Summary

• A single-center, retrospective study assessed the impact of low-dose vs standard-dose XARELTO on clinical outcomes in elderly patients with nonvalvular atrial fibrillation (NVAF). At 1-year follow-up, thromboembolic events occurred in 20 patients (15.38%) in the standard-dose group and 16 patients (19.0%) in the low-dose group. This difference was not statistically significant (hazard ratio [HR], 1.13; 95% CI, 0.83-1.56; P=0.532). Major bleeding events included 2 intracranial hemorrhages in the standard-dose group and none in the low-dose group (P=0.498). All-cause mortality did not differ statistically between low-dose group vs standard-dose group (5.9% vs 4.6%; P=0.732). Unplanned cardiovascular-related readmissions were observed in 23 patients (27.4%) in the low-dose group and 26 patients (20%) in the standard-dose group.¹
• A single-center, retrospective, observational study evaluated the safety and efficacy of direct oral anticoagulants (DOACs), including XARELTO, in geriatric patients with NVAF. Patients aged ≥80 years showed a higher prevalence of all-cause and cardiovascular (CV) death, but no difference was seen in the prevalence of stroke or systemic embolism (SSE).²
• In a subgroup analysis of patients, ≥80 years old, with NVAF in the ARISTOPHANES study, the primary outcomes included stroke/systemic embolism (SSE) and major bleeding following propensity score matching. All non-vitamin K oral anticoagulants (NOACs) in comparison to warfarin were associated with a lower risk of SSE and a higher risk of major bleeding was observed in XARELTO compared to warfarin.^3,4
• An observational study evaluated the safety outcomes of XARELTO 10-20 mg once daily (OD) in elderly patients (median age, >65 years) with NVAF. Treatment with XARELTO (10 mg, 15 mg, and 20 mg) reduced the risk of mortality; however, the risk of bleeding in patients receiving XARELTO 20 mg was almost twice that in those receiving XARELTO 10 mg.⁵
• A retrospective study evaluated the efficacy and safety of XARELTO in elderly patients with atrial fibrillation (mean age, 76.6 years). In patients aged ≥85 years, reduced-dose XARELTO (10 mg) decreased the risk of allcause mortality, cardiac-related mortality, and hospitalization for heart failure compared with full-dose XARELTO (20 mg or 15 mg). In patients aged <85 years, reduced-dose XARELTO increased the risk of all-cause mortality and decreased clinically relevant bleeding complications compared with full-dose XARELTO.⁶
• A real-world, observational study evaluated treatment with low and high doses of XARELTO in elderly Chinese patients (aged ≥60 years) with newly diagnosed venous thromboembolism (VTE). Treatment with low dose of XARELTO (10 mg QD) significantly reduced the incidence of total bleeding, minor bleeding, and recurrent VTE compared with treatment with high doses of XARELTO (15 and 20 mg QD).⁷
• A systematic review of real-world studies was conducted evaluating the effectiveness, safety, costs, and healthcare utilization of XARELTO vs warfarin in elderly patients (≥65 years) with NVAF or acute VTE. The majority of the studies showed “positive” or “neutral” outcomes for stroke and systemic embolism, ischemic stroke, major bleeding, intracranial hemorrhage (ICH), and cost of stroke/systemic embolism and major bleeding. An effect was deemed “positive” when XARELTO significantly improved the outcome compared with warfarin and “neutral” when no significant relationship was observed.⁸
• In a retrospective claims database analysis evaluating effectiveness and safety of XARELTO vs warfarin in frail patients diagnosed with VTE, compared with warfarin, XARELTO was associated with significant reduction in the hazard of developing the composite of recurrent VTE or major bleeding and recurrent VTE alone. No significant difference in major bleeding was observed between cohorts.⁹
• Another retrospective claims database analysis evaluating effectiveness and safety of XARELTO, apixaban, and dabigatran vs warfarin in frail patients with NVAF found XARELTO, but not apixaban or dabigatran, to be associated with reduced hazard of SSE and ischemic stroke vs warfarin. None of these oral anticoagulants demonstrated a significant difference in major bleeding vs warfarin.¹⁰
• A nationwide, register-based cohort study from Sweden compared the bleeding risk of XARELTO with apixaban in cancer-free elderly patients (≥65 years) treated for VTE. During the primary treatment phase, XARELTO was associated with higher rates of major and gastrointestinal (GI) bleeding, with consistently elevated bleeding risk across multiple subgroups. During the secondary treatment phase, major bleeding rates remained comparable, although mortality was higher with XARELTO. Subgroup analyses showed agedependent differences in recurrence risk, favoring XARELTO in younger elderly patients (65 to <80 years) during primary treatment phase and apixaban in patients ≥80 years during secondary treatment phase.¹¹
• In the Shikoku Rivaroxaban Registry Trial (SRRT), a retrospective analysis evaluating use of XARELTO for stroke prevention in elderly patients with NVAF in Japan, compared with the control group (<80 years of age), those in the extreme elderly group (≥80 years of age) had significantly lower body weight, creatinine clearance (CrCl), and prevalence of diabetes. In contrast, the extreme elderly group had significantly higher CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores and prevalence of heart failure, stroke/transient ischemic attack (TIA), and vascular disease vs the control group. Incidence rates of cerebral infarction, ICH, and GI bleeding did not significantly differ between groups.¹²
• In a prospective follow-up evaluation consisting of patients from the DRESDEN NOAC registry in Germany, thromboembolic and bleeding outcomes were assessed in 935 patients over 80 years of age. The composite event rate (all indications) consisting of stroke, TIA, systemic embolism (SE), or VTE resulted in a 1.0 event/100 patient-years (95% confidence interval [CI]: 0.8-1.2). The overall international society on thrombosis and hemostasis (ISTH) major bleeding rate was 1.0 event/100 patient-years (95% CI: 0.8-1.2).¹³
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^14-22

