Summary

• As part of the global CALLISTO oncology program,¹ an analysis was conducted, based on clinical pathway guidelines, to evaluate the safety and efficacy of XARELTO for use in cancer patients. A total of 4.4% of patients receiving XARELTO experienced recurrent venous thromboembolism (VTE) within 6 months and major bleeding was observed in 1.6% of patients receiving XARELTO.²
• SELECT-D (Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism), also a part of the global CALLISTO oncology program,¹ evaluated efficacy and safety of XARELTO vs dalteparin in the treatment of VTE in cancer patients. XARELTO was associated with a lower 6-month VTE recurrence rate vs dalteparin (4% vs 11%) but a higher clinically relevant nonmajor bleeding rate (13% vs 4%).³
  • Patients with residual deep vein thrombosis (RDVT) or index pulmonary embolism (PE) who completed 6 months of the SELECT-D study were randomized to a further 6 months of XARELTO or placebo (second randomization). XARELTO was associated with a lower 6-month VTE recurrence rate vs placebo (4% vs 14%) after second randomization but a higher clinically relevant nonmajor bleeding rate (4% vs 0%).⁴
• CASSINI, another study within the global CALLISTO oncology program,¹ evaluated efficacy and safety of XARELTO thromboprophylaxis in high-risk ambulatory cancer patients initiating a new systemic cancer regimen. During the 180-day study period, no significant reduction in VTE or VTE-related death was observed with XARELTO vs placebo; however, during the intervention period (first receipt of treatment to last dose+2 days) of the prespecified supportive analysis, XARELTO substantially reduced such events, with a low incidence of major bleeding.⁵
• In the EINSTEIN pooled subgroup analysis, recurrent VTE occurred in 36 (5.0%) patients with active cancer (present at baseline or diagnosed during the study) compared with 145 (2.0%) patients with no active cancer (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.14-4.54). Recurrent VTE occurred at a similar frequency between patients who received XARELTO and patients who received enoxaparin/vitamin K antagonist (VKA).⁶
• A subgroup of patients that received XARELTO in the EINSTEIN-Extension and EINSTEIN-Choice studies had active cancer. Efficacy and safety results were not stratified for this subgroup of patients.^7,8
• In the phase 3 MAGELLAN study, a subgroup analysis by age, sex, and medical condition found that at day 35, the primary efficacy outcome occurred in 9.9% of XARELTO-treated patients with active cancer and in 7.4% of enoxaparin/placebo-treated patients with active cancer. The primary safety outcome occurred in 5.4% of XARELTO-treated patients with active cancer and in 1.7% of enoxaparin/placebo-treated patients with active cancer.^9,10
• In the MARINER (Medically Ill Patient Assessment of Rivaroxaban versus Placebo In Reducing Post-Discharge VeNous Thrombo-Embolism Risk) study, patients with active cancer were excluded.^11,12
• The CASTA DIVA (Cancer ASsociated Thrombosis, A Pilot Treatment StuDy Using RIVAroxaban) study evaluated if XARELTO was noninferior to dalteparin for the treatment of VTE in patients with active cancer and a high risk of recurrent VTE. Recurrent VTE occurred in 4 patients (6.4%) taking XARELTO and in 6 patients (10.1%) taking dalteparin. One patient (1.4%) in the XARELTO group and 3 patients (3.7%) in the dalteparin group experienced major bleeding.¹³
• In the CONKO-011 study, patients with active cancer and cancer-associated thrombosis reported improved treatment satisfaction with XARELTO vs low-molecular-weight heparin especially in the reduction of anticoagulation-related burden. The relative range of the ACTS Burden and Benefits score for XARELTO at 4 weeks was 88% (n=53/60) and 77% (n=12/15), respectively.¹⁴
• In the COSIMO study, patients with active cancer reported improved treatment satisfaction with XARELTO after transitioning from traditional anticoagulation therapy (low-molecular-weight heparin, VKA, or fondaparinux) with a mean change in the Anti-Clot Treatment Scale (ACTS) Burdens score of 3.9 from baseline to week 4 (51.8 vs 55.6, respectively).¹⁵
• The PRIORITY study was a multicenter, open-label, randomized, controlled phase II trial that evaluated the safety and efficacy of XARELTO and apixaban compared with dalteparin as a treatment for cancer-associated venous thromboembolism (CA-VTE) in patients with currently active and advanced upper GI tract, hepatobiliary, or pancreatic cancer. XARELTO had an increased risk of clinically relevant bleeding and major bleeding compared to dalteparin.¹⁶
• Additional citations are included in the REFERENCES section for your review.^17-42

