Real-World Evidence: Use of XARELTO in Cancer-Associated Thrombosis

Summary

• In a subgroup analysis of the XALIA study, the XARELTO cohort experienced a lower rate of major bleeding compared with all other treatment cohorts of patients with cancer, except for the early switchers cohort. Rates of recurrent venous thromboembolism (VTE) and all-cause mortality were also lower in the XARELTO cohort compared with all other cohorts, with the exception of the early switchers cohort and the standard anticoagulation and early switchers cohorts, respectively.¹
• In a prospective study of patients who were enrolled in a single-center registry, real-world efficacy of XARELTO was found to be similar for VTE patients with and without active malignancy. Borderline higher rates of major bleeding and clinically relevant nonmajor bleeding (CRNMB) were observed in XARELTO-treated VTE patients with cancer.²
• In a large, retrospective cohort analysis designed to evaluate the efficacy and safety of XARELTO in patients with active cancer and VTE, higher recurrent VTE rates were observed in patients with previous episodes of VTE than in those without (P=0.034). Patients with higher Eastern Cooperative Oncology Group (ECOG) scores were more likely to have any bleeding (P=0.053).³
• In a retrospective analysis designed to evaluate outcomes of VTE management in cancer patients treated with XARELTO vs enoxaparin, rates of recurrent VTE, major bleeding, and mean time to recurrence were similar between groups. A significant difference was observed in mean treatment duration, with XARELTO being associated with a longer duration.⁴
• In a retrospective claims database analysis designed to estimate the cumulative incidence of recurrent VTE, major bleeding, and mortality/hospice care in patients with cancer-associated thrombosis treated with outpatient XARELTO, event rates observed with XARELTO were consistent with those observed in prior studies of patients with XARELTO-managed cancer-associated thrombosis.⁵
• A retrospective, real-world analysis found that cancer patients with VTE treated with XARELTO had significantly lower risk of recurrent VTE and similar risk of bleeding compared to those treated with low-molecular-weight heparin (LMWH) or warfarin.⁶
• In another retrospective, real-world analysis assessing the risk of recurrent VTE and major bleeding in younger cancer patients with VTE, the rate of recurrent VTE was significantly lower for patients treated with XARELTO vs LMWH and similar among patients treated with XARELTO vs warfarin. Rates of major bleeding were similar between XARELTO vs LMWH and XARELTO vs warfarin.⁷
• A retrospective, single-center study found that compared to LMWH, XARELTO was associated with a higher incidence of clinically relevant bleeding in gastrointestinal (GI) tract cancer patients presenting with VTE. No difference was observed between the groups in the incidence of major bleeding or VTE recurrence rates. All-cause mortality was significantly higher with LMWH vs XARELTO.⁸
• The OSCAR-US study was a retrospective cohort study that evaluated the effectiveness and safety of XARELTO vs LMWH for the treatment of cancer-associated thrombosis. There was a significant relative hazard reduction in the risk of recurrent VTE associated with XARELTO compared with LMWH at 90 days (overlap weighted hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51-0.92) and 180 days (overlap weighted HR, 0.74; 95% CI, 0.57-0.97).^9,10
• A retrospective cohort analysis of OSCAR comparing the effectiveness and safety of XARELTO vs apixaban for the treatment of cancer-associated venous thromboembolism (Ca-VTE) demonstrated that XARELTO was associated with similar effectiveness and safety as apixaban for the composite outcome of recurrent VTE or any bleeding-related hospitalization at 3 months.¹¹
• The OSCAR-UK study was a retrospective, observational cohort study that evaluated the effectiveness and safety of XARELTO vs LMWH for the treatment of Ca-VTE. For XARELTO vs LMWH, the 12-month overlap-weighted subdistribution hazard ratios (SHRs) for VTE recurrence, all significant bleeds, and all-cause mortality were 0.80 (95% CI: 0.37-1.73), 1.01 (95% CI: 0.57-1.81), and 0.49 (95% CI: 0.23-1.06), respectively.¹²
• A retrospective cohort study was conducted to evaluate the efficacy and safety of XARELTO in patients with Ca-VTE. The 6-month cumulative incidence rate of recurrent VTE was 3.4% and the 6-month cumulative incidence rates for major bleeding and CRNMB were 8.8% and 4.2%, respectively.¹³
• A subanalysis of the J’xactly study was conducted to evaluate the long-term administration, effectiveness, and safety of XARELTO in VTE patients with or without active cancer. The cumulative incidence of recurrence or aggravation of symptomatic VTE at 3, 6, and 12 months in patients with/without active cancer was 0%/0.9%, 0.6%/1.4%, and 1.9%/3.4%, respectively. The cumulative incidence of major bleeding at 3, 6, and 12 months in patients with/without active cancer was 2.2%/1.2%, 4.3%/1.3%, and 5.8%/2.4%, respectively.¹⁴
• A retrospective cohort study was conducted to compare the efficacy and safety of XARELTO and LMWH in Chinese patients with lung cancer and acute non-high-risk pulmonary embolism (PE) with or without deep vein thrombosis (DVT). After 1:1 propensity score matching, XARELTO and LMWH showed similar risks for composite outcome (P=0.22), VTE recurrence (P=0.28), major bleeding (P=0.54) and CRNMB (P=0.69). However, all-cause mortality was significantly lower in the XARELTO group compared with LMWH group (P<0.001).¹⁵
• A single-center retrospective chart review was conducted to compare the safety and effectiveness of XARELTO vs apixaban in patients with GI cancer and Ca-VTE. Major bleeding was reported in 6% of patients treated with XARELTO vs 2.7% of patients treated with apixaban (P=0.1). CRNMB was reported in 6% of patients treated with XARELTO vs 5% of patients treated with apixaban (P=0.66). Recurrent VTE was reported in 9% of patients treated with XARELTO vs 6.7% of patients treated with apixaban (P=0.39).¹⁶
• The OSCAR-SE study was a nationwide, population-based cohort analysis comparing XARELTO vs LMWH in Swedish patients with Ca-VTE, which showed similar rates of recurrent VTE and major bleeding between treatments and also a lower all-cause mortality associated with XARELTO across the 12-month, 24-month, and overall follow-up periods. The authors noted that the observed reduction in allcause mortality may potentially be attributable to residual confounding.¹⁷
• The PRIMECAST study was a prospective, multicenter observational analysis evaluating real-world outcomes of XARELTO in patients with Ca-VTE, which showed low rates of recurrent/worsening VTE (1.9%) and major bleeding (2.8%) and no VTE-related or cardiovascular deaths within 24 weeks.¹⁸
• A single-center, retrospective cohort analysis comparing XARELTO vs warfarin in Ethiopian patients with cancer-associated thrombosis showed that XARELTO significantly reduced the risk of the composite outcome (VTE recurrence, major bleeding, or all-cause mortality) compared with warfarin (adjusted HR, 0.48; 95% CI, 0.24-0.97; P=0.041).¹⁹
• Additional citations have been included in the REFERENCES section for your review.^20-33