Real-world evidence

Yu et al (2025)¹ conducted a single-center, retrospective study to evaluate the impact of different XARELTO doses on clinical outcomes in elderly patients with NVAF.

• Primary efficacy outcome was thromboembolic events, including stroke, myocardial infarction, and systemic embolism.
• Primary safety outcome was major bleeding (intracranial hemorrhage and bleeding requiring transfusion of >2 units of red blood cells).
• Secondary outcomes included non-major bleeding events and cardiovascular-related readmissions rates.
• Thromboembolic and bleeding risks were assessed using the CHA₂DS₂-VASc score and HAS-BLED score.
• A total of 214 elderly patients (mean [SD] age 76.93 [8.35] years; 60.2% male) diagnosed with NVAF between January and December 2022 were included. Of these, 84 received low-dose XARELTO (10 mg/day) and 130 received standard-dose XARELTO (15-20 mg/day).
• The mean (SD) age was significantly higher in the low-dose group than in the standard-dose group (79.2 [8.2] vs 75.4 [8.0] years; P=0.001), and a greater proportion of patients in the low-dose group had a history of bleeding vs standard-dose group (21.42% vs 7.79%; P=0.004).
• No significant differences were observed in CHA₂DS₂-VASc (P=0.783) or HAS-BLED scores (P=0.586) between groups.
• At 1-year follow-up, thromboembolic events occurred in 20 patients (15.38%) in the standard-dose group and 16 patients (19.0%) in the low-dose group. This difference was not statistically significant (HR, 1.13; 95% CI, 0.83-1.56; P=0.532).
• Major bleeding events included 2 intracranial hemorrhages in the standard-dose group and none in the low-dose group (P=0.498).
• All-cause mortality did not differ statistically between low-dose group vs standard-dose group (5.9% vs 4.6%; P=0.732). Unplanned cardiovascular-related readmissions were observed in 23 patients (27.4%) in the low-dose group and 26 patients (20%) in the standard-dose group.
• Kaplan-Meier analysis showed no significant differences in cumulative thromboembolic (P=0.308) or bleeding events (P=0.187).
• The standard-dose group had a significantly higher cumulative survival rate at 12 months vs low-dose group (HR, 0.61; 95% CI: 0.39-0.95; log rank P=0.03).
• Binary multivariate logistic regression analysis showed that age (odds ratio [OR], 0.95; 95% CI, 0.91-0.98; P=0.004) and a prior history of bleeding (OR, 0.36; 95% CI, 0.14-0.95; P=0.038) were independent predictors of being prescribed low-dose XARELTO.

Sabbatinelli et al (2023)² conducted a single-center, retrospective, observational study to evaluate the safety and efficacy of DOACs (dabigatran, XARELTO, edoxaban, and apixaban) in geriatric patients with NVAF.

