 1.59±0.30 mg/L) than for group B (mean and SD, 1.21±0.16, 2.22±0.27, and 2.08±0.18 mg/L). A statistically significant difference in D-dimer levels was not detected between groups A and B.
  • At every timepoint after the surgery, compared with group A (mean±SD, 30.17±24.31, 35.51±21.28, and 36.26±17.12 mg/L), the CRP level was significantly lower in group B (mean±SD, 25.42±23.23, 23.07±20.31, and 29.62±24.45 mg/L) and group C (mean±SD, 24.10±15.60, 25.80±14.66, and 29.46±14.34 mg/L). A statistically significant difference in CRP levels was not detected between groups B and C.
• The rates of allogeneic blood transfusion among all the groups were similar, whereas the rates of autologous blood transfusion in groups B and C were significantly lower than group A (P<0.05).
• Compared with group C, there was a higher VTE rate in group B (P<0.05). A significant difference in VTE rate was not observed between group A and B. See Table: Primary Outcomes-II.
• Among all patients in the 3 groups, no fatal complications such as a PE or an epidural hematoma occurred, and there were no clinical symptoms of TXA toxicity, such as epilepsy.

• No significant differences or abnormalities were observed among the 3 groups in terms of liver, kidney, and blood coagulation function.
• Age, BMI, number of fixation segments, and operative time were found to be positively correlated with obvious TBL (P<0.05).
• Logistic regression analysis showed that BMI, high-density lipoprotein (HDL), number of fixation segments, bone density, and T-scores of the lumber spine were the risk factors for the formation of thrombus (P<0.1).

Zhou et al

Zhou et al (2023)³⁵ conducted a prospective randomized study to compare the effects of different antithrombotic agents on patients after primary unilateral total knee arthroplasty (TKA) in the context of applied TXA.

Methods

• A total of 180 patients (aged 55-80 years and diagnosed with knee osteoarthritis according to the Kellgren-Lawrence grading system [≥grade 3]) undergoing primary unilateral TKA were included.
• The average±SD follow-up period was 3.02±0.09 months, with no loss to follow-up.
• Patients received the following treatments:
  • Group 1 (n=60): XARELTO 10 mg orally 12 hours postoperatively and then QD 30 days.
  • Group 2 (n=60): dalteparin sodium 2500 IU subcutaneously 12 hours postoperatively and then QD 30 days.
  • Group 3 (n=60): aspirin (ASA) 100 mg orally 12 hours postoperatively and then QD 30 days.
• All patients were given 60 mg/kg TXA intravenously 5 minutes prior to prosthesis placement.
• Primary outcomes included the following: Post-treatment drainage volume (defined as the total amount of fluid drained from the drainage tube 24 hours after treatment [including the 24th hour]) and thrombotic complication rate (determined by dividing the number of patients with thrombosis in each group by the total number of patients).

Results

• Drainage volume and TBL after treatment were significantly lower in group 3 than in group 1 and 2 (P<0.001). Additionally, group 1 had significantly lower drainage volume and TBL in comparison to group 2 (P<0.001).
• There was no significant difference in intraoperative blood loss among the 3 groups (P=0.5), see Table: Blood Loss Parameters Among the 3 Groups.
• Difference in the thrombotic complication rate between the 3 groups of patients was not significant (P=0.6), see Table: Thrombotic Complications Among the 3 Groups
• No PE was reported in any of the 3 groups.

Douketis et al (2024)

Douketis et al (2024)¹⁸ conducted a post hoc subanalysis of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial to evaluate the perioperative management and clinical outcomes in patients who required a surgery or invasive procedure during the trial and were receiving low-dose XARELTO and/or ASA.

Methods

• A total of 2632 patients who had undergone an elective or urgent surgery or procedure were included.
• The most common surgeries or procedures that patients underwent during the trial were percutaneous coronary intervention (~43%), carotid or other arterial angioplasty (~15%), pacemaker or internal cardiac defibrillator implantation (~9%), and coronary artery bypass graft surgery (~7%).
• Patients received the following treatments:
  • Group 1 (n=875): XARELTO 2.5 mg twice daily+ASA 100 mg once daily (mean age: 68.8 years; female, n=176)
  • Group 2 (n=857): XARELTO 5 mg twice daily (mean age: 68.1 years; female, n=163)
  • Group 3 (n=900): ASA 100 mg once daily (mean age: 68.3 years; female, n=176)
• Perioperative management was at the discretion of the treating physician. Patients were observed from 7 days before the surgery/procedure until 30 days after the surgery/procedure.
• The following outcomes were included: composite of myocardial infarction and angina, stroke, and acute limb ischemia; composite of myocardial ischemia, stroke, acute limb ischemia, and cardiovascular death; and any bleeding (major or minor). Individual outcomes were bleeding (major, minor, or any), stroke (ischemic or hemorrhagic), myocardial ischemia, venous thromboembolism, and all-cause mortality.

Results

• Approximately 1/3 of the patients continued the study drug without interruption, and the remaining patients interrupted the study drug between 1 and ≥10 days before the surgery/procedure; the longest interruption interval was 14 days.
• For clinical outcomes during the perioperative period (day -7 to day +30), see Table: Perioperative Clinical Outcomes

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 08 July 2024.