Summary

• The XAMOS study demonstrated that XARELTO was associated with lower incidences of symptomatic thromboembolic events compared with standard of care (SoC), without significant increases in major bleeding events.^1-4
• A retrospective study conducted using data from a national healthcare claims database showed that 2.5% and 1.4% of patients in the XARELTO group experienced postoperative venous thromboembolism (VTE) and transfusion, respectively, within 90 days of total hip arthroplasty (THA). XARELTO was associated with a higher odds of VTE vs aspirin (P<0.0001).⁵
• A retrospective study conducted using data from a national healthcare claims database compared the incidence of postoperative VTE and bleeding by underlying risk factors in patients who underwent primary THA or total knee arthroplasty (TKA). It showed that the cumulative 90-day postoperative incidence of VTE and bleeding was 1.86% and 5.33%, respectively. A multivariate analysis showed that the 30-day incidence of VTE and bleeding was lower with aspirin vs XARELTO (P≤0.001).⁶
• A real-world study conducted using data from the EPOC (Evidence Based Processes and Outcomes of Care) study compared the effectiveness and safety of aspirin vs LMWH and DOACs (XARELTO) in patients who underwent elective THA or TKA for osteoarthritis. It showed that 2.4% of patients receiving DOACs and 1.6% of patients receiving aspirin reported symptomatic VTE within 90 days of the operation. The use of prophylactic DOACs was not associated with a significant difference in the 90-day postoperative symptomatic VTE rate as compared to prophylactic aspirin.⁷
• A retrospective cohort study in patients who underwent primary elective THA or TKA reported the 90-day risk of postoperative prothrombotic complications and bleeding events with XARELTO vs aspirin and XARELTO vs enoxaparin.⁸
  • Patients who received XARELTO after TKA had a higher risk of deep vein thrombosis (DVT; P=0.022) and combined bleeding (P<0.001) outcomes than those who received aspirin. Similarly, XARELTO was associated with an increased risk of DVT (P=0.457) and combined bleeding (P<0.001) outcomes than enoxaparin.
  • Patients who received XARELTO after THA had a higher risk of DVT (P=0.602) and combined bleeding (P<0.001) outcomes than those who received aspirin. XARELTO and enoxaparin showed a similar DVT risk (P=0.251); however, XARELTO was associated with a higher risk of combined bleeding (P<0.001) events than enoxaparin.
• A prospective cohort study conducted in patients who underwent THA and TKA reported a significantly lower incidence of symptomatic DVT in the XARELTO group compared with the dabigatran group (0.3% vs 2.2%; P<0.01). Major bleeding was reported in 1.4%, 1.2%, and 0.8% of patients in the XARELTO, dabigatran, and apixaban groups, respectively.⁹
• A retrospective study showed that the overall VTE rates in patients who underwent hip and knee replacement surgery were 1.04% and 0.66% in the inpatient enoxaparin and extended aspirin groups and the modified XARELTO group, respectively.¹⁰
• A nationwide claims database analysis including patients who underwent hip arthroplasty showed that DVT occurred more frequently in the aspirin group compared with the XARELTO group (1.3% vs 0.5%; P<0.013), and major bleeding events were similar between the XARELTO and aspirin groups (2.1% vs 1.9%, respectively; P=0.579).¹¹
• A retrospective, postmarketing safety surveillance study evaluating major bleeding in patients who underwent total hip replacement (THR) or total knee replacement (TKR) and received XARELTO showed that the incidence proportion of clinically relevant bleeds based on exploratory analyses of inpatient secondary diagnosis codes or emergency department visits was 0.46% and 0.21%, respectively.¹²
• Postmarketing safety data evaluating XARELTO use in patients undergoing THR and/or TKR procedures showed major bleeding rates to be 0.04%.¹³

Real-World EVIDENCE

The XAMOS (XArelto^® in the prophylaxis of post-surgical venous thromboembolism after elective Major Orthopedic Surgery of hip or knee)^1-4 study was an international, noninterventional, observational, open-label study that assessed the efficacy and safety of XARELTO in daily clinical practice for prophylaxis of VTE in patients after elective THR or TKR.