REAL-WORLD EVIDENCE

XALIA

XALIA was a multicenter, international, prospective, noninterventional study designed to evaluate the efficacy and safety of XARELTO vs a standard anticoagulation regimen (initial treatment with unfractionated heparin, LMWH, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist [VKA]) for the treatment of objectively confirmed DVT.

Ageno et al (2017)¹ conducted a subgroup analysis of the XALIA study to identify the baseline demographics and clinical characteristics, treatment patterns, and outcomes of the patients with known and newly diagnosed cancer. Treatment, dose, and duration were at the physician’s discretion. The following cohorts were identified for the subgroup analysis: XARELTO (XARELTO alone or after heparin or fondaparinux for ≤48 hours); early switchers (XARELTO after heparin or fondaparinux for >48 hours to 14 days or a VKA for 1-14 days); standard anticoagulation (heparin or LMWH or fondaparinux and a VKA); LMWH alone; and miscellaneous (other heparins, fondaparinux alone, or a VKA alone). Primary outcomes included major bleeding, recurrent VTE, and all-cause mortality.

• Of the 5136 patients analyzed in the XALIA study, 587 (11.4%) had known or newly diagnosed cancer at baseline; of these patients, 146 (24.9%) received XARELTO, 30 (5.1%) were early switchers, 141 (24.0%) received standard anticoagulation, 223 (38.0%) received LMWH alone, and 47 (8.0%) were in the miscellaneous cohort.
• The median treatment duration was 152 days with XARELTO and 164 days with LMWH.
• Common reasons for choosing XARELTO therapy included: living conditions, age of patient, guidelines, comorbidities, and drug availability.
• Genitourinary cancer was the most common type of cancer in all cohorts except the LMWH cohort. GI cancer was the most common type of cancer in the LMWH cohort.
• Rates of major bleeding were as follows: 5.0% (7/141) in the standard anticoagulation cohort, 4.3% (2/47) in the miscellaneous cohort, 3.6% (8/223) in the LMWH cohort, 1.4% (2/146) in the XARELTO cohort, and 0% (0/30) in the early switchers cohort.
• Rates of recurrent VTE were as follows: 4.5% (10/223) in the LMWH cohort, 4.3% (6/141) in the standard anticoagulation cohort, 4.3% (2/47) in the miscellaneous cohort, 3.4% (5/146) in the XARELTO cohort, and 3.3% (1/30) in the early switchers cohort.
• Rates of all-cause mortality were as follows: 24.7% (55/223) in the LMWH cohort, 14.9% (7/47) in the miscellaneous cohort, 4.8% (7/146) in the XARELTO cohort, 4.3% (6/141) in the standard anticoagulation cohort, and 0% (0/30) in the early switchers cohort.

Bott-Kitslaar et al (2016)² evaluated the efficacy and safety of XARELTO in patients with VTE and active malignancy as part of a single-center registry. Patients received XARELTO for DVT or PE. Patients were enrolled in the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry between March 1, 2013, and April 30, 2015 and were followed prospectively.

