BACKGROUND

Spinal/Epidural Anesthesia or Puncture

The risk of epidural hematoma with neuraxial anesthesia is increased 15-fold with the use of anticoagulants if appropriate precautions are not taken. This risk is further increased with the use of postoperative, indwelling catheters. Appropriate management is critical to minimize the risk of developing a spinal/epidural hematoma in these patients. One measure used to minimize this risk is to determine the appropriate timing of needle placement and catheter removal relative to the timing of drug administration to ensure that the anticoagulant drug concentration is at its lowest.⁹

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 (18 hours in young patients aged 20-45 years and 26 hours in elderly patients aged 60-76 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.¹

CLINICAL STUDIES

REgulation of Coagulation in ORthopedic surgery to prevent Deep vein thrombosis (RECORD)

The RECORD clinical development program, a comprehensive program of 4 phase III studies with over 12,000 patients, studied XARELTO (rivaroxaban tablets) for the prophylaxis of venous thromboembolism (VTE) in patients undergoing knee (RECORD 3 and 4) or hip (RECORD 1 and 2) replacement surgery. The data from the RECORD program were submitted to the US Food and Drug Administration (FDA). XARELTO was approved on July 1, 2011 by the FDA for the indication studied in the RECORD program.

In the RECORD 4 study, patients received either oral XARELTO 10 mg once daily, beginning at least 6–8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12–24 hours after surgery. Data from RECORD 4 are not included in the approved product labeling for XARELTO.

Since publication of RECORD 4 findings, the sponsor company conducted a verification of the data for all patients in this clinical trial. With respect to study findings, additional adverse events/serious adverse events were identified; however, the distribution of those was balanced between study groups. In the company’s view, verification findings did not appreciably change the conclusions of the study. Thus, the RECORD 4 findings reported in the publication remain consistent with the overall results from the total RECORD program.

The 4 randomized, double-blind, double-dummy, multinational studies of the RECORD program compared the efficacy and safety between oral XARELTO 10 mg once daily and subcutaneous enoxaparin 40 mg once daily (RECORD 1, 2, and 3) or 30 mg twice daily (RECORD 4).^10-13

• XARELTO was started 6 to 8 hours after surgery in all 4 studies. Enoxaparin was started 12 hours before surgery and restarted 6 to 8 hours after wound closure for RECORD 1, 2, and 3, and was started 12 to 24 hours after wound closure in RECORD 4.
• The primary efficacy endpoint was a composite of any deep vein thrombosis (DVT; proximal and/or distal); nonfatal, symptomatic, objectively confirmed pulmonary embolism (PE); and all-cause mortality. The major safety outcome was the incidence of on-treatment major bleeding, occurring after the first dose of study drug and up to 2 days after the last dose of study drug.
  • Efficacy and safety outcomes were similar for all 4 trials.
  • In all 4 studies, the incidence of the composite endpoint of DVT, nonfatal PE, and allcause mortality was significantly lower in patients treated with XARELTO than in those treated with enoxaparin. In THR, the relative risk reduction (RRR) in total VTE when XARELTO was compared to enoxaparin was 70% in RECORD 1 and 79% in RECORD 2. In TKR, the RRR in total VTE when XARELTO was compared to enoxaparin was 49% in RECORD 3 and 31% in RECORD 4.
  • In all 4 studies, no significant differences were observed in rates of major bleeding or any on-treatment bleeding between the XARELTO and enoxaparin treatment groups.

Rosencher et al (2013)² conducted an observational analysis from the pooled RECORD data to determine the incidence of neuraxial hematoma in patients undergoing THR or TKR and receiving neuraxial anesthesia.