• Primary efficacy outcome was a composite of CV death and SSE, and the primary safety outcome was thrombosis and major bleeding. Major bleeding was defined as fatal and/or symptomatic bleeding in a critical area or organ, such as the intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or bleeding leading to a fall in hemoglobin level ≥2 g/dL, or leading to transfusion of two or more units of whole blood or red cells.
• Secondary efficacy outcomes were CV death, SSE, and all-cause death. Secondary safety outcomes were minor bleeding and the composite of major or minor bleeding (total bleeding).
• Between May 2014 and May 2021, 1154 patients (median [range] age, 84 [57-100] years) who received DOACs (dabigatran [n=190], XARELTO [n=438], edoxaban [n=83], and apixaban [n=443]) for long-term anticoagulation in NVAF were included. Of these 1154 patients, 862 (74.7%) were ≥80 years old.
• During the 78-month observation period, a total of 140 events (CV death or SSE) were recorded.
• Overall, 237 (20.5%) major or minor bleeding events, including 18 (1.6%) major bleeding events were reported.
• Patients aged ≥80 years showed a higher prevalence of all-cause and CV death, but no difference was seen in the prevalence of SSE.
• During the follow-up period, 18 (1.6%) and 222 (19.2%) patients reported major and minor bleeding, respectively.
• Among patients who received the appropriate dose, the prevalence of major or minor bleeding events was comparable between age groups, but the differences for efficacy outcomes were confirmed.
• No drug-related differences were observed in the prevalence of efficacy and safety outcomes in patients aged ≥80 years.
• Among patients aged ≥80 years, the prevalence of composite primary efficacy outcomes in those who received nonrecommended low dose vs recommended dose or nonrecommended high dose of XARELTO was 17.7% vs 11.1% (P=0.033). The prevalence of composite primary efficacy outcomes in those who received nonrecommended high dose vs recommended dose or nonrecommended low dose of XARELTO was 17.6% vs 13.5% (P=0.296).
• The prevalence of major bleeding in patients ≥80 years who received nonrecommended low dose vs recommended dose or nonrecommended high dose of XARELTO was 1.5% vs 1.5% (P=0.033). The prevalence of major bleeding in those who received nonrecommended high dose of XARELTO vs recommended dose or nonrecommended low dose of XARELTO was 1.2% vs 1.5% (P=1.000).

Deitelzweig et al (2020)^3,4 conducted a retrospective, observational, subgroup analysis of the ARISTOPHANES (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) study, comparing the risk of SSE and major bleeding amongst ≥80 year old NVAF patients prescribed NOAC or warfarin.

• Data were pooled from the United States (US) Centers for Medicare & Medicaid Services (CMS) database and 3 US commercial claims databases between January 1, 2013 and September 30, 2015.
• A total of 149,761 patients were included in the study with a median follow-up time of 4 to 5 months. Following propensity score matching, in 6 matched cohorts, the XARELTO cohorts are referenced in Table: Matched Cohorts.

• Primary outcomes included SSE and major bleeding stratified by ischemic stroke, hemorrhagic stroke, SE and GI bleeding, ICH, and other bleeding respectively.
• Baseline patient characteristics were similar across all the cohorts.
• In the comparisons to warfarin, apixaban and XARELTO were associated with a lower risk of SSE, XARELTO (hazard ratio [HR]: 0.79; 95% CI: 0.71-0.88).
  • A higher risk of major bleed was observed in XARELTO (HR: 1.14; 95% CI: 1.07-1.21) compared to warfarin. Rates of SSE and major bleeding of XARELTO compared to warfarin are referenced in Table: XARELTO and Warfarin Comparisons.

• Apixaban was associated with a lower rate of SSE and major bleed compared with XARELTO (SSE, HR: 0.77; 95% CI: 0.67-0.88; major bleeding, HR: 0.53; 95% CI: 0.49-0.57. Compared to XARELTO, dabigatran had a similar risk of SSE (HR: 1.19; 95% CI: 0.93-1.52) and a lower risk of major bleeding (HR: 0.82; 95% CI: 0.72-0.94). Rates of SSE and major bleeding compared across the NOACs and XARELTO are referenced in Table: XARELTO and NOAC Comparisons.

