Summary

• XARELTO is not indicated for venous thromboembolism (VTE) prevention in hip and other fractures.
• Results from a study assessing XARELTO’s efficacy in preventing deep vein thromboses (DVTs) after pelvic trauma displayed a reduction in DVT incidence after pelvic fractures when administering antithrombotics within 24 hours of injury or, if the patient was hemodynamically unstable, 24 hours after stabilization (6/64; 9.4%), as compared to those receiving delayed treatment (8/20; 40%; P<0.001 Fisher’s exact test).¹
• A study to evaluate the efficacy and safety of XARELTO vs low-molecular-weight heparin (LMWH) for thromboprophylaxis in patients with lower limb fractures revealed incidences of symptomatic VTE for the XARELTO group was 4.9% and the LMWH group was 8.6% (P=0.008), and the rates of major bleeding were 0.2% in the XARELTO group and 0.6% in the LMWH group (P=0.244).²
• In patients undergoing fracture-related surgery, XARELTO or standard-of-care (SOC) was given for VTE prophylaxis. Symptomatic thromboembolic events were 1 (0.5%) vs 2 (1.0%) and treatment-emergent bleeding events were 6 (2.9%) vs 7 (3.4%) respectively.³
• A subset of patients from XAMOS and XAMOS-Extra were treated with XARELTO or SOC for VTE prophylaxis after fracture related surgery. At 3 months post-surgery the incidence of symptomatic thromboembolic events was 0.57% in the XARELTO group and 1.14% in the SOC group (odds ratio [OR]: 0.50; 95% confidence interval [CI]: 0.10-2.59) and the rates of major bleeding events were 0.29% in the XARELTO group and 0.45% in the SOC group (OR: 0.63; 95% CI: 0.06-6.95).⁴
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^5,6

CLINICAL STUDIES

Monzon et al (2011)¹ assessed XARELTO’s efficacy in preventing DVTs after pelvic trauma. Patients admitted to the trauma center with pelvic or acetabular fractures between June 2009 and June 2010 were included in this study and received the following standard protocol for thromboprophylaxis:

• The administration of XARELTO 10 mg, orally once a day within 24 hours of injury or upon the establishment of hemodynamic stability
• Preoperative, postoperative, and 30-day investigation for DVT using duplex ultrasound
• A ventilation-perfusion scintigraphy (V/Q lung scan) if the patient showed clinical signs of pulmonary embolism (PE)
• A clinical evaluation at 45, 90, and 120 days

Patients with the presence of a severe neurological injury (Glasgow Coma Scale [GCS] #8), spinal cord injury, identifiable hepatic or splenic injuries, a known hypersensitivity to heparin, and hemodynamic instability secondary to continued bleeding were excluded from this study. The last XARELTO dose was given the day before surgery and resumed within 12 hours after surgery, or when hemodynamic stability was achieved. XARELTO therapy was continued for 30 days after surgery.

Of the 84 patients included in the study group, 47 patients had lower limb injuries. See Table: Types of Pelvic and Acetabular Fractures in Study Patients for the types of pelvic and acetabular fractures.

The average patient Injury Severity Score (ISS) was 21.4 (range, 16-50 points), and the average GCS score was 13.6 (range, 9-15 points). Sixty-five patients who presented to the trauma center initially had an average wait of 4.8 days until surgery, with 57 of these patients starting prophylaxis within 24 hours. Nineteen patients who transferred from other hospitals waited an average of 9.4 days for surgery, while 12 of these patients did not receive thromboprophylaxis before transfer. There was a significant difference in non-symptomatic DVT between patients who received thromboprophylaxis within 24 hours of injury (6/64; 9.4%) compared to those receiving delayed treatment (8/20; 40%; P<0.001 Fisher’s exact test). No significant differences were observed between the two groups’ ISS based upon arrival to the trauma center (P=0.742; nonsignificant [NS]), or between genders (P=0.832; NS). One patient died of a PE. There was no increase in intra- or postoperative bleeding in surgical wounds. At follow-up evaluations at 45, 90, and 120 days, there were no reports of clinical manifestations of DVT.

Real-Word Evidence

Long et al (2014)² conducted a retrospective cohort study to evaluate the efficacy and safety of XARELTO vs LMWH in patients undergoing surgery for a lower limb fracture.  Between January 2009 and December 2012 data was collected on patients admitted to the Department of Orthopedics and Trauma at the PLA General Hospital (China). Lower limb fractures included proximal femoral fractures, femoral shaft fractures, distal femur fractures, patella fractures, proximal tibial fractures, tibia and fibula fractures, distal tibial fractures, and ankle and foot fractures.

