Summary

Use in Venous Thromboembolism (VTE)

• A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies was conducted to provide a detailed analysis of the efficacy and safety of XARELTO in key clinical subgroups, including fragile patients.¹
  • In fragile patients, recurrent VTE occurred in 2.7% and 3.8% of XARELTO and standard therapy patients, respectively (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.39-1.18). In nonfragile patients, recurrent VTE occurred in 1.9% of XARELTO and standard therapy patients (HR, 0.98; 95% CI, 0.69-1.38).¹
  • Rates of major bleeding were significantly lower in the XARELTO treated group (1.3%) compared with the standard-therapy group (4.5%) in fragile patients (HR, 0.27; 95% CI, 0.13-0.54; absolute risk reduction (RR), 3.2%; 95% CI, 1.6-4.9). Rates of major bleeding were lower in the XARELTO treated group (0.9%) compared with the standard-therapy group (1.1%) in nonfragile patients (HR, 0.80; 95% CI, 0.49-1.29; P-value=0.01 for interaction).¹
• In a prospective analysis of consecutive, fragile patients presenting with acute VTE receiving XARELTO or apixaban for initial and for long-term therapy and enrolled in Registro Informatizado de Enfermedad Trombo Embòlica (RIETE), there was no statistical difference in the risk of the composite outcome of recurrent VTE and major bleeding when comparing XARELTO and apixaban for the entire cohort, both recommended and non-recommended doses (HR, 1.72; 95% CI, 0.63-4.69; P=0.292). When comparing only recommended doses, there was no statistical difference in the composite outcome between XARELTO and apixaban (HR, 1.34; 95% CI, 0.35-5.06; P=0.667).²
• In a retrospective analysis of claims data from January 2012 to December 2016, frail patients using XARELTO had a reduction in the hazard of composite outcome of recurrent VTE or major bleeding (HR, 0.75; 95% CI, 0.57-0.98) and recurrent VTE (HR, 0.65; 95% CI, 0.44-0.97) vs warfarin.³

Use in Coronary Artery Disease (CAD) and/or Peripheral Artery Disease (PAD)

• In a subanalysis of the VOYAGER PAD trial that evaluated the efficacy and safety of low-dose XARELTO plus aspirin to aspirin monotherapy in patients with symptomatic PAD undergoing revascularization, frailty status did not impact the effect of XARELTO on the primary efficacy and safety outcomes. Primary efficacy endpoint was composite (time to first occurrence) of acute limb ischemia (ALI), major amputation of vascular causes, myocardial infarction (MI), ischemic stroke, or CV death (frail HR, 0.93; 95% CI, 0.75-1.15; nonfrail HR, 0.83; 95% CI, 0.72-0.97; P interaction=0.37). Primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding (frail HR, 1.54; 95% CI, 0.82-2.91; nonfrail HR, 1.37; 95% CI, 0.84-2.23; P interaction=0.65).⁴
• In a subanalysis of the COMPASS trial that evaluated the efficacy and safety of aspirin alone vs XARELTO plus aspirin in patients with chronic atherosclerotic vascular disease, there was a significant difference found between the frail and nonfrail groups. Primary efficacy endpoint was the composite of MI, stroke, or CV death (nonfrail HR, 0.69; 95% CI, 0.59-0.80; frail HR, 1.06; 95% CI, 0.79-1.42; P interaction=0.011). Primary safety endpoint was major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria (nonfrail HR, 1.87; 95% CI, 1.51-2.31; frail HR, 1.10; 95% CI, 0.71-1.70; P interaction=0.032).⁵

Use in Nonvalvular Atrial Fibrillation (NVAF)