• Of the 404 VTE patients in the registry, 296 received XARELTO and had at least 3 months of follow-up.
• Of these patients, 118 (40%) had active malignancy (51% female; mean age 66±10 years) and 178 had no cancer (47% female; mean age 55±15 years).
• Of the cancer patients, 90 (76%) were receiving chemotherapy at the time of VTE diagnosis.
• Cancer sites included genitourinary (23.6%), GI (20.3%), lung (13.5%), hematologic/myeloma (10.1%), breast (9.3%), pancreatic (8.4%), renal (6.7%), sarcoma (1.6%), brain (1.6%), and other (4.2%; includes thyroid, oral, metastatic melanoma, and uncertain primary site).
• Safety and efficacy events seen over a mean follow-up of 1.36±0.5 years are presented in Table: Safety and Efficacy Outcomes.
• No deaths among cancer patients were attributed to VTE or bleeding complications.

Pignataro et al (2017)³ conducted a single-center, retrospective cohort study to evaluate efficacy and safety of XARELTO use in patients with active cancer and VTE. A total of 400 patients with active cancer and associated symptomatic, acute VTE (DVT or PE) were assessed from January 2012 to June 2015. Primary efficacy outcomes included recurrence of symptomatic VTE and VTE-related death. Primary safety outcomes included major bleeding and CRNMB.

• Of the 400 patients enrolled, mean age was 60.1 years, 223 (55.8%) patients were female, 362 (90.5%) had solid tumors, and 244 (61%) had metastatic disease.
• A total of 302 (75.5%) patients received initial parenteral therapy with enoxaparin followed by XARELTO; 98 (24.5%) were treated with on-label XARELTO treatment.
• Median anticoagulant treatment duration was 118 days (mean: 163.9 days).
• The incidence of VTE recurrence was 3.25% (n=13 patients [DVT, n=8; isolated PE, n=5 (fatal, n=1)]).
  • Higher recurrent VTE rates were observed in patients with previous episodes of VTE than in those without (4/37 [10.8%] patients vs 9/350 [2.5%] patients; P=0.034).
• The incidence of major bleeding was 5.5% (n=22 patients [fatal, n=1]).
• The incidence of CRNMB was 15.2% (n=61 patients).
  • Patients with higher ECOG scores were more likely to have any bleeding (10.8%, 15.7%, 24.2%, and 25.8% in patients with ECOG scores of 0, 1, 2, and 3+4, respectively; P=0.053).

Nicklaus et al (2018)⁴ conducted a retrospective, single-center, chart review analysis to evaluate outcomes of VTE management in cancer patients treated with XARELTO compared with enoxaparin. Electronic medical records were used to identify patients that were prescribed XARELTO or enoxaparin between 1/1/12 and 8/31/15 and followed up in clinic within 90 days of treatment initiation. The XARELTO group included patients who were initially on an alternative anticoagulant at VTE diagnosis and switched to XARELTO within 30 days of initiation, either during hospitalization or at first clinic visit. The enoxaparin group included patients who were initially on an alternative anticoagulant at VTE diagnosis and were discharged on therapeutic enoxaparin. The primary outcome was incidence of recurrent VTE and/or clot extension. Secondary outcomes included a comparison of rates of bleeding, mean treatment duration, and mean time to VTE recurrence.

• A total of 45 patients were included in each group.
• Baseline characteristics were similar among groups, with the exception of higher DVT and PE prevalence at treatment initiation in the enoxaparin group.
• A significant difference between groups in the rate of recurrent VTE was not observed, with an incidence of 8.9% vs 13.3% in XARELTO-treated patients vs enoxaparin-treated patients, respectively (P=0.74).
• Significant differences were not observed among the secondary outcomes (major bleeding: XARELTO, ~2%; enoxaparin, ~4.5%; minor bleeding: XARELTO, ~29%; enoxaparin, ~22%; mean time to recurrence: XARELTO, 47±66 days; enoxaparin, 50±45 days [P=0.95]), with the exception of longer mean treatment duration with XARELTO vs enoxaparin (169 days vs 110 days, respectively; P=0.04).

Kohn et al (2018)⁵ conducted a retrospective, single-arm, administrative claims database analysis to estimate the cumulative incidence of recurrent VTE, major bleeding, and mortality/hospice care in patients with cancer-associated thrombosis treated with XARELTO. United States (US) Truven Health Analytics MarketScan claims data from January 2012 through June 2015 were used to identify adult patients with active cancer who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received XARELTO as the first outpatient anticoagulant within 30 days of the index VTE. Continuous medical/prescription coverage for ≥180 days prior to the index VTE was required. Patients were excluded if they had a previous claim for VTE, atrial fibrillation, or valvular disease or if they were receiving baseline anticoagulation. Primary outcomes included recurrent VTE, major bleeding, and all-cause mortality or a claim for hospice care in the 180 days following the index VTE event.

• A total of 949 patients with active cancer were initiated on XARELTO following their index VTE.
• Time from active cancer diagnosis to index cancer-associated thrombosis was ≤90 days for 27% of patients, 91-180 days for 19%, and >180 days for 54%. Median time from index VTE to first outpatient XARELTO fill was 2 days and median time between first and last XARELTO prescription was 114 days.
• Mean age of patients was 62.5 years, 43.6% had PE, and 42.6% had metastatic disease.
• A total of 37 cases of recurrent VTE, 22 cases of major bleeding (17 GI, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims were noted during the 6-month follow-up period.
  • The 180-day cumulative incidence estimates were as follows: 4.0% (95% CI: 2.8-5.4%) for recurrent VTE, 2.7% (95% CI: 1.7-4.0%) for major bleeding, and 11.3% (95% CI: 9.2-13.6%) for mortality/hospice care.