Unselected, consecutive patients (n=2050) received XARELTO 10mg (n=608) or LMWH (nadroparin, n=717) subcutaneously at a dose volume of 0.2-0.4 ml and 725 patients did not receive any drugs.  Both cohorts were dosed once a day in the evening of admission to the evening before surgery and restarted at least 8 hours after surgery and up to 35 days post-surgery.  

Primary efficacy outcome, all VTE within 3 months post-surgery, was 4.9% and 8.6% in the XARELTO and LMWH groups, respectively (P=0.008). Efficacy outcomes included PE, 0% and 0.3% (P=0.192), and DVT 4.9% and 8.6% (P=0.008), respectively. Proximal thrombosis was not significantly different in the 2 groups, XARELTO 0.9% vs LMWH 2.9%; P=0.123, single distal venous thrombosis was significantly different 1.8% for XARELTO vs 5.7% for the LMWH group; P=0.036. Major bleeding (defined as fatal bleeding, bleeding in critical sites, reoperation, bleeding in extra-surgical sites leading to a 20g/L or greater fall in hemoglobin, or transfusion of more than 2 units of whole blood/red blood cells) was 0.2% in the XARELTO group vs 0.6% in the LMWH group, (P=0.244). Additional safety outcomes included non-major bleeding (1.0% vs 1.8% P=0.207), receiving blood transfusions >3 units (23.7% vs 24.0% P=0.897), and length of hospital stay (12.2 + 5.1 days vs 13.1 + 7.4 days P=0.016) in the XARELTO group vs LMWH group, respectively.

Several limitations were observed in this study:

• Significant differences in baseline demographic characteristics were identified between the groups. Patients in the XARELTO group had lower median ages and multiple fractures compared to the LMWH group. Both groups were significantly different regarding types of anesthesia and surgery.
• Follow up in the study was 3 months after surgery and patients did not undergo routine venous ultrasonography or venography, ultrasound examination only for suspect VTE.
• Symptomatic or asymptomatic VTE could not be determined since the information had not been correctly recorded.
• Medication compliance could not be assessed and there was no control for use of mechanical thromboprophylaxis measures after discharge.

Hoffmeyer et al (2017)³ investigated the effectiveness and the outcomes of XARELTO vs the SOC for venous thromboembolic prophylaxis in patients undergoing major (hip/femur) and minor lower limb (tibia, fibula, ankle, and foot) fracture-related surgery. All patients (n=413), from 9 Swiss orthopedic and trauma centers, represent a subpopulation of the international study, XAMOS⁷. Eligible patients were older than 18 years, had fracture-related surgery of the hip/femur or lower limb, and were prescribed pharmacologic prophylaxis, XARELTO (n=208) or SOC (n=205). In the SOC treatment group 187 (91.2%) patients received low-molecular-weight heparin, median dose 4000IU (range, 2000-7500 IU). Patient demographics were similar in the 2 treatment groups and prophylaxis treatment assignments were proportional. Data collected included symptomatic thromboembolic and bleeding events, complications due to surgery, death, adverse events, time to mobilization and hospital discharge, and patient discharge location.  

Clinical efficacy outcomes between the XARELTO treatment group vs SOC treatment group, respectively were:

• Symptomatic thromboembolic events: 1 (0.5%) vs 2(1.0%)
• Treatment-emergent bleeding events: 6 (2.9%) vs 7 (3.4%)
• Time to discharge after mobilization, median (range), d: 5 (0-27) vs 7 (0-41)
• Overall hospital stay, median (range), d: 10(3-28) vs 11 (3-63)

Clinical tolerability outcomes between XARELTO treatment group vs SOC treatment group, respectively were:

• Treatment-emergent adverse events, any: 44 (21.2) vs 65 (31.7%)
• Serious treatment-emergent adverse events, any: 8 (3.8%) vs 23 (11.2%)
• Treatment-emergent adverse event related to prophylaxis of thromboembolic events: 12 (5.8%) vs 12 (5.9%)
• Serious treatment-emergent adverse event related to prophylaxis of thromboembolic events: 1 (0.5%) vs 3 (1.5%)

In the subgroup analysis more patients had minor surgery (n=307, 74.3%) than major surgery (n=106, 25.7%).  In the patients undergoing minor surgery, 167 XARELTO treatment vs 140 SOC treatment, reported no symptomatic thromboembolic events and no major bleeding events.  In the major surgery subgroup, 41 XARELTO treatment vs 65 SOC treatment, reported, respectively, 1 (2.4%) vs 2 (3.1%) symptomatic thromboembolic events and major bleeding events.

