Summary

• In RECORD (REgulation of Coagulation in major ORthopaedic surgery reducing the risk of DVT and PE) 1, the rate of major bleeding was similar in the 2 groups (0.3% with XARELTO vs 0.1% with enoxaparin; P=0.18).¹ In RECORD 2, major bleeding was reported in 0.1% of patients in both treatment groups.²
• In RECORD 3, the rate of major bleeding was similar in the 2 groups (0.6% with XARELTO vs 0.5% with enoxaparin; P=0.77).³ In RECORD 4, the rate of major bleeding was similar in the 2 groups (0.7% with XARELTO vs 0.3% with enoxaparin; P=0.11).⁴
• In MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism (VTE) in hospitalized acutely iLL medical patients comparing rivaroxabAN with enoxaparin), the rate of the clinically relevant bleeding from day 1 to day 10 was 2.8% in the XARELTO group and 1.2% in the enoxaparin group (P<0.001); and from day 1 to day 35 it was 4.1% in the XARELTO group and 1.7% in the enoxaparin group (P<0.001).⁵
  • A benefit-risk analysis of MAGELLAN was conducted, where patients at the highest risk of major bleeding were excluded, identified by five risk factors.⁶
  • In this population, about 80% of the total MAGELLAN population, the rate of clinically relevant bleeding from day 1 to day 10 was 2.5% in the XARELTO arm and 1.1% in the enoxaparin arm, and from day 1 to day 35 it was 3.5% in the XARELTO arm and 1.5% in the enoxaparin group.⁶
    • In this subpopulation, major bleeding was not significantly different between the XARELTO and enoxaparin/placebo groups at day 10 (0.4% vs 0.3%) or day 35 (0.7% vs 0.5%).
• In MARINER (Medically Ill Patient Assessment of XARELTO versus Placebo in Reducing Post-Discharge Venous Thromboembolism Risk), the rates of major bleeding were 28% and 15% in the XARELTO and placebo groups, respectively (hazard ratio: 1.88; 95% confidence interval [CI]: 0.844.23).⁷
• In UNIVERSE, 1 patient (2%) had a major bleeding event (epistaxis) adjudicated in the XARELTO part B group. There were no patients with major bleeding events reported in the aspirin part B or in the XARELTO part A group.⁸
• Additional studies have been included in the REFERENCES section for your review^9-14

CLINICAL STUDIES

Phase 3 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 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 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 hours after surgery, or subcutaneous (SC) 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 phase 3 RECORD clinical trial programs were randomized, double-blind, double-dummy, multinational studies comparing the efficacy and safety of oral XARELTO and SC enoxaparin for prevention of VTE in patients undergoing elective total hip arthroplasty (RECORD 1 and 2)^1,2 or total knee arthroplasty (RECORD 3 and 4).^3,4

The endpoints evaluated for safety were the same in all trials.

• Primary safety outcome: Major bleeding occurring after the first dose of study drug and up to 2 days after the last dose of study drug, defined as; bleeding that was fatal, occurred into a critical organ, required reoperation, or was clinically overt from an extrasurgical site and associated with a fall in hemoglobin of ≥2 g/dL or a transfusion of ≥2 units of blood^1-4
• Secondary safety outcome: Nonmajor bleeding (including clinically relevant nonmajor bleeding, hemorrhagic wound complications, and other nonmajor bleeding)^1-4
  • Clinically relevant nonmajor bleeding included events such as: bleeding associated with multiple source bleeding; spontaneous hematoma >25 cm²; excessive wound hematoma; spontaneous nose bleeding, gingival bleeding, or prolonged bleeding after venipuncture lasting more than 5 minutes; macroscopic hematuria (spontaneous or lasting >24 hours if associated with an intervention); spontaneous rectal bleeding; coughing up of blood; or hematemesis.
  • Hemorrhagic wound complication is a composite of surgical-site bleeding and excessive wound hematoma.^1-4

RECORD 1 - 4

RECORD 1¹ compared efficacy and safety between oral XARELTO 10 mg once daily and SC injections of enoxaparin 40 mg once daily for extended VTE prophylaxis in patients undergoing elective total hip arthroplasty.