Streiff et al (2018)⁶ conducted a retrospective, observational, real-world analysis to compare the risk of VTE recurrence and major bleeding in older cancer patients with VTE treated with XARELTO, LMWH, or warfarin. Humana claims data were used to identify newly diagnosed cancer patients who developed their first VTE between 1/1/2013 and 05/31/2015 and were initiated on XARELTO, LMWH, or warfarin. The observation period spanned from initiation of anticoagulant therapy until the earliest of either end of data availability (June 2015) or end of eligibility. Efficacy was assessed via VTE recurrence, defined by hospitalization with a primary diagnosis of VTE ≥7 days following the first VTE. Safety was assessed via major bleeding events.

• A total of 2428 patients who developed a VTE and were treated with anticoagulant agents within 7 days of VTE diagnosis were identified, including 1061 treated with warfarin, 707 treated with XARELTO, and 660 treated with LMWH.
• Median duration of treatment was 3 months with XARELTO, 3.5 months with warfarin, and 1 month with LMWH.
• Patient characteristics were well balanced after weighting. Mean age was 73 years, ~50% of patients were female, PE represented between 25-30% of the index VTE, and DVT represented between 55-60% of the index VTE.
• During follow-up, 13% of XARELTO-treated patients, 18% of LMWH-treated patients, and 18% of warfarin-treated patients experienced a recurrent VTE event.
• XARELTO users experienced a trend toward lower VTE recurrence rates vs LMWH users at 6 months (13.2% vs 17.1%; P=0.060), and significantly lower rates at 12 months (16.5% vs 22.2%; P=0.030) (HR, 0.72; 95% CI, 0.52-0.95; P=0.024).
• XARELTO users experienced significantly lower VTE recurrence rates vs warfarin users at 6 months (13.2% vs 17.5%; P=0.014) and at 12 months (15.7% vs 19.9%; P=0.017) (HR, 0.74; 95% CI, 0.56-0.96; P=0.028).
• Major bleeding rates were similar across cohorts, the majority of which were GI-related.
  • At 6 months, rates of major bleeding for LMWH and XARELTO users were 8.3% and 8.2%, respectively (HR, 1.03; 95% CI, 0.64-1.65; P=0.917).
  • At 6 months, rates of major bleeding for warfarin and XARELTO users were 8.7% and 9.0%, respectively (HR, 1.01; 95% CI, 0.71-1.43; P=0.961).

Khorana et al (2019)⁷ conducted a retrospective cohort study to compare the risk of recurrent VTE and major bleeding in younger, commercially-insured cancer patients treated with XARELTO, LMWH, or warfarin after a first episode of VTE. Cancer patients with a VTE (only lower-extremity DVT and PE) between January 2013 and September 2016 who were treated with XARELTO, warfarin, or LMWH within 7 days of their index VTE event were identified from the Truven Health MarketScan Research database.

• Recurrent VTE was defined as a hospitalization with VTE as the primary diagnosis ≥7 days after the index VTE. Major bleeding was defined using the validated Cunningham algorithm.
• For VTE, the follow-up period spanned from the index date until the end of eligibility or data availability. For major bleeding, the follow-up period spanned from the index date until anticoagulant treatment discontinuation.
• Inverse probability of treatment weighting (IPTW) was used to adjust for baseline cohort differences.
• A total of 3370 XARELTO-treated patients, 4774 warfarin-treated patients, and 4313 LMWH-treated patients were included in the study. Mean ages were 62.6 years, 63.9 years, and 60.2 years, respectively.
• Mean treatment duration was 5.5, 3.5, and 5.8 months for patients initiated on XARELTO, LMWH, and warfarin, respectively.
• The rate of recurrent VTE was 17% lower for patients treated with XARELTO vs LMWH (HR, 0.83; 95% CI, 0.73-0.96; P=0.010).
• The rate of recurrent VTE was similar among patients treated with XARELTO vs warfarin (HR, 0.95; 95% CI, 0.83-1.09; P=0.456).
• Rates of major bleeding were similar in both the following XARELTO comparisons:
  • XARELTO vs LMWH (HR, 0.91; 95% CI, 0.71-1.17; P=0.455)
  • XARELTO vs warfarin (HR, 1.08; 95% CI, 0.86-1.37; P=0.500)

Lee et al (2019)⁸ conducted a retrospective, single-center study to compare the incidence of bleeding and other outcomes in GI and pancreatobiliary cancer (GI tract cancer) patients treated with XARELTO or LMWH for VTE.