Yu et al (2024)⁵ conducted an observational study to evaluate safety outcomes in elderly patients with NVAF treated with no anticoagulants or XARELTO 10-20 mg QD.

• The outcomes studied were 1-year all-cause mortality and bleeding, including major and other bleeding.
• Between January 2019 and December 2021, 1131 patients with NVAF were enrolled in the study. Of these, 402 did not receive any anticoagulant (median [interquartile range (IQR)] age, 76.0 [68.0-82.0] years), while 300 received XARELTO 10 mg (median [IQR] age, 76.0 [70.0-82.0] years), 301 received XARELTO 15 mg (median [IQR] age, 71.0 [65.0-75.5] years), and 128 received XARELTO 20 mg (median [IQR] age, 67.0 [64.0-70.0]).
• During the 1-year follow-up period, patients who were treated with XARELTO (all dosages) had a significantly lower risk of mortality compared with those who received no anticoagulant (10 mg, [HR: 0.14; 95% CI: 0.07-0.28; P<0.001]; 15 mg, [HR: 0.20; 95% CI: 0.09-0.43; P<0.001]; and 20 mg, [HR: 0.22; 95% CI: 0.05-0.96; P=0.044]).
• The risk of bleeding was similar between patients receiving XARELTO 15 mg and XARELTO 10 mg (HR: 0.95; 95% CI: 0.52-1.71; P=0.855). However, the risk of bleeding was almost twice as high in patients receiving XARELTO 20 mg vs those receiving XARELTO 10 mg (HR: 1.93; 95% CI: 1.02-3.65; P=0.044).

Chiou et al (2023)⁶ conducted a retrospective study of medical records to evaluate the efficacy and safety of XARELTO full-dose (20 mg/15 mg) and reduced-dose (10 mg) in elderly patients with atrial fibrillation.

• Primary efficacy outcomes were all-cause and cardiac-related mortality.
• Primary safety outcomes were rates of clinically relevant bleeding complications (including ICH, GI bleeding, and reduction in the hemoglobin level by ≥2 g/L) and bleeding complications that needed surgical intervention.
• Between December 2011 and November 2016, 2386 patients (mean [±SD] age, 76.6 [±10.5] years) with atrial fibrillation receiving XARELTO for ≥1 month were enrolled in the study (older age group, ≥85 years [n=593]; younger age group, <85 years [n=1793]).
  • Of these, 377 and 216 patients in the older age group received reduced- and full-dose XARELTO, respectively; 831 and 962 patients in the younger age group received reduced- and fulldose XARELTO, respectively.
• Efficacy and safety outcomes are presented in Table: Efficacy and Safety Outcomes.

• In patients aged ≥85 years, reduced-dose XARELTO decreased the risk of all-cause mortality (crude HR: 0.49; 95% CI: 0.27-0.89; P=0.02), cardiac-related mortality (crude HR: 0.36; 95% CI: 0.14-0.93; P=0.03), and hospitalization for heart failure (crude HR: 0.44; 95% CI: 0.26-0.72; P<0.01) compared with full-dose XARELTO.
• In patients aged <85 years, reduced-dose XARELTO increased the risk of all-cause mortality (crude HR: 2.14; 95% CI: 1.18-3.87; P=0.01) and decreased clinically relevant bleeding complications (crude HR: 0.63; 95% CI: 0.40-0.97; P=0.04) compared with full-dose XARELTO. However, there was no significant difference in the risk of cardiac-related mortality (crude HR: 1.66; 95% CI: 0.63-4.4; P=0.30) and hospitalization for heart failure (crude HR, 0.80; 95% CI, 0.55-1.15; P=0.23).
• Neither age nor dosage had any impact on the risk of MI or stroke.
• In multivariate logistic regression analyses for patients aged ≥85 years, reduceddose XARELTO decreased the risk of all-cause mortality (adjusted hazard ratio [aHR]: 0.40; 95% CI: 0.21-0.74; P<0.01) and hospitalization for heart failure (aHR: 0.54; 95% CI: 0.29-0.99; P=0.05) compared with full-dose XARELTO after adjusting for confounders. In patients aged <85 years, reduced-dose XARELTO decreased the risk of clinically relevant bleeding complications (aHR: 0.62; 95% CI: 0.39-0.97; P=0.03) and GI bleeding (at borderline significance; aHR: 0.52; 95% CI: 0.26-1.03; P=0.06) compared with full-dose XARELTO after adjusting for confounders. No other significant associations were observed between the dose of XARELTO and efficacy/safety outcomes in both age groups after adjusting for confounders.