Inclusion/exclusion criteria: consecutive adult patients (≥18 years of age) undergoing elective THR/TKR (or hip fracture surgery where indicated) were included in the study. Patients were prescribed pharmacological VTE prophylaxis by their treating physician and provided written consent where necessary. Patients were excluded based on the approved local product information.

Study design: the study enrolled 17,701 patients to receive XARELTO or SoC for thromboprophylaxis. Current SoC included low-molecular-weight heparins (LMWHs), fondaparinux, and vitamin K antagonists. The type and dose of the drug, as well as the duration of treatment, was to be determined by the attending physician. Enrolled patients were from 37 countries and 252 centers. Data was collected at the start of therapy, at hospital discharge, 1 week after therapy completion, and 3 months after surgery. Bleeding and other adverse events (AEs) were considered treatment-emergent if the event started on or after the day of the first dose and up to 2 days after the last dose of a VTE prophylactic drug. Serious AEs were followed until a final outcome was obtained.

Outcome measures: the main outcome measures were symptomatic thromboembolic events, bleeding events, uncommon AEs, and mortality. Additional outcome measures included convenience of treatment, health care resource use, compliance, use in special populations such as those with renal impairment, and the use of certain concomitant medications.

Results: a total of 17,413 patients were included in the safety population (XARELTO, n=8778; SoC, n=8635). Demographics of the patient population are presented in Table: Demographic Data. In the SoC group, most patients (81.7%) received LMWHs.

The most commonly reported comorbidity was hypertension (XARELTO, 49.5%; SoC, 53.0%), followed by hypercholesterolemia (XARELTO, 10.6%; SoC, 10.8%), and diabetes mellitus (XARELTO, 10.5%; SoC, 11.7%).²

Compared with SoC, patients receiving XARELTO had a lower incidence of symptomatic thromboembolic events (arterial and venous). The incidences of treatment-emergent bleeding events in the safety populations were similar, as represented in Table: Incidence of Thromboembolic and Other Treatment-Emergent Events.

Hepatic disorders occurred in 46 and 37 patients in the XARELTO (0.52%) and SoC (0.43%) treatment groups, respectively (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.79-‍‍1.89). Thrombocytopenia occurred in 7 and 20 patients in the XARELTO and SoC treatment groups, respectively (OR, 0.34; 95% CI, 0.15-0.81). Mortality was low in both groups (0.1% vs 0.1%, respectively) and was not related to treatment.

Wound complications: there was no significant difference in the incidence of treatmentemergent postoperative wound infection or wound hemorrhage between the groups. The incidence of treatment-emergent, postprocedural wound discharge was higher in the XARELTO group than in the SoC group (0.4% vs 0.1%, respectively; OR, 3.65; 95% CI, 1.78-8.24).

The Rating of Health Care Utilization based on patient reporting is presented in Table: Rating of Health Care Utilization.

Concomitant platelet aggregation inhibitor (PAI) users had higher incidences of total symptomatic thromboembolic events than the nonusers in both the treatment groups. The incidence of VTE events was higher in the PAI users vs the nonusers within the SoC group compared with the XARELTO group.

The incidence of total symptomatic thromboembolic events was similar between nonsteroidal anti-inflammatory drug (NSAID) users and nonusers in the XARELTO and SoC groups. XARELTO was associated with a lower incidence of total symptomatic thromboembolic and symptomatic VTE events (0.89% and 0.23%, respectively). See Table: Incidence of Thromboembolic and Treatment-Emergent Bleeding Events in Patients With or Without Concomitant Use of PAIs and NSAIDs.

Moore et al (2024)⁵ conducted a retrospective study using data from a national healthcare claims database to evaluate the incidence of 90-day postoperative VTE and transfusions with prophylactic XARELTO, aspirin, dabigatran, enoxaparin, and warfarin in patients who underwent primary THA (January 01, 2016 to December 31, 2022).