• GI tract cancer patients who were treated for VTE (PE or DVT) with XARELTO or LMWH (dalteparin, enoxaparin, or nadroparin) between January 1, 2012, and December 31, 2016, were analyzed. Eligible patients were identified through anticoagulant prescribing information contained in the electronic medical record system at Asan Medical Center in Korea.
• The primary outcomes were incidence of major bleeding (defined as any bleeding event occurring during treatment with LMWH or XARELTO that: 1) was associated with death; 2) occurred at a fatal site [intracranial, intraocular, retroperitoneal, intraspinal, or pericardial]; or 3) required a transfusion of ≥2 units of packed red blood cells or led to hemoglobin decrease of ≥2.0 g/dL) and clinically relevant bleeding (any obvious bleeding occurring during treatment with LMWH or XARELTO and resulting in medical intervention, unscheduled visits with clinicians, discontinuance of anticoagulants, or a decline in the activities of daily life). Secondary outcomes included incidence of recurrent VTE and mortality.
• Of the 375 GI tract cancer patients diagnosed with VTE, 281 were included in the analysis (XARELTO, n=78; LMWH, n=203). Compared to the LMWH group, the XARELTO group had a higher proportion of patients with good ECOG performance status and recent surgery. The LMWH group had a higher proportion of patients with metastasis, a history of chemotherapy, and stomach cancer than the XARELTO group.
• Clinically relevant bleeding occurred in 24.4% (n=19) of XARELTO-treated patients and in 15.3% (n=31) of LMWH-treated patients (P=0.074). Major bleeding occurred in 5.1% (n=4) and 8.9% (n=18) of patients, respectively (P=0.296).
• No difference was observed for VTE recurrence rate (XARELTO, 3.8%; LMWH, 3.9%; P>0.999) or symptomatic recurrence rate (XARELTO, 0%; LMWH, 0.5%; P>0.999) between the groups.
• All-cause mortality was significantly higher with LMWH vs XARELTO, with 29 (37.2%) deaths in the XARELTO group and 138 (68.0%) deaths in the LMWH group (P<0.001); however, no significant difference was found for mortality secondary to PE or bleeding between the groups.
• A multivariate Cox proportional hazards analysis for age, cancer type, metastasis, history of chemotherapy or recent surgery, and ECOG performance status revealed a 1.904-fold higher risk of clinically relevant bleeding with XARELTO than LMWH (1.031-3.516; P=0.040). Regarding the HR for all-cause mortality, no significant difference was observed between the groups.

OSCAR-US

Coleman et al (2022)^9,10 conducted a retrospective cohort analysis that evaluated the effectiveness and safety of XARELTO vs LMWH for the treatment of cancer-associated thrombosis using the US Optum^® de-identified electronic health record dataset (from January 1, 2013 through December 31, 2020).

Methods

• This analysis was conducted in the International Society on Thrombosis and Hemostasis (ISTH) cohort that included cancers based upon those endorsed for non-VKA oral anticoagulant use in the ISTH guidelines.
  • The definition of this cohort was determined and endorsed by the OSCAR steering committee.
  • This cohort excluded patients with esophageal, gastric, unresected colorectal, bladder, central nervous system (CNS) other than brain, and nonlymphoma or myeloma hematologic cancers.
• Patients with active cancer with acute DVT and/or PE on or after January 1, 2013, who were treated with XARELTO or LMWH on day 7 after the VTE event were included.
• Primary outcomes of interest included the risk of recurrent VTE, any clinically relevant bleeding-related hospitalization, and all-cause mortality.

Results

• A total of 4935 patients with active cancer and cancer-associated thrombosis treated with XARELTO (n=1093) or LMWH (n=2615) were identified.
• There was a significant relative hazard reduction in the risk of recurrent VTE associated with XARELTO compared with LMWH at 90 days (overlap weighted HR, 0.69; 95% CI, 0.51-0.92) and 180 days (overlap weighted HR, 0.74; 95% CI, 0.57-0.97).
• There were no statistically significant differences in the incidences of bleeding-related hospitalization or all-cause mortality at any time point among patients using XARELTO or LMWH.
• See Table: Clinical Outcomes With XARELTO vs LMWH in the ISTH Cancers and All-Cancers Cohort.

Coleman et al (2023)³⁴ conducted a meta-analysis of the OSCAR program study findings from the US, the United Kingdom (UK), and Sweden.

• A total of 1690 patients treated with XARELTO and 9741 patients treated with LMWH were included in the analysis.
• At 3 and 6 months, respectively, XARELTO was associated with a 29% and 24% reduced risk of developing VTE vs LMWH.
• At 3 months, there was no significant difference in the risk of major bleeding between XARELTO and LMWH. At 6 months, XARELTO was associated with a 27% reduced risk of major bleeding vs LMWH.

Caroti (2023)¹¹ conducted a retrospective cohort analysis to compare the effectiveness and safety of XARELTO vs apixaban for Ca-VTE treatment in patients with active cancer considered at a low risk of bleeding using US Optum^® de-identified electronic health data (from January 1, 2012, to December 31, 2020).

Methods

• Adult patients with active cancer (excluding esophageal, gastric, unresected colorectal, bladder, leukemia, or non-cerebral CNS cancers), who were admitted to the hospital, emergency department, or observation unit for acute DVT and/or PE on or after January 1, 2013, and treated with therapeutic doses of XARELTO or apixaban on day 7 after the qualifying VTE diagnosis, were included.
• The primary outcome was the composite of recurrent VTE or any bleeding-related hospitalization at 3 months.
• Secondary outcomes included a composite of recurrent VTE or any critical organ bleeding (defined as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome), recurrent VTE, any bleeding-related hospitalization, and any critical organ bleeding at 3 and 6 months.