• Major bleeding occurred in 0.3% of patients (6/2209) receiving XARELTO and in 0.1% of patients (2/2224) receiving enoxaparin (P=0.18).
• For a complete summary of the incidence of bleeding events reported during the RECORD 1 study, refer to Table: Bleeding Results for RECORD 1 and RECORD 2 - Total Hip Arthroplasty (Safety Population).

RECORD 2² compared efficacy and safety between an extended thromboprophylaxis regimen of oral XARELTO 10 mg once daily and a short-term thromboprophylaxis regimen of SC injections of enoxaparin 40 mg once daily.

• Major bleeding occurred in <0.1% of patients receiving XARELTO (1/1228) or enoxaparin (1/1229)
• For a complete summary of the incidence of bleeding events reported during the RECORD 2 study, refer to Table: Bleeding Results for RECORD 1 and RECORD 2 - Total Hip Arthroplasty (Safety Population).

RECORD 3³ compared oral XARELTO 10 mg once daily with SC enoxaparin 40 mg once daily administered for 10-14 days.

• The incidence of major bleeding was 0.6% (7/1220) with XARELTO and 0.5% (6/1239) with enoxaparin (P=0.77).
• For a complete summary of the incidence of bleeding events reported during the RECORD 3 study, refer to Table: Bleeding Results for RECORD 3 and RECORD 4 - Total Knee Arthroplasty (Safety Population).

RECORD 4⁴ compared oral XARELTO 10 mg every day started 6-8 hours after surgery and SC enoxaparin 30 mg every 12 hours started 12-24 hours after surgery and continued until days 10-14.

• Major bleeding was reported in 0.7% of patients (10/1526) receiving XARELTO and in 0.3% of those (4/1508) receiving enoxaparin (P=0.11).
• For a complete summary of the incidence of bleeding events reported during the RECORD 4 study, refer to Table: Bleeding Results for RECORD 3 and RECORD 4 - Total Knee Arthroplasty (Safety Population).

Pooled Analysis of RECORD 1-4 Trials

Turpie et al (2011)¹⁵ conducted a pooled analysis of the 4 phase 3 clinical trials (RECORD 1, 2, 3, and 4).

• The pooled analysis of the RECORD 1-4 were prespecified in the statistical plan prior to the unblinding of the 4 studies.
• The safety analysis was limited to the 2-week enoxaparin-controlled period (also known as the 12±2 active treatment pool), which was common to all 4 studies.
• Primary safety endpoints were the incidence of major bleeding, major bleeding including surgical-site bleeding, major and clinically relevant nonmajor bleeding, and any bleeding.
• In an examination of results based on criteria that included major bleeding plus surgical site bleeding as an outcome, Turpie et al did not find a statistically significant difference in bleeding rates in the XARELTO vs enoxaparin patients. See Table: Bleeding Results for Pooled Analysis of RECORD1-4 (Safety Population) for a complete summary of all bleeding results.

MAGELLAN

MAGELLAN^2,5 was an international, randomized, double-blind, active-comparator-controlled study designed to evaluate the efficacy and safety of once-daily oral XARELTO compared to standard-duration, once-daily SC enoxaparin, and to evaluate the role of extended-duration XARELTO (up to 39 days) for the prevention of VTE in acutely ill medical patients who required hospitalization.

• The principal safety outcome was clinically relevant bleeding, defined as the composite of major bleeding and clinically relevant nonmajor bleeding events observed no later than 2 days after the last study drug was administered.
• Overall, bleeding rates were low but significantly higher in the XARELTO arm than in the enoxaparin/placebo arm during the entire study period. See Table: Safety Outcomes in the MAGELLAN Trial (Safety Population).

Spyropoulos et al (2019)⁶ conducted a retrospective analysis by applying 5 key exclusion criteria to evaluate the benefit-risk profile of daily XARELTO 10 mg for in-hospital administration and extended thromboprophylaxis in a subpopulation of MAGELLAN. Patients with these characteristics were identified as having increased risk of major bleeding.

• The exclusion criteria were active cancer, dual antiplatelet therapy (DAPT) at baseline, any bleeding ≤3 months before or during hospitalization, active gastroduodenal ulcer ≤3 months or currently symptomatic, bronchiectasis, or pulmonary cavitation.
• The risk of major bleeding with XARELTO was reduced during both treatment phases (days 1 to 10 and days 1 to 35). See Table: Safety Outcomes in the MAGELLAN Trial Subpopulation.