• In RECORD 1, 2, and 3, for subjects receiving neuraxial anesthesia, a spinal needle or epidural catheter was not to be inserted until 12 hours after preoperative enoxaparin or placebo injection. For postoperative analgesia, an indwelling epidural catheter was not to be withdrawn until at least 2 half-lives after the last dose of study drug.
• In RECORD 4, no anticoagulant was administered preoperatively. In patients receiving postoperative analgesia, an indwelling epidural catheter was not to be withdrawn until at least 20 hours after the most recent study drug dose.
• In all studies, the next study drug dose was to be administered at least 4 hours after catheter removal. No anticoagulant was administered preoperatively in RECORD 4.
• Of patients receiving neuraxial anesthesia in the safety population (n=8176), there were 4086 subjects in the XARELTO group and 4090 subjects in the enoxaparin group.
  • There were 1141/4086 (27.9%) subjects in the XARELTO group and 1160/4090 (28.4%) subjects in the enoxaparin group who received epidural anesthesia, of which there were 913 (80.0%) and 897 (77.3%) subjects, respectively, who had indwelling epidural catheters.
  • There was a total of 4948 subjects receiving spinal anesthesia, with 2489 in the XARELTO group and 2459 in the enoxaparin group. A total of 2130 subjects received spinal anesthesia with other types of anesthesia, with 1048 in the XARELTO group and 1082 in the enoxaparin group.
• Across all 4 RECORD studies, there were 2 incidents of intraspinal hematoma events.
  • A 74-year-old female with severe renal impairment receiving enoxaparin 40 mg QD for TKR experienced a serious, compressive, epidural hematoma. Catheter placement and removal was in accordance with published guidelines. This event was resolved after laminectomy, with no signs of a recurrent hematoma.
  • One patient receiving XARELTO for TKR experienced a traumatic puncture during spinal anesthesia, which occurred before XARELTO administration. The event was considered mild and not related to study drug.
• Two minor events (spots of blood at the epidural catheter injection site and traumatic puncture during epidural catheter insertion) occurred in the enoxaparin 40 mg QD group, both of which were considered non-serious and not related to study drug. A blood-tinged epidural catheter event occurred in the XARELTO 10 mg QD and enoxaparin 30 mg BID groups, both of which were considered non-serious and not related to study drug.
• Incidence of VTE was similar regardless of what type of anesthesia was used but was observed to be less with XARELTO compared with the enoxaparin regimens.

XArelto in the prophylaxis of post-surgical VTE after elective Major Orthopedic Surgery of hip or knee (XAMOS)¹⁴

XAMOS was an international, non-interventional, open-label study that assessed adverse events, including bleeding and thromboembolic events, between XARELTO and standard-of-care for VTE prophylaxis in patients after elective THR or TKR.

• Of the 17,413 patients included in the safety population, 8778 received XARELTO (10 mg QD) and 8635 received standard of care (SOC; including low-molecular-weight heparins, fondaparinux, and dabigatran etexilate).
• Treatment-emergent bleeding events were defined as those starting on or after the day of the first dose and within 48 hours of the last dose of thromboprophylactic drug, while thromboembolic events were defined as those occurring within 3 months after surgery.
  • Bleeding events were categorized as major or nonmajor. The primary safety outcome was major bleeding, as defined in the RECORD trials.
• Overall, the results of the XAMOS study showed a lower incidence of symptomatic, thromboembolic events in patients treated with XARELTO than in those treated with SOC. Treatment-emergent major bleeding events occurred at a similar incidence.

Haas et al (2016)³ evaluated subsets of data from the XAMOS study to determine the influence of the type of anesthesia on clinical outcomes in patients undergoing major orthopedic surgery in routine clinical practice.

• A total of 6373 (36.6%) patients received general anesthesia, 10,355 (59.5%) received neuraxial anesthesia (spinal or epidural), 113 (0.6%) received peripheral anesthesia, and 523 (3%) received combinations.
• For both surgery types, neuraxial anesthesia was used more than any other form of anesthesia. General anesthesia was used more often in hip surgery than knee surgery. The types of anesthesia used were similar between groups.
• Regardless of the anesthesia type, the incidence of symptomatic, thromboembolic events was lower in XARELTO-treated patients than in SOC-treated patients.
  • General anesthesia: XARELTO, 1.2% vs SOC, 1.7% (OR=0.71; 95% CI 0.47-1.07).
  • Neuraxial anesthesia: XARELTO, 0.6% vs SOC, 1.1% (OR=0.56; 95% CI 0.36-0.87).
• Treatment-emergent major bleeding events occurred at a similar incidence between treatment groups and were not influenced by the type of anesthesia used.
  • General anesthesia: XARELTO, 0.4% vs SOC, 0.4% (OR=0.90; 95% CI 0.42-1.91).
  • Neuraxial anesthesia: XARELTO, 0.4% vs SOC, 0.3% (OR=1.40; 95% CI 0.72-2.71).
• Across both treatment groups, there were no reports of spinal hematomas in patients receiving neuraxial anesthesia.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 September 2024.