• In a subanalysis of a retrospective study (RIVA-DM) that evaluated the impact of age (<80 vs ≥80 years) on the effectiveness and safety of XARELTO vs warfarin in patients with NVAF and type 2 diabetes mellitus (T2DM), no significant interaction for XARELTO vs warfarin by age was observed for any outcome, including stroke/systemic embolism (SSE; HR, 0.95; 95% CI, 0.87-1.04; P_interaction, ≥0.23 vs HR, 1.05; 95% CI, 0.92-1.19) and hospitalization for major or clinically relevant nonmajor bleeding (CRNMB; HR, 0.90; 95% CI, 0.84‑0.96; P_interaction, ≥0.23 vs HR, 1.06; 95% CI, 0.96-1.18).⁶
• A retrospective analysis was conducted to evaluate the efficacy and safety of oral anticoagulation (OAC) vs non-OAC therapy and compare the clinical outcomes of XARELTO with those of warfarin therapy in frail patients with atrial fibrillation (AF). The weighted event rate for net adverse clinical event (NACE) was lower for XARELTO (22.6/100 person-years [PYs]) compared with warfarin (30.4/100 PYs) during the 1-year follow up period. The weighted event rates for NACE were 20.8/100 PYs and 21.8/100 PYs for XARELTO and warfarin, respectively, during the overall follow up period.⁷
• A retrospective, observational study was conducted to evaluate the impact of frailty on the clinical outcomes of direct oral anticoagulants (DOACs), including XARELTO, dabigatran, and apixaban, vs warfarin therapy in older patients with AF. The rates of composite event for XARELTO and warfarin, respectively, were 200.8/1000 PYs and 219.8/1000 PYs (HR, 0.96; 95% CI, 0.89-1.04; rate difference [RD], -19.0; 95% CI, 35.2 to 2.9) in the frail patient population.⁸
• In a subgroup analysis of frail NVAF patients (N=150,487) in the ARISTOPHANES study, XARELTO (N=42,228) use was associated with a lower risk of the combined outcome of stroke and SE compared to warfarin (HR, 0.79; 95% CI, 0.72-0.87; P<0.001). Compared to XARELTO, apixaban (N=35,780) was associated with a lower risk of the combined outcome of stroke and SE (HR, 0.80; 95% CI, 0.70-0.90; P<0.001). Compared to dabigatran (N=9324), XARELTO was associated with a similar risk of stroke and SE (HR, 1.03; 95% CI, 0.83-1.28; P=0.795).⁹
• In a retrospective analysis of claims data from November 2011 to December 2016, frail patients with NVAF using XARELTO were evaluated after 2 years. XARELTO patients were associated with a reduced hazard of SE (HR, 0.68; 95% CI, 0.49-0.95) and ischemic stroke alone (HR, 0.69; 95% CI, 0.480.99) vs warfarin, without significantly altering major bleeding risk (HR, 1.07; 95% CI, 0.81-1.32).¹⁰
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^11-16

CLINICAL STUDIES

Use in Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE)

EINSTEIN-DVT and EINSTEIN-PE Pooled Analysis

A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies¹ was conducted in subgroups, including fragile patients who were defined as those meeting 1 or more of the following criteria: age >75 years, calculated CrCl <50 mL/min, and/or low body weight (≤50 kg). Patients were randomized to either oral XARELTO 15 mg twice daily for 3 weeks, followed by 20 mg once daily or subcutaneous enoxaparin 1.0 mg/kg twice daily for at least 5 days in combination with a vitamin K antagonist (VKA) started within 48 hours of randomization, for a treatment duration of 3, 6, or 12 months in patients with symptomatic DVT or PE. The primary efficacy outcome was symptomatic recurrent VTE, which was defined as a composite of fatal or nonfatal PE or DVT. The principal safety outcome was clinically relevant bleeding, which was defined as a composite of major and clinically relevant nonmajor bleeding.

There were 8282 patients enrolled; 4151 were assigned to receive XARELTO and 4131 received standard therapy (enoxaparin/VKA). Nineteen percent (n=1573) of patients were categorized as fragile because of age (n=1279), moderate or severe renal impairment (n=649), or low body weight (n=107). Efficacy outcomes in all patients and selected patient subgroups are presented in the Table: Efficacy Outcomes in All Patients and Selected Patient Subgroup.