Results

• A total of 2437 patients were included in the study, of whom 1093 and 1344 were treated with XARELTO and apixaban, respectively. After IPTW, the baseline characteristics were similar in both groups.
  • Of the included patients, 29.0% were ≥75 years of age and 56.9% were female; the most common cancer types (>10% prevalence) included breast (23.5%), lung (20.1%), prostate (14.6%), and hepatobiliary (12.1%).
• XARELTO was associated with similar effectiveness and safety as apixaban for the composite of recurrent VTE or bleeding-related hospitalization at 3 months (5.3% vs 6.0%; HR, 0.87; 95% CI, 0.60-1.27) and 6 months (7.5% vs 7.5%; HR, 1.00; 95% CI, 0.71-1.40). No significant differences were observed for any secondary outcomes at 3 or 6 months. See Table: Effectiveness and Safety Outcomes With XARELTO vs Apixaban.

OSCAR-UK

Cohen et al (2024)¹² conducted a retrospective, observational cohort study using data from the UK Clinical Practice Research Datalink GOLD and Aurum databases to evaluate the safety and effectiveness of XARELTO vs LMWH for the treatment of Ca-VTE (from January 1, 2013 through October 31, 2020).

Methods

• Patients with active cancer who had an incident VTE and received XARELTO or LMWH within 30 days of the VTE were included in the study.
• The outcomes of interest were VTE recurrence, significant bleeding (major bleeding or CRNMB needing hospitalization), and all-cause mortality.

Results

• A total of 2259 patients with active cancer and Ca-VTE treated with XARELTO (n=314) or LMWH (n=1945) were included in the analysis.
• See Table: Safety Outcomes With XARELTO vs LMWH.

Chang et al (2022)¹³ conducted a retrospective cohort study to evaluate the efficacy and safety of XARELTO in patients with Ca-VTE.

• Patients newly diagnosed with cancer or those with cancer recurrence between 2014 and 2018 and who were newly prescribed XARELTO between January 2015 and January 2019 for the treatment of VTE only, were included.
• The primary endpoint was the rate of recurrent VTE at day 180 (defined as VTE confirmed by imaging evidence to have originated from a new intraluminal filling defect).
• The secondary endpoint was safety, including rates of major bleeding (defined as a decrease in hemoglobin level of 2 g/dL within 24 hours, followed by a transfusion of ≥2 units of leukocyte-poor red blood cells, or a bleeding event that occurred at a critical site such as intraspinal space, intraocular area, pericardium, or retroperitoneum) and CRNMB (defined as bleeding in clinically overt episodes that did not meet the criteria for major bleeding but resulted in medical intervention, unscheduled contact with a physician, or XARELTO interruption) at day 180 or until discontinuation.
• Of the 185 patients enrolled in the study, 65 were prescribed XARELTO for Ca-VTE.
  • Median age was 67 years, 36 (55.4%) patients were male, and 47 (72.3%) patients had symptomatic VTE, including 10 (15.4%) with symptomatic PE and 38 (58.5%) with symptomatic DVT.
  • Lung cancer was the primary tumor type in majority of patients (n=19; 29.2%), followed by colorectal cancer in 12 (18.5%) patients.
• Median initiation dose was 23.9 mg/day.
  • Of the 65 patients prescribed a starting dose, 30 (46.2%) initiated XARELTO at 15 mg twice a day and 14 (21.5%) initiated XARELTO at 15 mg and 10 mg once a day each.
  • Of the 35 patients who did not receive the standard initiation dose, 3 had renal insufficiency, 1 had abnormal liver function test, and 16 had shifted from another anticoagulant before XARELTO.
• Median maintenance dose was 13.1 mg/day.
  • A maintenance dose was prescribed in 53 patients, of whom 10 discontinued the treatment within 3 weeks, and 2 were lost to follow-up.
  • Of the remaining patients on maintenance therapy, 28 (43.1%) were on XARELTO 15 mg once a day and 22 (33.8%) were on XARELTO 10 mg once a day.
• Overall, 21 patients received XARELTO for more than 180 days and 44 received XARELTO for less than 180 days.
  • Reasons for XARELTO discontinuation within 180 days were critical situation (n=7; 10.8%), improvement in VTE (n=5; 7.7%), switch to another anticoagulant (n=5; 7.7%), bleeding events (n=4; 6.2%), hemodynamic instability (n=4; 6.2%), patient expiration (n=3; 4.6%), and others (n=9; 13.8%; including surgery [n=2; 3.1%], patient’s own decision [n=1; 1.5%], and unknown [n=6]).
• Recurrent VTE occurred in 2 (3.1%) patients within 180 days.
  • Both patients had symptomatic DVT, and the primary tumor sites were the rectum and lung; no fatality related to VTE occurred during the follow-up period.
• The 6-month cumulative incidence rate of recurrent VTE was 3.4%.
• Major bleeding and CRNMB occurred in 5 (7.7%) and 2 (3.1%) patients, respectively.
  • All events of major bleeding involved GI bleeding, and the cancer types in patients with major bleeding included gastric, pancreatic, rectal, and ovarian cancers.
• The 6-month cumulative incidence rates for major bleeding and CRNMB were 8.8% and 4.2%, respectively.