CLINICAL STUDIES

CALLISTO

CALLISTO is a global oncology research program that includes 9 studies for XARELTO.¹

CASSINI Study

Khorana et al (2019)⁵ conducted a phase 3b, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to assess the efficacy and safety of XARELTO thromboprophylaxis in high-risk ambulatory cancer patients initiating a new systemic cancer regimen.

• Patients were eligible for inclusion if they: were ≥18 years of age; were ambulatory (outpatients) with a solid tumor or lymphoma; had a baseline Khorana score of ≥2 (higher scores indicating a higher risk of VTE); and had an expected survival of >6 months, with a plan to start a new systemic regimen within 1 week of initiating study drug.
• Patients were excluded if they had the following: primary brain tumors or known brain metastases; Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≥3; or active bleeding/risk for bleeding.
• Patients without thrombosis were randomized 1:1 to receive either XARELTO 10 mg orally once daily or placebo orally once daily for 180 (±3) days and were stratified by whether pancreas was the primary site. Follow-up visits occurred at week 8 (±7 days), week 16 (±7 days), and day 180/end of treatment (±3 days), with compression ultrasonography conducted at each visit.
• Primary efficacy endpoint: composite of objectively-confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper-extremity or distal lower-extremity DVT, symptomatic or incidental PE, and VTE-related death, as adjudicated by an independent blinded clinical endpoint committee.
• Primary safety endpoint: occurrence of major bleeding, as defined by the International Society on Thrombosis and Hemostasis (ISTH; bleeding requiring transfusion or >2 g/dL fall in hemoglobin), during the on-treatment period (first dose of study drug through last dose plus 2 days)
• Secondary efficacy endpoints: components of the primary, including symptomatic VTE, as well as clinically relevant events not included in the primary composite, such as all-cause mortality, confirmed arterial thromboembolism, and confirmed visceral thromboembolism; secondary safety endpoints: clinically relevant nonmajor bleeding
• Of 1080 enrolled patients, 841 were randomized (XARELTO, n=420; placebo, n=421) and included in the intent-to-treat efficacy analyses, while 809 were included in the safety analysis.
• With the exception of a greater number of XARELTO-treated patients having a history of VTE, baseline characteristics were well balanced between groups. Median age was 63 years, 50.9% of patients were male, the most common primary cancer was pancreatic (32.6%), and 54.5% of solid tumor patients had metastatic disease.
• In the up-to-day-180 period, the primary efficacy composite endpoint occurred in 25/420 patients (6.0%) and 37/421 patients (8.8%) in the XARELTO and placebo groups, respectively (HR, 0.66; 95% CI, 0.40-1.09; P=0.10).
• In a prespecified on-treatment analysis of all randomized patients, the primary efficacy composite endpoint occurred in 11/420 patients (2.6%) and 27/421 patients (6.4%) in the XARELTO and placebo groups, respectively (HR, 0.40; 95% CI, 0.20-0.80).
• Arterial thromboembolism occurred in 4/420 patients (0.95%) and 7/421 patients (1.66%) in the XARELTO and placebo groups, respectively.
• In regards to all-cause mortality in the up-to-day-180 period, there were 84 deaths (20.0%) in the XARELTO group and 100 deaths (23.8%) in the placebo group (HR, 0.83; 95% CI, 0.62-1.11).
• Major bleeding occurred in 8/405 patients (2.0%) and 4/404 patients (1.0%) in the XARELTO and placebo groups, respectively (HR, 1.96; 95% CI, 0.59-6.49; P=0.26). Clinically relevant nonmajor bleeding occurred in 2.7% and 2.0% of XARELTO- and placebo-treated patients, respectively (HR, 1.34; 95% CI, 0.54-3.32; P=0.53). One fatal bleeding event occurred in the XARELTO group.