Lu et al (2024)⁷ conducted a real-world, multicenter, observational cohort to evaluate the efficacy and safety of different doses of XARELTO in elderly Chinese patients with VTE.

• Efficacy outcome was recurrence of symptomatic VTE. Primary safety outcomes were incidence of total bleeding, major bleeding, and nonmajor clinically relevant (NMCR) bleeding.
• Between January 2019 and February 2022, 576 patients aged ≥60 years (median [IQR] age, 70 [65-77] years) with newly diagnosed VTE treated with XARELTO (10 mg [n=134]; 15 mg [n=134]; 20 mg [n=308]) were enrolled in the study. Median (IQR) duration of treatment was 100 (83-135) days. The patients were followed up for at least 3 months.
• Efficacy and safety outcomes are presented in Table: Efficacy and Safety of Different Doses of XARELTO.

• The incidence of bleeding and recurrent VTE after treatment with low and high doses of XARELTO are presented in Table: Effect of XARELTO on Incidence of Bleeding and Recurrent VTE.

• The effect of XARELTO on hematological factors is presented in Table: Effect of XARELTO on Hematological Factors.

Baker et al (2023)⁸ conducted a systematic review of real-world studies comparing the effectiveness, safety, costs, and healthcare utilization associated with XARELTO vs warfarin in elderly patients (≥65 years) with NVAF or acute VTE. The studies were identified using MEDLINE and EMBASE.

• For the NVAF studies, the outcomes evaluated were incidence of major bleeding, ICH, extracranial bleeding, stroke and/or systemic embolism (including ischemic stroke and ICH), ischemic stroke, costs, and healthcare resource utilization. For the VTE studies, the outcomes evaluated were recurrent VTE, incidence of major bleeding, ICH, extracranial bleeding, costs, and healthcare utilization.
• Effect of XARELTO on an outcome was compared with that of warfarin, and the association was deemed “positive” when XARELTO significantly improved the outcome compared with warfarin, “negative” when XARELTO significantly worsened the outcome compared with warfarin, and “neutral” when no significant relationship was observed.
• A total of 29 real-world studies published between January 2010 and April 2023 were included (NVAF [n=24]; VTE [n=5]) in the analyses. Of the 5 studies that reported comparative results in patients with recurrent VTE, 3 were neutral and 2 were positive for XARELTO.
• For stroke and systemic embolism, 16 studies (NVAF [n=16]) reported comparative results for XARELTO and warfarin; 68.8% of these studies showed “positive” outcomes, favoring XARELTO. For ischemic stroke, 14 studies (NVAF [n=14]) reported comparative results for XARELTO and warfarin; 71.4% of these studies showed “positive” outcomes, favoring XARELTO.
• For major bleeding, 26 studies (NVAF [n=23]; VTE [n=3]) reported comparative results for XARELTO and warfarin; 3.8% of these studies showed “positive” outcomes, 57.7% showed “neutral” outcomes, and 38.5% showed “negative” outcomes with XARELTO vs warfarin. For ICH, 15 studies (NVAF [n=15]) reported comparative results for XARELTO and warfarin; all studies showed “positive” or “neutral” outcomes with XARELTO vs warfarin.
• Two studies in the NVAF population showed positive effects of XARELTO vs warfarin on the cost of stroke or systemic embolism and neutral effect on the cost of major bleeding.

Frail Patients

Coleman et al (2018)⁹ conducted a retrospective claims database analysis to assess the effectiveness and safety of XARELTO vs warfarin in frail patients diagnosed with VTE.