MARINER

MARINER⁷ was a multinational, randomized, doubleblind, placebo-controlled study designed to evaluate the efficacy and safety of once-daily XARELTO 10 mg (dose adjusted for renal insufficiency) vs placebo for extended thromboprophylaxis (45 days) in medically ill patients at risk for VTE. Treatment was assigned at hospital discharge based on the modified International Medical Prevention Registry on Venous Thromboembolism score.

• Principal safety outcome: Major bleeding, defined as overt bleeding associated with a decrease in hemoglobin by ≥2 g/dL, bleeding resulting in transfusion of ≥2 units of packed red cells or whole blood, bleeding in a critical site (i.e., intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding.
• The difference in risk of major bleeding between XARELTO and placebo was 0.13% (95% CI: -0.03 to 0.30). Overall incidence of major bleeding and incidence according to prespecified stratification based on creatinine clearance are summarized in Table: Safety Outcomes in the MARINER Trial (Safety Population).
• No significant interaction between the trial regimen and any subgroup variable was identified with the exception of duration of index hospitalization (P=0.02) and in-hospital receipt of thromboprophylaxis (P=0.03).¹⁶

UNIVERSE

UNIVERSE⁸ was a prospective, randomized, multicenter, 2-part, open-label study in pediatric patients 2 to 8 years of age with single-ventricle physiology, who had completed the Fontan procedure within 4 months prior to enrollment. Part A (N=12) was designed to characterize the single- and multiple-dose pharmacokinetic and pharmacodynamic profiles following oral XARELTO administration while part B evaluated the safety and efficacy of XARELTO (N=66) compared to aspirin (N=34) for thromboprophylaxis. XARELTO was dosed twice daily by body weight using a 0.1% [1 mg/mL] oral suspension for 12 months in parts A and B. Aspirin was given ~5 mg/kg once daily for up to 12 months in part B.

• The primary safety outcome was major bleeding events, as defined by the International Society on Thrombosis and Haemostasis (ISTH): overt bleeding and associated with a decrease in hemoglobin of ≥2 g/dL, leading to a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood in adults, occurring in a critical site (intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal), or contributing to death. The secondary safety outcomes were clinically relevant nonmajor bleeding defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, discomfort for the patient, such as pain, or impairment of activities of daily life, and trivial (minimal) bleeding event defined as any other overt bleeding event that does not meet criteria for clinically relevant nonmajor bleeding.^17,18
• There was 1 patient (2%) with a major bleeding event (epistaxis) adjudicated in the XARELTO part B group. There were no patients with major bleeding events reported in the aspirin part B or in the XARELTO part A group. The proportion of patients with clinically relevant nonmajor bleeding events was less in the XARELTO group (4/64 [6%]) than in the aspirin group (3/34 [9%]) in part B. For a complete summary of bleeding events reported in the UNIVERSE study, refer to Table: Summary of Bleeding Events (Safety Population)

Phase 2 Studies

The phase 2 ODIXa (Oral, DIrect factor Xa inhibitor) clinical trial program included 3 studies (ODIXa-HIP1, ODIXa-HIP2, ODIXa-OD-HIP) and compared oral XARELTO with SC enoxaparin for VTE prevention in patients undergoing total hip replacement surgery.^19-21 A fourth study under this phase 2 ODIXa clinical trial program (ODIXa-KNEE) compared efficacy and safety between oral XARELTO and SC enoxaparin for VTE prevention in patients undergoing elective total knee replacement surgery.²²

• In ODIXa-HIP1¹⁹, major postoperative bleeding occurred in 0%-10.8% of patients receiving XARELTO and in 0% of those receiving enoxaparin.
• In ODIXa-HIP2²⁰, major postoperative bleeding occurred in 0.8%-5.4% of patients receiving XARELTO 2.5 mg and in 1.5% of those receiving enoxaparin; rates with XARELTO 5 mg, 10 mg, and 20 mg (total daily dose) were similar to those with enoxaparin.
• In ODIXa-OD-HIP²¹, major postoperative bleeding occurred in 0.7%-5.1% of patients receiving XARELTO and 1.9% of patients receiving enoxaparin.
• In ODIXa-KNEE²², major postoperative bleeding occurred in 1.0%, 0%, 1.9%, 3.1%, and 7.5% of patients in the respective XARELTO dose groups and in 1.9% of patients receiving enoxaparin.

LITERATURE SEARCH

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