SELECT-D Study

Young et al (2018)³ conducted a randomized, open-label, multicenter pilot study in the United Kingdom to evaluate the efficacy and safety of XARELTO vs dalteparin in the treatment of VTE (symptomatic PE, incidental PE, or symptomatic lower-extremity proximal DVT) in patients with active cancer (solid and hematologic malignancies). Patients were randomized to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or XARELTO (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding.

• Of the 406 patients that were recruited, 203 were randomly assigned to each group.
• Baseline characteristics were comparable between arms. Forty-eight percent of patients had symptomatic DVT or PE, 52% had incidental PE, 58% had metastases, 25% had colorectal cancer, and 69% were receiving anticancer treatment at the time of VTE, a majority (83%) of whom were receiving chemotherapy.
• Median duration of treatment was 5.8 months for dalteparin and 5.9 months for XARELTO.
• Recurrent VTE was reported in 26 patients (dalteparin, n=18; XARELTO, n=8) within the first 6 months following randomization, including 1 fatal PE in each arm.
• The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7-16%) with dalteparin and 4% (95% CI, 2-9%) with XARELTO (HR, 0.43; 95% CI, 0.19-0.99).
• The site of the primary tumor and VTE type predicted VTE recurrence.
• The 6-month cumulative rate of major bleeding was 4% (95% CI, 2-8%) for dalteparin and 6% (95% CI, 3-11%) for XARELTO (HR, 1.83; 95% CI, 0.68-4.96), with most events being gastrointestinal (GI)-related. Corresponding rates of clinically relevant nonmajor bleeding were 4% (95% CI, 2-9%) and 13% (95% CI, 9-19%), respectively (HR, 3.76; 95% CI, 1.63-8.69), with most events being GI- or urologic-related.
• Overall survival (OS) at 6 months was 70% (95% CI, 63-76%) with dalteparin and 75% (95% CI, 69-81%) with XARELTO.

Marshall et al (2020)⁴ reported results of the SELECT-D study beyond 6 months. Patients with active cancer and RDVT or index PE who completed 6 months of SELECT-D were randomized to a further 6 months of XARELTO (20 mg orally once daily) or placebo (second randomization). Patients who had VTE in the first 6 months were excluded from the second randomization. Also, patients without RDVT were ineligible for the second randomization and were mandated to discontinue anticoagulant therapy at 6 months. The primary outcome was VTE recurrence at 12 months after first randomization (ie, 6 months from second randomization). Secondary outcomes included major bleeding, clinically relevant nonmajor bleeding, and OS at 12 months (ie, 6 months from second randomization).

• Of the 136 eligible patients, 92 were randomized 1:1 to XARELTO or placebo.
• Baseline patient characteristics were comparable between the groups. Overall, 11% of patients had symptomatic DVT, 24% had symptomatic PE, 65% of patients had incidental PE, and 48% had metastases. Most patients (54%) received XARELTO during the first randomization.
• Overall, 63% (n=58/92) of patients participating in the second randomization completed 6 months of additional study.
• Recurrent VTE was reported in 8 patients (XARELTO, n=2; placebo, n=6) within 6 months from second randomization, including 2 events of incidental PE in the placebo group.
• The Kaplan-Meier estimates of VTE recurrence were 4% (95% CI, 1-16) for XARELTO and 14% (95% CI, 7-29) for placebo at 6 months from second randomization (HR, 0.32; 95% CI, 0.06-1.58).
• At 6 months from second randomization, the major bleeding rate was 5% for XARELTO (95% CI, 1-18) and 0% for placebo. The corresponding clinically relevant nonmajor bleeding rate was 4% for XARELTO (95% CI, 1-17) and 0% for placebo.
• OS at 6 months from second randomization was 89% (95% CI, 75-95) with XARELTO and 87% (95% CI, 73-94) with placebo (HR, 1.16; 95% CI, 0.36-3.81).

Mantha et al (2017)

Mantha et al (2017)² conducted an analysis based on clinical pathway guidelines to evaluate the safety and efficacy of XARELTO for use in cancer patients. The analysis focused on high-risk patients (N=200) with active cancer and cancer-related VTE, including patients with PE and symptomatic, proximal, lower-extremity DVT. Patients received a full course of anticoagulation with XARELTO and up to 3 days of parenteral anticoagulation. Primary endpoints included recurrent VTE, major bleeding, all-cause mortality, and clinically relevant nonmajor bleeding leading to discontinuation of XARELTO. As part of the clinical pathway, patients were offered XARELTO or enoxaparin after they were provided with explanations about the current knowledge base for both agents.