• Of all patients who underwent primary THA, 11,790 received XARELTO, 36,346 received aspirin, 11,380 received enoxaparin, 13,065 received dabigatran, and 6326 received warfarin.
• Among patients receiving XARELTO, 290 (2.5%) and 170 (1.4%) reported postoperative VTE and transfusion within 90 days of THA, respectively. See Table: Incidence of 90-Day Postoperative VTE and Transfusions.
• XARELTO was associated with a higher odds of VTE vs aspirin (P<0.0001). See Table: Odds of 90-Day Postoperative VTE and Transfusions.

Simon et al (2023)⁶ conducted a retrospective analysis of data from a national healthcare claims database to compare the incidence of postoperative VTE and bleeding by underlying risk factors in patients who underwent primary THA or TKA (January 01, 2017 to December 31, 2019). Using propensity score matching, these outcomes were also compared for direct oral anticoagulants (DOACs) vs aspirin.

• Of the 29,264 patients who underwent primary THA or TKA, 7068 (24.2%) received XARELTO, 10,082 (34.5%) received aspirin, 5764 (19.7%) received enoxaparin, 3253 (11.1%) received apixaban, and 3097 (10.6%) received warfarin.
• At 30 and 90 days, the cumulative incidence of VTE was 1.19% (95% CI, 1.06-1.32) and 1.86% (95% CI, 1.70-2.02), respectively.
• At 30 and 90 days, the cumulative incidence of bleeding was 3.43% (95% CI, 3.22-3.64) and 5.33% (95% CI, 5.07-5.59), respectively.
• A multivariate analysis showed that at 30 days, the incidence of VTE (OR, 2.00; 95% CI, 1.47-2.74; P<0.001) and bleeding (OR, 1.38; 95% CI, 1.15-1.66; P=0.001) was lower with aspirin vs XARELTO.
• The propensity score-matched cumulative incidences of VTE and bleeding after 30 and 90 days of DOACs vs aspirin are shown in Table: PSM Analysis of Postoperative VTE and Bleeding.

Sidhu et al (2023)⁷ conducted a real-world analysis using data from the EPOC study (a multicenter, prospective, observational, cohort study) to evaluate the effectiveness and safety of aspirin vs LMWH and DOACs (XARELTO) after elective THA or TKA for osteoarthritis.

• Of 1867 eligible patients, 170 (9%) received DOACs, 365 (20%) received aspirin, 762 (41%) received LMWH, and 482 (26%) received LMWH and aspirin.
• At 90 days, the rate of symptomatic VTE was 2.4% with DOACs, 1.6% with aspirin (P=0.6), and 2.7% for the entire cohort. See Table: Primary and Secondary Outcomes Within 90 Days.
• Univariate and multivariate analyses showed that the use of prophylactic DOACs was not associated with a significant difference in the 90-day postoperative symptomatic VTE rate as compared to prophylactic aspirin. See Table: Univariate and Multivariate Analysis for Rate of Symptomatic VTE Within 90 Days.

Piple et al (2023)⁸ conducted a retrospective cohort study that compared the efficacy and safety of XARELTO with those of aspirin or enoxaparin for VTE prophylaxis in patients who underwent primary elective THA or TKA (January 01, 2015, to December 31, 2020).