Hisatake et al (2023)¹⁴ conducted a subanalysis of the J’xactly study that evaluated the long-term administration, effectiveness, and safety of XARELTO in VTE patients with or without active cancer.

• Outcomes assessed were the incidence of symptomatic VTE recurrence, death from any cause, recurrence or aggravation of symptomatic PE, recurrence of symptomatic DVT, and major and minor bleeding. Additionally, the severity of VTE recurrence, death related to VTE, death from any cause, and major bleeding were evaluated according to the simplified pulmonary embolism severity index (PESI; 1 point vs ≥2 points) that includes the following 6 variables of equal weight (1 point per variable): age >80 years, history of cancer, chronic cardiopulmonary disease, pulse rate ≥110 beats/min, systolic blood pressure <100 mm Hg, and percutaneous oxygen saturation <90%.
• Of the 1016 patients in the modified intention-to-treat population with DVT, PE, or both, 193 had active cancer.
  • Overall, mean age was 69 years and 51.3% were female; median (interquartile range [IQR]) follow-up duration was 21.3 (18.1-24.2) months.
• The standard XARELTO treatment regimen in patients with VTE diagnosis at the time of the study was 15 mg twice daily for 3 weeks followed 15 mg once daily thereafter.
• An initial XARELTO dose of 30 mg/day was used in >60% of patients with or without active cancer, with no difference in the initial dose distribution between the groups.
• Patients with active cancer received XARELTO for a longer duration than those without active cancer, with median durations being 11.6 and 8.3 months, respectively; however, there was no significant difference in the treatment duration between the groups (P=0.074).
• The cumulative incidence of recurrence or aggravation of symptomatic VTE at 3, 6, and 12 months in patients with/without active cancer was 0%/0.9%, 0.6%/1.4%, and 1.9%/3.4%, respectively.
• The cumulative incidence of major bleeding at 3, 6, and 12 months in patients with/without active cancer was 2.2%/1.2%, 4.3%/1.3%, and 5.8%/2.4%, respectively.
• Effectiveness and safety outcomes in patients with or without active cancer are summarized in Table: Clinical Outcomes in Patients With or Without Active Cancer.
• Effectiveness and safety outcomes per simplified PESI scores in patients with PE are summarized in Table: Clinical Outcomes per Simplified PESI Scores. There was no significant difference observed in the outcomes between the groups.

Song et al (2023)¹⁵ conducted a retrospective cohort study to compare the efficacy and safety of XARELTO and LMWH in Chinese patients with lung cancer and acute non-high-risk PE with or without DVT.

• Patient data were collected from the Zhongshan Hospital database from January 1, 2016, to December 31, 2020.
• Primary outcomes were the composite of VTE recurrence or major bleeding, and all-cause mortality at 12 months.
• Secondary outcomes were VTE recurrence, major bleeding, and CRNMB at 12 months.
• After 1:1 propensity score matching, the XARELTO and LMWH groups consisted of 191 patients each.
  • In the XARELTO and LMWH groups, respectively, mean age was 65 and 64 years, 26 (13.6%) and 24 (12.6%) patients were aged ≥75 years, and 85 (44.5%) patients each were female.
• XARELTO and LMWH groups showed similar risks for composite outcome (HR, 0.73; 95% CI, 0.45-1.21; P=0.22), VTE recurrence (HR, 0.69; 95% CI, 0.36-1.34; P=0.28), major bleeding (HR, 0.79; 95% CI, 0.37-1.68; P=0.54) and CRNMB (HR, 1.13; 95% CI, 0.62-2.09; P=0.69). However, all-cause mortality was significantly lower in the XARELTO group compared with LMWH group (HR, 0.52; 95% CI, 0.36-0.75; P<0.001).
• Efficacy and safety outcomes between XARELTO and LMWH are summarized in Table: Efficacy and Safety Outcomes Between XARELTO and LMWH in Propensity Score-Matched Population at 12 Months.

Ullah et al (2023)¹⁶ conducted a single-center retrospective chart review to compare the safety and effectiveness of XARELTO vs apixaban in patients with GI cancer and Ca-VTE.

• Patients receiving direct oral anticoagulants between March 2016 and September 2021 were included in the analysis.
• Primary outcomes were major bleeding and CRNMB during 6 months treatment period (safety), and recurrent VTE (effectiveness).
• Secondary outcomes were time to first bleeding (safety) and time to recurrent VTE (effectiveness).
• Of 433 total patients, 133 were treated with XARELTO and 300 were treated with apixaban.
• Efficacy and safety outcomes with XARELTO vs apixaban are summarized in Table: Efficacy and Safety Outcomes With XARELTO vs Apixaban.

OSCAR-SE

Linder et al (2024)¹⁷ conducted a nationwide, population-based cohort study to evaluate the efficacy and safety of XARELTO vs LMWH and to assess the occurrence of recurrent VTE, major bleeding events, and overall all-cause mortality among patients diagnosed with Ca-VTE.