There were 200 patients with 6 months of follow-up who were included in the analysis; 136 patients had PE with or without DVT and 64 patients had proximal, symptomatic, lower-extremity DVT. Solid tumors were reported in 183 patients and hematologic malignancies were reported in 17 patients. Of the patients with solid tumors (excluding brain tumors), 142 had stage 4 disease. Less than 1% of the cohort chose enoxaparin as their therapy.

Recurrent VTE and major bleeding occurred at an incidence of 4.4% (95% CI, 1.4-7.4%) and 2.2% (95% CI, 0-4.2%), respectively.

• The incidence of clinically relevant nonmajor bleeding leading to discontinuation of XARELTO was 3.8% (95% CI, 1.0-6.5%).
• All-cause mortality occurred at an incidence of 17.6% (95% CI, 11.7-23.0%).

EINSTEIN

EINSTEIN-DVT and EINSTEIN-PE Pooled Analysis

A pooled subgroup analysis of patients enrolled in the EINSTEIN-DVT and EINSTEIN-PE studies was conducted to assess outcomes in patients with active cancer (either present at baseline or diagnosed during the study), a history of cancer, or no cancer.⁶

• In the pooled analysis, 655/8281 patients (7.9%) had active cancer.
  • 5.6% (462/8281) of patients had active cancer at baseline.
  • 2.3% (193/8281) of patients were diagnosed with cancer during the study.
  • 5.7% (469/8281) of patients had a history of cancer, but not active cancer.
  • 86% (7157/8281) of patients never had cancer.
• A total of 13/16 recurrent VTE events in the XARELTO group and 16/20 events in the enoxaparin/VKA group occurred while patients were receiving active treatment.
• Clinically relevant bleeding occurred in 15% of patients (97/651) with active cancer compared with 9.0% of patients (703/7595) with no active cancer (HR: 1.73; 95% CI: 1.39-2.14). The incidence of clinically relevant bleeding was similar between treatment groups among patients with active cancer.
• Major bleeding occurred in 4.0% (23/651) of patients with active cancer and in 1.0% (89/7595) of patients with no active cancer (adjusted HR, 2.87; 95% CI, 1.80-4.58). In patients with active cancer, major bleeding occurred in 2.0% of XARELTO-treated patients and in 5.0% of patients treated with enoxaparin/VKA (HR, 0.42; 95% CI, 0.18-0.99; P=0.047).
• Table: Recurrent VTE and Major Bleeding in Patients With Cancer By Cancer Site from Prins et al (2014)⁶ shows that recurrent VTE and major bleeding events were concentrated in patients with lung cancer, upper GI cancer, genitourinary tract cancer, and hematologic malignancies.

EINSTEIN-Extension and EINSTEIN-Choice

In the EINSTEIN-Extension and EINSTEIN-Choice studies, no analyses were performed for safety and efficacy measures in the subgroup of patients with active cancer.^7,8

MAGELLAN

MAGELLAN was a phase 3, international, randomized, double-blind trial designed to evaluate efficacy and safety of extended thromboprophylaxis with XARELTO compared with standard duration enoxaparin for the prevention of VTE in hospitalized acutely ill medical patients during the inpatient and post-discharge periods.^9,43

• About 17% of patients in each treatment group had a history of cancer at baseline.^9,10
• A total of 7.3% (296/4050) of patients in the XARELTO group and 7.3% (296/4051) of patients in the enoxaparin/placebo group had active cancer at baseline. Active cancer was defined as being admitted for chemotherapy or for treatment of active cancer complications.^9,10
• In a subgroup analysis, the primary efficacy outcome at Day 35 occurred in 9.9% (20/202) of XARELTO-treated patients with active cancer and in 7.4% (15/203) of enoxaparin/placebo-treated patients with active cancer.
• The primary safety outcome occurred in 5.4% (16/294) of XARELTO-treated patients with active cancer and in 1.7% (5/290) of enoxaparin/placebo-treated patients with active cancer at day 35.¹⁰
• See Table: Primary Efficacy and Safety Outcomes Stratified by Patients With Active Cancer.