• Of the 802,524 patients who underwent primary elective TKA, 86,721 (10.8%) received XARELTO, 408,038 (50.8%) received aspirin, and 108,377 (13.5%) received enoxaparin.
  • After controlling for potential confounding factors, patients who received XARELTO after TKA had a higher risk of combined prothrombotic (P=0.061) and bleeding (P<0.001) outcomes than those who received aspirin. Similarly, XARELTO was associated with an increased risk of combined prothrombotic (P=0.499) and bleeding (P<0.001) outcomes than enoxaparin.
• Of the 445,570 patients who underwent primary elective THA, 42,469 (9.5%) received XARELTO, 242,876 (54.5%) received aspirin, and 59,727 (13.4%) received enoxaparin.
  • After controlling for potential confounding factors, patients who received XARELTO after THA had a higher risk of combined prothrombotic (P=0.775) and bleeding (P<0.001) outcomes than those who received aspirin. However, XARELTO was associated with a lower risk of combined prothrombotic (P=0.036), but a higher risk of combined bleeding (P<0.001) outcomes than enoxaparin.
• Data regarding the 90-day risk of postoperative prothrombotic complications and bleeding events with XARELTO vs aspirin and enoxaparin in patients who underwent TKA are summarized in Table: Differences in the Risk of 90-Day Outcomes With XARELTO vs Aspirin and XARELTO vs Enoxaparin in Patients Who Underwent TKA.
• Data regarding the 90-day risk of postoperative prothrombotic complications and bleeding events with XARELTO vs aspirin and enoxaparin in patients who underwent THA are summarized in Table: Differences in the Risk of 90-Day Outcomes With XARELTO vs Aspirin and XARELTO vs Enoxaparin in Patients Who Underwent THA.

Highcock et al (2020)⁹ conducted a prospective cohort study to evaluate the efficacy and safety of XARELTO, dabigatran, and apixaban in patients who underwent THA and TKA.

• Overall, 2431 patients were included, of whom 911 received dabigatran (October 1, 2011 to April 30, 2012), 720 received apixaban (June 1, 2013 to January 1, 2014), and 800 received XARELTO (January 2, 2015 to November 10, 2015).
• Overall, 1127 and 1304 patients underwent THA and TKA, respectively.
• A statistically significant reduction in VTE was observed in the XARELTO group vs the dabigatran group (0.8% vs 3%; P<0.01) and the apixaban group (0.8% vs 2.1%; P<0.01).
  • A lower rate of symptomatic DVT was observed in the XARELTO group vs the dabigatran group (0.3% vs 2.2%; relative risk [RR], 0.11; 95% CI, 0.03-0.49; P<0.01) and the apixaban group (0.3% vs 0.8%; RR, 0.30; 95% CI, 0.06-1.48; P=0.14).
  • A low rate of symptomatic pulmonary embolism (PE) was observed in the XARELTO (0.5%), dabigatran (0.8%), and apixaban (1.3%) groups.
• Major bleeding in the XARELTO vs dabigatran vs apixaban group was observed in 1.4% vs 1.2% vs 0.8% of patients, respectively.
• Wound problems in the XARELTO vs dabigatran vs apixaban group were observed in 2.8% vs 1.1% vs 3.6% of patients, respectively.

Ní Cheallaigh et al (2020)¹⁰ conducted a retrospective cohort study to evaluate the efficacy and safety of aspirin compared with enoxaparin or XARELTO for the prevention of VTE following hip and knee replacement surgery.

• All patients who underwent elective primary TKR or THR in a large orthopedic hospital in Ireland between January 1, 2010 and June 30, 2016, were included.
• VTE rates in the 6 months following surgery were compared between patients receiving extended aspirin and those receiving inpatient enoxaparin or a modified XARELTO regimen (enoxaparin 40 mg once daily initiated 12 hours postoperatively for 3 doses followed by XARELTO 10 mg once daily for 14 days [TKR] or 35 days [THR]).
• Of the 6945 patients admitted during the study period, 6548 were eligible for inclusion. The mean age was 65.4 years, the mean body mass index was 30.3 kg/m², 55.3% of patients were female, and 55.8% underwent THR.
• The overall VTE rate was 0.99% (65/6548). The VTE rate in both the inpatient enoxaparin group (n=961) and extended aspirin group (n=3460) was 1.04%, while the VTE rate in the modified XARELTO group (n=1212) was 0.66% (P=0.154).
• A noninferiority analysis showed the extended aspirin regimen to be equivalent to the modified XARELTO regimen (unadjusted VTE risk difference comparing the extended aspirin regimen to the modified XARELTO regimen was 0.38%).
• A history of VTE was the only significant demographic risk factor for postoperative VTE (0.87% vs 3.54%; P=0.0002).