• Frail patients who had ≥1 primary hospitalization/emergency department visit diagnosis code for VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) and received XARELTO or warfarin as their first outpatient oral anticoagulant within 30 days of the index event were identified using US Truven MarketScan claims data from January 2012 to December 2016. Patients also had to have ≥12 months of insurance prior to the index VTE event.
  • Frailty status was determined using the Johns Hopkins Claims-Based Frailty Indicator scoring algorithm (score ≥0.12 indicating frailty). This algorithm weighs 21 criteria identifiable in claims data, including demographics (eg, age, race, etc.), physical and cognitive dysfunction, and the Charlson comorbidity index.
• Patients with an atrial fibrillation or valvular heart disease claim or a prescription claim for any anticoagulant during the baseline period were excluded from the study.
• The primary endpoint was the composite of recurrent VTE or major bleeding at 12 months.
• Secondary endpoints included recurrent VTE and major bleeding as separate endpoints, ICH, and GI bleeding.
• Patient claims were tracked for up to 12 months following the index VTE event or until endpoint occurrence, discontinuation/switch of oral anticoagulant, insurance disenrollment, or end of follow-up.
• Differences in baseline covariates between cohorts were adjusted using inverse probability of treatment weights (IPTW) based on propensity scores.
• A total of 58,089 incident VTE patients were identified, of which 6869 (~12%; XARELTO, n=1365; warfarin, n=5504) were classified as frail.
• Mean age was 82 years, 36% of patients were male, 45% had a PE, and 35% had a prior hospitalization within the past 6 months. Mean time on anticoagulant treatment was 5 months and time to the first outpatient anticoagulant prescription was 6 days.
  • Baseline characteristics were well balanced following IPTW.
• Compared with warfarin, XARELTO was associated with a significant reduction in patients’ hazard of the composite of recurrent VTE or major bleeding (25% reduction; HR: 0.75; 95% CI: 0.57-0.98) and recurrent VTE alone (35% reduction; HR: 0.65; 95% CI: 0.44-0.97).
• Patients’ hazards of major bleeding (HR: 0.88), GI bleeding (HR: 0.71), and ICH (HR: 0.73) were reduced with XARELTO compared with warfarin; however, a significant difference in major bleeding was not observed between cohorts (95% CI: 0.61-1.27).

Martinez et al (2018)¹⁰ conducted a retrospective claims database analysis to assess the effectiveness and safety of apixaban, dabigatran, and XARELTO vs warfarin in frail NVAF patients treated in routine practice.

• Frail, oral anticoagulant-naïve patients with NVAF and ≥12 months of continuous insurance coverage prior to oral anticoagulant initiation were identified using US Truven MarketScan claims data from November 2011 to December 2016.
  • Frailty status was determined using the Johns Hopkins Claims-Based Frailty Indicator scoring algorithm (score ≥0.20 indicating frailty). This algorithm weighs 21 criteria identifiable in claims data, including demographics (eg, age, race, etc.), physical and cognitive dysfunction, and the Charlson comorbidity index.
• XARELTO, apixaban, and dabigatran users were 1:1 propensity score-matched to warfarin users, with residual absolute standardized differences <0.1 being achieved for all covariates after matching.
• The primary effectiveness outcome was SSE, including ischemic stroke, hemorrhagic stroke, or SE (determined by the presence of an inpatient discharge diagnosis code in the primary position); the primary safety outcome was major bleeding (determined using the validated Cunningham algorithm for detection of bleeding-related hospitalizations).
• Follow-up continued for up to 2 years or until an event (thrombotic or major bleeding outcome), insurance disenrollment, or end of study follow-up.
• A total of 5270, 2700, and 2784 patients were included in the XARELTO, apixaban, and dabigatran propensity-score matched analyses, respectively, to warfarin.
• Median age (interquartile range) for the XARELTO group (N=2635) within the XARELTO vs warfarin 1:1 propensity score-matched cohort was 85 (82, 89) years; 2.1% of patients were between 65 to 74 years of age and 97.8% were ≥75 years of age.
• At 2 years, XARELTO was associated with a reduced hazard of SSE (HR: 0.68; 95% CI: 0.49-0.95) and ischemic stroke alone (HR: 0.69; 95% CI: 0.48-0.99) vs warfarin, without significantly altering major bleeding risk (HR: 1.07; 95% CI: 0.81-1.32).
  • In contrast, neither apixaban nor dabigatran were associated with differences in SSE hazard (HR: 0.78; 95% CI: 0.46-1.35 and HR: 0.94; 95% CI: 0.60-1.45, respectively) or major bleeding hazard (HR: 0.72; 95% CI: 0.49-1.06 and HR: 0.87; 95% CI: 0.63-1.19, respectively) vs warfarin.
• Endpoint event rates for XARELTO vs warfarin at 1 and 2 years of follow-up are presented in Table: Event Rates for XARELTO vs Warfarin at 1 and 2 Years of Follow-Up.