• In a retrospective analysis of the MAGELLAN study, patients with 5 risk factors for major and fatal bleeding (including active cancer) were excluded. The resulting subpopulation (approximately 80% of patients) demonstrated an improved benefit risk profile for in-hospital and extended thromboprophylaxis with XARELTO.⁴⁴

MARINER

The MARINER^12,45 study was a phase 3, multicenter, randomized, double-blind study that evaluated the efficacy and safety of XARELTO 10 mg once daily (7.5 mg once daily if creatinine clearance [CrCl] ≥30 to <50 mL/min) vs placebo in the prevention of symptomatic VTE and VTE-related death in high-risk, medically ill patients for a period of 45 days post-hospital discharge.

• Patients had to have an increased VTE risk, as demonstrated by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk score ≥4 or a risk score of 2-3 with a plasma D-dimer >2 times the upper limit of normal (ULN). The IMPROVE score ranges from 0 to 10, with increased scores signifying a higher risk of VTE.
  • History of cancer was included in the modified IMPROVE score and counted for 2 points. About 8-9% of patients in MARINER had a history of cancer at baseline.
• Patients with active cancer (cancer not in remission or requiring active chemotherapy or adjunctive therapies) were excluded from MARINER.¹¹

CASTA DIVA

The CASTA DIVA study¹³ was an investigator-initiated study designed as a noninferiority, open-label, randomized clinical trial to assess if XARELTO was noninferior to dalteparin for the treatment of VTE in patients with active cancer and a high risk of recurrent VTE.

Study Design/Methods

• Patients with solid cancer or high-grade lymphoma or thalidomide or lenalidomide-treated myeloma diagnosed with symptomatic or incidental proximal lower-limb DVT and/or symptomatic or incidental iliac, inferior vena cava thrombosis or PE, and a high risk of recurrent VTE despite anticoagulation as estimated by a modified Ottawa score >1 were eligible for enrollment.
• A total of 158 patients were randomized to receive either dalteparin (n=84) (once daily subcutaneous injections of 200 IU/kg for one month, then 150 IU/kg for 2 months) or XARELTO (n=74) (15 mg tablets twice daily for 3 weeks followed by 20 mg once daily for the remaining 3-month treatment period).
• Primary Endpoint: Cumulative incidence of recurrent VTE during the 3-month study period, including a composite of symptomatic or incidental recurrent DVT or PE, and worsening of pulmonary vascular or venous obstruction on systematic imaging at 3 months.
• Secondary Endpoints: Symptomatic recurrences of PE or DVT of the legs, major bleeding events according to the ISTH definition, a composite of major and clinically relevant nonmajor bleedings, and deaths.

Results

• Recurrent VTE occurred in 4 patients (cumulative incidence 6.4%) in the XARELTO group and in 6 patients (10.1%) in the dalteparin group (subdistribution hazard ratio [SHR] 0.75, 95% CI 0.21-2.66, p=0.13 for noninferiority).
• One patient in the XARELTO group and 3 patients in the dalteparin group experienced major bleeding (cumulative incidences of 1.4% vs 3.7%, SHR 0.36, 95% CI 0.04-3.43). Major bleeding or clinically relevant nonmajor bleeding occurred in 9 patients (cumulative incidence 12.2%) and 8 patients (9.8%) in the XARELTO and dalteparin groups, respectively (SHR 1.27, 95% CI 0.49-3.26). Nineteen patients (25.7%) in the XARELTO group and 20 patients (23.8%) in the dalteparin group died during the study period (HR 1.05, 95% CI 0.56-1.97) mainly due to cancer progression. Two patients in the dalteparin group died due to bleeding.

CONKO-011

The CONKO-011 study¹⁴ was an open-label, prospective study that evaluated patient-reported satisfaction with anticoagulation treatment (XARELTO vs low-molecular-weight heparin) for cancer-associated thrombosis and clinical outcomes.