Kim et al (2019)¹¹ conducted a nationwide claims database analysis to evaluate the efficacy and safety of XARELTO vs aspirin as thromboprophylaxis in real‐world Korean patients who underwent hip arthroplasty.

• Patients aged ≥18 years with ≥1 hip arthroplasty (including total and partial hip replacements and hip replacement revisions) during the period of July 2009-June 2013 were identified from the Health Insurance Review and Assessment (HIRA) claims database.
• Patients were 1:1 propensity score-matched (aspirin, n=2071; XARELTO, n=2071) to minimize selection bias and potential confounding factors.
• In the aspirin cohort, 65.7% of patients received >3‐week treatment; in the XARELTO cohort, 31.7% received >3‐week treatment.
• Aspirin was associated with a significantly higher incidence of overall VTE within 90 days after surgery compared with XARELTO (1.6% vs 0.6%; RR reduction, 59.4%; P<0.004).
  • DVT occurred more frequently with aspirin than with XARELTO (1.3% vs 0.5%; P<0.013), but PE occurred at similar rates between the 2 groups.
• Major bleeding events were similar among XARELTO- and aspirin-treated patients (2.1% vs 1.9%, respectively; P=0.579).

POSTMARKETING SAFETY SURVEILLANCE

Kwong et al (2017)¹² conducted an interim analysis at 2.5 years of an ongoing, 5-year, observational, retrospective, postmarketing safety surveillance study utilizing the United States Department of Defense healthcare database to evaluate major bleeding in patients who had undergone THR or TKR and were treated with XARELTO postoperatively.

• Patients who had received a THR, TKR, or both between January 1, 2013, to June 30, 2015, with incident XARELTO exposure within 2 days prior to surgery through the respective guideline-recommended length of treatment were included.
• Of the 12,429 XARELTO users identified during the 2.5-year study period who received THR and/or TKR surgery, 9 users experienced the primary efficacy outcome of major bleeding (2 after THR and 7 after TKR) based on the Cunningham algorithm. The bleeding incidence proportion in those with THR only was 0.05% (95% CI, 0.0-0.12) and was 0.09% (95% CI, 0.02-0.16) for those with TKR only.
• Based on exploratory analyses of inpatient secondary diagnosis codes or emergency department visits, the incidence proportion of clinically relevant bleeds (not considered major bleeding events in primary analysis) was 0.46% (95% CI, 0.34-0.58) and 0.21% (95% CI, 0.13-0.29), respectively.
• Major bleeding patients were more likely to be younger than those without major bleeding (63.1 vs 67.3 years) and male (55.6% vs 43.2%). Comorbidities were more prevalent in the major bleeding cohort compared with the nonmajor bleeding group. The most commonly reported comorbidities were hypertension (77.8% vs 53.6%) and coronary heart disease (44.4% vs 10.9%).
• No patients experienced a fatal outcome while hospitalized.
• This was a retrospective study using data originally collected for electronic medical record and accounting/claims purposes. Study results of major bleeding incidence rates and comparisons between major bleeding and nonmajor bleeding patients are limited by the small representation of major bleeding events, use of pharmacy records that capture drug dispensing information rather than actual administration of the drug, varying surgeon skill, and inherent limitations of the databases.

Tamayo et al (2014)¹³ conducted a retrospective, observational study evaluating longitudinal safety data of XARELTO in patients undergoing THR and/or TKR procedures. The data presented below represents the first 18 months (January 2013 - June 2014) of this ongoing, 5-year observational study.

• Of the 7977 patients evaluated in the THR/TKR cohort, 3 (0.04%; 95% CI, 0-0.09) experienced a major bleeding event, of which 1 (33.3%) had a gastrointestinal hemorrhage and 2 (66.6%) had unspecified major bleeding. There were no reported deaths.
• In the THR/TKR cohort, the mean age of those who experienced major bleeding was higher than those that did not bleed (70.7 and 66.7 years for major and nonmajor bleeding, respectively).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 02 May 2024.