Methods

• This study utilized Swedish national health registry data (2013-2019) to identify patients diagnosed with cancer who subsequently developed VTE within 6 months of cancer diagnosis.
• Patients were monitored from the date of their first VTE following cancer diagnosis (defined as the index event) and the start of follow-up until the occurrence of an outcome, death, emigration, or the end of the study period on December 31, 2020, which occurred first.
• The outcomes were incidence of recurrent VTE, major bleeding, and all-cause mortality using propensity score overlap weighting (85 covariates for confounding adjustment). Outcomes were assessed using incidence rates per 1000 person-years and propensity score overlap-weighted HRs.

Results

• Of 5464 total patients with Ca-VTE, 283 were treated with XARELTO and 5181 were treated with LMWH.
• The majority of index VTE events were pulmonary embolism (XARELTO, 60%; LMWH, 55%).
• XARELTO showed similar incidence rates of recurrent VTE and major bleeding to LMWH, with no statistically significant differences. See Table: Incidence Rate of Recurrent VTE, Major Bleeding, and All-Cause Mortality.

PRIMECAST

Tamura et al (2025)¹⁸ presented a prospective, multicenter observational study to evaluate real-world clinical outcomes of XARELTO in patients with ca-VTE.

Methods

• The study included patients with cancer (solid tumors excluding lymphoma and sarcoma) with VTE who received XARELTO (15 mg twice daily for the first 3 weeks, followed by 15 mg once daily) or warfarin and were sequentially enrolled at 27 Japanese institutions between August 2018 and December 2021. The observation period was 24 weeks from initial administration.
• Endpoints were evaluated only in XARELTO-treated patients.
  • Primary endpoint: recurrence or worsening of symptomatic VTE within 24 weeks after administration
  • Secondary endpoints: major bleeding and all-cause mortality

Results

• Of 348 enrolled patients, 327 received XARELTO and 21 received warfarin; of these, 322 XARELTO-treated patients were included in the analysis.
• The follow-up rate was 86.3% of patients at 12 weeks and 64.6% of patients at 24 weeks.
• Pulmonary thromboembolism and deep vein thrombosis were observed in 53.4% and 86.3% of patients, respectively.
• Recurrent VTE or worsening was observed in 6 patients (1.9%), with a VTE recurrence/worseining-free survival rate of 98.0% (95% CI, 95.7-99.1) at 24 weeks.
• No VTE-related or cardiovascular deaths were reported within 24 weeks; 33 cancer-related deaths and 4 deaths from other causes were reported during follow-up.
• Major bleeding events were reported in 9 patients (2.8%).

TASH

Tasamma et al (2025)¹⁹ conducted a single-center, retrospective cohort study to compare the efficacy and safety of XARELTO vs warfarin for the management of cancer-associated thrombosis in a resource-limited setting in Ethiopia.

Methods

• The study included adult patients (≥18 years old) with histologically confirmed solid or hematologic malignancies who were newly diagnosed with cancer-associated thrombosis and were on follow-up at Tikur Anbessa Specialized Hospital (Addis Ababa) between December 2023 and February 2024.
• Patients were excluded if they did not receive anticoagulation therapy; were treated with agents other than warfarin or XARELTO; had <1 week of follow-up; had a history of VTE; received anticoagulation therapy for indications other than cancer-associated thrombosis; initiated therapy more than 30 days after diagnosis of cancer-associated thrombosis; or had incomplete data.
• VTE was defined as imaging-confirmed venous thrombosis (usual or unusual sites). Treatment discontinuation was defined as a >7-day gap in therapy.
• Patients were assigned to one of 2 groups based on the initial anticoagulant prescribed: warfarin or XARELTO.
• Patients were retrospectively followed for 12 months, and outcomes were compared between those treated with XARELTO and warfarin.
• The primary endpoint was a composite of recurrent VTE, major bleeding events, or all-cause mortality.

Results

• Of 14,132 patients with cancer, 201 patients with cancer-associated thrombosis were included in the final analysis (XARELTO, n=98; warfarin, n=103).
• The mean (standard deviation) age was 48.4 (15.0) years; 140 (69.7%) patients were female; and the most common cancers were gynecologic (28.9%), hematologic (21.4%), and intra-abdominal (16.9%).
• The most frequent thrombotic event was deep vein thrombosis (77.1%), with a median (IQR) time to thrombosis of 3.30 (0.11-14.20) months.
• The primary composite outcome comprising recurrent VTE, major bleeding, or all-cause mortality was met in 11 (11.2%) patients treated with XARELTO vs 25.0 (24.3%) patients treated with warfarin (adjusted HR, 0.48; 95% CI, 0.24-0.97; P=0.041). See Table: Primary Outcomes With XARELTO vs Warfarin.
• The final patient outcomes were as follows: 36 patients met the composite endpoint; 89 patients completed 1 year of follow-up without developing any of the outcomes of interest. Anticoagulation therapy was discontinued in 23 patients, and 14 patients were lost to follow-up. A total of 15 patients switched treatment (warfarin to XARELTO, n=11; XARELTO to warfarin n=4) and the follow-up of 24 patients was discontinued on August 31 (prior to reaching 1 year of follow-up).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 23 March 2026.