• Patients with acute symptomatic VTE and active cancer were included.
• Patients’ satisfaction with anticoagulant treatment was measured by ACTS and analyzed at weeks 4, 8, and 12.
• The primary endpoint was the ACTS Burdens score at 4 weeks.
• A total of 247 patients were randomized to XARELTO (n=123) or low-molecular-weight heparin (n=124).
• Baseline patient characteristics were well balanced between the 2 groups. The index VTE was symptomatic and incidental in 76% and 24% of patients, respectively.
• Patient-reported treatment satisfaction was improved with XARELTO especially in the reduction of anticoagulation-related burden. The relative range of ACTS Burden and Benefits score for XARELTO at 4 weeks was 88% (n=53/60) and 77% (n=12/15), respectively.
• Clinical outcomes are presented in the Table: Clinical Outcomes with XARELTO and LowMolecular-Weight Heparin.

COSIMO

Cohen et al (2021)¹⁵ evaluated patient-reported treatment satisfaction in patients who transitioned from a low-molecular-weight heparin, VKA, or fondaparinux to XARELTO for the treatment of cancer-associated thrombosis (N=505).

Study Design/Methods

• Prospective, noninterventional, international (Australia, Canada, and Europe), single-arm cohort study (COSIMO study; NCT02742623).
• Inclusion criteria: adult patients with active cancer (diagnosis or treatment of cancer within the last 6 months or recurrent or metastatic cancer), ECOG PS score of <3, patients with acute VTE receiving anticoagulation therapy for ≥4 weeks and were changing to XARELTO.
• Exclusion criteria: adults with basal cell carcinoma or squamous cell carcinoma of the skin, VTE while taking anticoagulation therapy, and contraindication to XARELTO.
• Primary endpoint: change in ACTS Burdens score (maximum score of 60) between baseline and week 4.

Results

Patient characteristics

• The median duration of anticoagulation therapy prior to transitioning to XARELTO was 100 days (3.3 months) (interquartile range, 47 to 181 days [1.5 to 6.0 months]).
• Reasons for changing to XARELTO included the desire to stop parenteral administration (26.9%), improve quality of life (18.6%), general patient preference (15.0%), and physician’s decision (34.5%).

Efficacy

• The mean ACTS Burdens score was significantly higher at week 4 compared to baseline (55.6 vs 51.8) with a mean improvement of 3.9 from baseline. Additionally, the improvement in ACTS Burdens score was observed at 3 months and 6 months.

PRIORITY

Kim et al (2022)¹⁶ prospectively evaluated the safety and efficacy of DOACs (specifically XARELTO and apixaban) compared with dalteparin as a treatment for CA-VTE in patients with currently active and advanced upper GI tract, hepatobiliary, or pancreatic cancer (N=92).

Study Design/Methods

• Multicenter, open-label, randomized, controlled phase II trial conducted across five institutions in Korea.
• Inclusion criteria: patients aged ≥ 19 and <80 years old, with histologically confirmed, advanced upper GI tract, hepatobiliary, or pancreatic cancer, and newly diagnosed (within 2 weeks before randomization) symptomatic or incidental lower extremity or upper extremity DVT or PE.
• Exclusion criteria: patients taking anticoagulant therapy for more than three days prior to randomization, any dose of thrombolysis therapy, continuous antiplatelet agent use, a history of VTE, hemodynamic unstable PE, current active bleeding or uncontrolled bleeding history within 4 weeks before randomization, liver cirrhosis (Child–Pugh score ≥ 7), uncontrolled hypertension, and brain metastasis.
• Outcomes: The primary safety outcome was clinically relevant bleeding (CRB) incidence. Efficacy outcomes were rate and time to symptomatic or incidental thromboembolic recurrence.

Results

• XARELTO had an increased risk of major bleeding and clinically relevant bleeding, compared to dalteparin (major bleeding, 16.1% vs. 4.3%; P=0.078; clinically relevant bleeding, 29.0% vs. 13.0%, P=0.082).
• There were no significant differences between XARELTO and apixaban in terms of major bleeding (16.1% vs. 23.1%; P=0.676) and clinically relevant bleeding (29.0% vs. 46.2%; P=0.313).
• Data for time to major bleeding or clinically relevant bleeding, indicated a trend of XARELTO being a risk factor for major bleeding (HR 3.89; P= 0.104) and clinically relevant bleeding (HR 2.37; P=0.102) compared to dalteparin.
• There were no significant differences between XARELTO and apixaban for time to major bleeding (HR =1.31;P=0.710) or clinically relevant bleeding (HR=1.58;P=0.386).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 November 2024.