National Patient Register

Roupe et al (2025)¹¹ evaluated the bleeding risk of XARELTO vs apixaban in cancer-free elderly patients (≥65 years) with VTE using a nationwide Swedish register-based cohort study.

• A total of 19,090 patients were included: 7572 received XARELTO and 11,518 received apixaban.
• The median age was 76 years (range: 65-100) for XARELTO users and 77 years (range: 65-100) for apixaban users.
• Apixaban users had more comorbidities (eg, heart failure, renal failure, chronic lower respiratory disease) and more concomitant medications (antiplatelets, proton pump inhibitors, selective serotonin reuptake inhibitors) compared with XARELTO users.
• Primary treatment phase (0-6 months):
  • Major bleeding occurred at rates of 4.4 (95% CI, 3.7-5.2) per 100 patient-years with XARELTO vs 3.3 (95% CI, 2.8-3.9) per 100 patient-years with apixaban.
  • The risk of major bleeding was higher with XARELTO than with apixaban (aHR, 1.46; 95% CI, 1.15-1.85).
  • Mortality rates were 12.3 (95% CI, 11.1-13.7) per 100 patients-years with XARELTO and 11.9 (95% CI, 10.9-12.9) per 100 patients-years with apixaban (aHR, 1.15: 95% CI, 1.00-1.31).
  • Subgroup analyses (age 65 to <80 years, ≥80 years, men, women) consistently showed higher bleeding risk with XARELTO.
  • The rate of GI bleeding was higher with XARELTO, 2.2 (95% CI, 1.7-2.8) per 100 patient-years, compared with rate of 1.4 (95% CI, 1.0–1.7) per 100 patient-years for apixaban (aHR, 1.79; 95% CI, 1.26-2.54).
• Secondary treatment phase (6 months to 5 years):
  • Major bleeding rates were 1.4 (95% CI, 1.2-1.7) per 100 patient-years with XARELTO vs 1.2 (95% CI, 1.0-1.5) per 100 patient-years with apixaban, with no statistically significant difference between the groups.
  • Mortality rates were 7.8 (95% CI, 7.2-8.5) per 100 patient-years with XARELTO and 6.5 (95% CI, 6.0-7.0) per 100 patient-years with apixaban (aHR, 1.27; 95% CI, 1.13-1.43).
• Recurrent PE during treatment: during the primary treatment phase, the exploratory subgroup analysis showed lower recurrence risk with XARELTO use in patients aged 65 to <80 years (aHR, 0.49; 95% CI, 0.28-0.86). During secondary treatment phase, a higher recurrence risk was observed with XARELTO use in patients ≥80 years (aHR, 1.55; 95% CI, 1.05-2.29)
• Intracranial bleeding: during the primary treatment phase, intracranial bleeding occurred at rates of 0.9 per 100 patient-years (95% CI, 0.6-1.3) with XARELTO and 0.8 per 100 patient-years (95% CI, 0.6-1.1) with apixaban. During the secondary treatment phase, the rate of intracranial bleeding was similar for both drugs, 0.5 per 100 patient-years (95% CI, 0.3-0.7) with XARELTO and 0.5 per 100 patient-years (95% CI, 0.3-0.6) with apixaban.
• Fatal bleeding: during the primary treatment phase, the rate of fatal bleeding was 0.8 per 100 patient-years (95% CI, 0.5-1.2) with XARELTO and 0.5 per 100 patient-years (95% CI, 0.3-0.8) with apixaban. During the secondary treatment phase , fatal bleeding rates were 0.3 per 100 patient-years (95% CI, 0.2-0.5) with XARELTO and 0.2 per 100 patient-years (95% CI, 0.2-0.4) with apixaban.

Registry Data (Japan)

Bando et al (2018)¹² evaluated the efficacy and safety of XARELTO in extreme elderly patients ≥80 years of age with NVAF in a retrospective study known as the SRRT.

