Summary

• XARELTOis approved for use in DVT prophylaxis following hip or knee replacement surgery in patients with CrCl ≥15 mL/min.¹
• In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment.¹
• Patients with a CrCl <30 mL/min were excluded from the four phase 3 RECORD studies.²
• Pooled analyses of the four pivotal phase 3 RECORD studies were conducted to determine the influence of several factors, including renal function, on the primary and main secondary efficacy outcomes and the incidence of any adjudicated bleeding events in each of the studies.^2,3

CLINICAL STUDIES

<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 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.>

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

Pooled analyses of the four pivotal phase 3 RECORD studies were conducted to determine the influence of several factors, including renal function, on the primary and main secondary efficacy outcomes and the incidence of any adjudicated bleeding events in each of the studies.^2,3 Total VTE (primary efficacy endpoint) and major VTE (major secondary efficacy endpoint) and any bleeding outcomes (XARELTO vs enoxaparin) were analyzed by level of creatinine clearance.³ Additionally, symptomatic VTE plus all-cause mortality was analyzed by level of creatinine clearance.² Please see Figures and Tables under sections: Effect of Renal Function on Efficacy Endpoints and Effect of Renal Function on Bleeding Endpoints.

Effect of Renal Function on Efficacy Endpoints

Effect of Renal Function on Bleeding Endpoints

• In the overall pooled population (randomized, N=12,729), the incidence of total VTE (primary efficacy endpoint), defined as the composite of DVT, non-fatal pulmonary embolism (PE), and all-cause mortality, was 0.8% for patients receiving XARELTO and 1.6% for those receiving enoxaparin (P<0.001).⁴
• Bleeding rates were similar between the treatment groups.⁴
• A subgroup analysis indicated that XARELTO had superior efficacy to enoxaparin for total VTE and major VTE, irrespective of mild to moderate renal impairment.³
• Patients receiving XARELTO demonstrated more consistent reductions than those receiving enoxaparin in the composite of symptomatic VTE plus all-cause mortality, irrespective of renal function; however, only the difference within the >80-mL/min subgroup was statistically significant (see Table: Incidence of Symptomatic VTE Plus All-Cause Mortality by Renal Function).²
• There were no differences between renal function subgroups for any treatment-emergent bleeding; there was a significant difference in the composite endpoint of major plus clinically relevant non-major bleeding between XARELTO and enoxaparin in patients with CrCl >80 mL/min, but not in any other subgroups.^2,3

LITERATURE SEARCH

A literature search of MEDLINE^® EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 21 November 2024.