The main limitations of this observational study include the following related to the noninterventional design and lack of randomization or stratification.

• Prophylaxis of thromboembolic events chosen was allocated per common practice in each participating center before patients were asked to participate in the study.
• Although patient demographics and treatment assignment were similar, other features in the 2 treatment groups were unequal, such as previous and concomitant treatments, previous and preoperative use of NSAIDs, and preoperative use of heparin.
• The population size, particularly for analysis of major and minor fracture related surgery was relatively small compared to the XAMOS⁷ study.

Lassen et al (2016)⁴ evaluated the effectiveness and safety of XARELTO for VTE prophylaxis compared to SOC in patients undergoing surgery for lower-limb fractures.  The patients in this study were a subset population included in the XArelto in the prophylaxis of postsurgical VTE after elective Major Orthopaedic Surgery of hip or knee (XAMOS)⁷ and XAMOS-Extra. The lower-limb fractures in this study included: hip/femur fractures or below-knee lower-leg fractures (knee, tibia, foot).

The prophylaxis given was determined by the attending physician and was comprised of XARELTO 10mg once daily or any other pharmacological prophylaxis (SOC). Clinical outcomes were recorded from 790 patients (n=350 XARELTO and n=440 SOC). Outcomes were collected and coded according to the standardized Medical Dictionary for Regulatory Activities:

• Symptomatic thromboembolic events (arterial and venous) during entire study period, 3 months after surgery.
• Major bleeding events were analyzed as defined in the RECORD studies and according to the European Medicines Agency (EMA) definition.
  • RECORD studies defined major bleeding as clinically overt bleeding that was fatal, occurred in a critical organ, required reoperation, was outside surgical site, saw a fall in hemoglobin of >2 g/dL, or blood transfusion of >2 units.
  • The EMA major bleeding definition was similar to RECORD with the inclusion of treatment discontinuation due to bleeding, surgical site bleeding, or bleeding leading to the use of any unusual medical intervention.
• Wound complications occurring post-operation included infection, discharge, and wound hemorrhage.
• Treatment-emergent events were events starting on the first day prophylaxis was given and up to 2 days after the last dose for VTE.

Patient demographics (age, sex, and body mass index) were similar at baseline between the XARELTO and SOC groups. Of the 440 patients receiving SOC, most were given LMWH (n=367) and others received unfractionated heparin (UHF, n=9), fondaparinux (n=20), dabigatran etexilate (n=4), acetylsalicylic acid (n=15), and other (n=25).  In hip/femur fractures, XARELTO was used in 178 patients and 286 patients received SOC. Prophylaxis use in below-knee lower-leg fractures occurred in 154 XARELTO patients and 172 SOC patients.

For fractures of all types, any symptomatic thromboembolic events occurred in 2 (0.57%) of patients in the XARELTO group vs 5 (1.14%) in the SOC group, OR: 0.50; 95% CI: 0.10-2.59. Hip/femur fracture surgery patients had 1 (N=178) symptomatic thromboembolic event in the XARELTO group and 5 (n=286) events in the SOC group (0.56% vs 1.75%; OR: 0.32; 95%CI:0.04-2.74). In patients undergoing surgery for lower-leg fracture, 1 (n=172) patient in the XARELTO group experienced an event (recorded as a venous thrombosis) and the SOC group reported no symptomatic thromboembolic events.

Treatment-emergent bleeding events, defined by RECORD and EMA, are shown below in Table: Incidence of Treatment-Emergent Bleeding.

In all fracture related surgeries any treatment-emergent adverse event was 15.71% (n=55) in the XARELTO group and 22.05% (n=97) in the SOC group, OR: 0.66; 95% CI: 0.46-0.95.  Any serious treatment-emergent adverse events were 2.57%(n=9) in the XARELTO group and 6.36% (n=28) in the SOC group, OR: 0.39; 95% CI: 0.18-0.83. The incidence of any wound complications was 2% (n=7) in the XARELTO group and 2.73% (n=12) in the SOC group, OR: 0.73; 95% CI: 0.28-1.87.

A limitation of this study was the patient population size.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 February 2025.