• Of the 1339 enrolled patients with NVAF treated with XARELTO and recruited from 8 hospitals in Shikoku, Japan, 33.8% (n=453) were extreme elderly, aged ≥80 years (extreme elderly group), and 66.2% (n=886) were <80 years of age (control group).
• The average age of the study patients was 84.6±6.4 years in men (n=220) and 85.0±3.8 years in women (n=233). Among these patients, 234 (119 men and 115 women) were between 80-84 years of age, 180 (84 men and 96 women) were between 85-89 years of age, 35 (17 men and 18 women) were between 90-94 years of age, and 4 (4 women) were between 95-100 years of age.
• In the extreme elderly group, 41.5% (n=188) of patients had low body weight (<50 kg), a proportion that was significantly higher (P<0.001) than that seen in the control group (13.1%); among these patients with low body weight in the extreme elderly group, 84.6% (n=159) had abnormal renal function (CrCl <50 mL/min).
• The average XARELTO treatment duration was 11.6±10.2 months and 12.1±9.1 months in the extreme elderly group and the control group, respectively.
• Mean CHADS₂, CHA₂DS₂-VASc, and HAS BLED scores in the extreme elderly group were 2.7, 4.4, and 2.3, respectively; all scores were significantly higher than those observed in the control group (P<0.001).
• Compared with the control group, the extreme elderly group had a significantly higher prevalence (P<0.001) of heart failure, stroke/TIA, and vascular disease, but a significantly lower prevalence (P<0.05) of diabetes.
• The average CrCl was significantly lower in the extreme elderly group vs the control group (45.4±16.1 ml/min vs 75.1±26.0 ml/min, respectively; P<0.001).
• The average XARELTO dose was 10.9±2.0 mg/day in the extreme elderly group, which was significantly lower than that in the control group (13.3 mg/day) (P<0.001).
  • Dosing criteria was met by 73.5% (n=333) of patients in the extreme elderly group; of these, 81.2% received XARELTO 10 mg daily.
• Within the extreme elderly group, cerebral infarction occurred in 4 patients (0.94%/person year), with 2 of these 4 patients being high-risk patients with a CHADS₂ score of ≥3, and ICH and GI bleeding occurred in 4 patients each (0.89%/person year and 0.93%/person year, respectively); incidence rates for these events were not significantly different from the control group.
• Patients who experienced cerebral infarction had been treated with a reduced XARELTO dose compared to that recommended by the dosing criteria.

DRESDEN NOAC Registry

Beyer-Westendorf et al (2018)¹³ evaluated the safety and efficacy of NOACs in patients over 80 years of age using prospective follow-up in the DRESDEN NOAC registry in Germany.

• A total of 935 patients were ≥80 years of age (mean age of 84.2 years). The NOACs consisted of XARELTO (487 [52.1%]), apixaban (198 [21.2%]), edoxaban (165 [17.6%]), and dabigatran (85 [9.1%]). The indications for treatment included NVAF (752 [80.4%]), VTE (179 [19.1%]), and other indications (4 [0.4%]).
• Patients were assessed via quarterly phone interviews to determine thromboembolic and bleeding outcomes.
• The mean follow-up in the intention-to-treat (all events) group was 970.7±642.2 days with a mean NOAC exposure of 815.3±64.5 days.
  • The composite event rate (all indications) consisted of stroke, TIA, SE, or VTE resulted in 1.0/100 patient-years (95% CI: 0.8-1.2). In the NVAF patients, the event rate for stroke, TIA, SE was 1.0/100 patient-years (95% CI: 0.8-1.2). In the VTE patients, the rate of recurrent DVT or PE was 0.4/100 patient-years (95% CI: 0.20.7).
• The overall ISTH major bleeding rate was 1.0/100 patient-years (95% CI: 0.8-1.2). The rate of bleeding was higher in the NVAF patients (1.2/100 patient-years; 95% CI: 0.91.5) compared to the VTE patients (0.4/100 patient-years; 95% CI: 0.2-0.7).
• A total of 120 patients (1.3/100 patient-years; 95% CI: 1.1-1.6) from the cumulative 255 (2.2/100 patient-years; 95% CI: 2.0-2.5) deaths occurred during or within 3 days of the last dose of NOAC.
  • CV events (n=86) was the most common cause of death which consisted of acute coronary syndrome (n=20), ischemic strokes (n=19), VTE (n=17), and SE (n=2). An additional 123 deaths were ruled potentially related to CV events.
  • Additional deaths were associated with age related (n=79), sepsis/infection (n=40) terminal malignant disease (n=26), fatal bleeding (n=11), and other reasons (n=13).
  • Most of the 58 fatal thromboembolic events were observed following the discontinuation of anticoagulation.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 20 February 2026.