Safety outcomes in all patients and selected patient subgroup are presented in the Table: Safety Outcomes in All Patients and Selected Patient Subgroup. In fragile patients, a first major or nonmajor clinically relevant bleeding event occurred in 12.3% and 14.0% of XARELTO and standard therapy patients, respectively (HR, 0.85; 95% CI, 0.64-1.11). In nonfragile patients, a first major or nonmajor clinically relevant bleeding event occurred in 8.7% and 9.1% of XARELTO and standard therapy patients, respectively (HR, 0.95; 95% CI, 0.81-1.12). In fragile patients, the rate of major bleeding was significantly lower in the XARELTO group than the standard therapy group.

EINSTEIN-DVT and EINSTEIN-PE Pooled Subanalysis

Wang et al (2013)¹⁷ conducted a subgroup analysis of the EINSTEIN-DVT and EINSTEINPE studies to assess the efficacy and safety of XARELTO in 439 Chinese patients. There were 211 patients with a DVT only, and 228 patients that had a PE with (n=67) or without (n=161) DVT. The primary efficacy outcome (symptomatic recurrent VTE) occurred in 7 patients (3.2%) in both XARELTO and enoxaparin-VKA groups (HR, 1.04; 95% CI, 0.36-3.0). The principal safety outcome (major or clinically relevant nonmajor bleeding) occurred in 13 patients (5.9%) in the XARELTO group compared with 20 patients (9.2%) in the enoxaparin-VKA group (HR, 0.63; 95% CI, 0.31-1.26). In the fragile Chinese patients (n=91), the principal safety outcome occurred in 4 patients (8.9%) in the XARELTO group compared with 7 patients (15.2%) in the enoxaparin-VKA group. Efficacy and safety outcomes in this subgroup analysis of Chinese patients are consistent with overall findings in the EINSTEIN-DVT and EINSTEIN-PE pooled analysis.

Use in CAD and/or PAD

Canonico et al (2024)⁴ conducted a subanalysis of VOYAGER PAD, which was a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of XARELTO 2.5 mg twice daily plus 100 mg aspirin with aspirin 100 mg in patients with symptomatic PAD undergoing revascularization.

This subanalysis compared the outcomes of 1674 frail patients vs 4670 nonfrail patients from the VOYAGER PAD trial. Patients were categorized as frail if age >75 years or weight ≤50 kg, or baseline estimated glomerular filtration rate <50 mL/min/1.73 m². In the frail and nonfrail groups, respectively, the median ages were 77 and 64 years; 40.6% and 20.8% were women.

• In the intention-to-treat analysis, the 3-year Kaplan-Meier cumulative incidences of the primary efficacy endpoint (composite [time to first occurrence] of acute limb ischemia, major amputation of vascular causes, MI, ischemic stroke, or CV death) was not modified by frailty status.
  • Frail XARELTO vs placebo 20.8% vs 23.6% (HR, 0.93; 95% CI: 0.75-1.15); nonfrail 14.3% vs 18.3% (HR, 0.83; 95% CI: 0.72-0.97); P interaction=0.37.
• In the on-treatment safety analysis, the 3-year Kaplan-Meier cumulative incidences of the primary safety endpoint (TIMI major bleeding) was not modified by frailty status.
  • Frail XARELTO vs placebo 4.6% vs 4.3% (HR, 1.54; 95% CI: 0.82-2.91); nonfrail 2.1% vs 1.5% (HR, 1.37; 95% CI: 0.84-2.23); P interaction=0.65
• Efficacy and safety outcomes in this subgroup analysis of fragile patients are consistent with overall findings in the VOYAGER PAD trial.

Leong et al (2024)⁵ conducted a post hoc analysis of the COMPASS trial, which was a randomized controlled trial that evaluated the efficacy and safety of 100 mg aspirin daily plus 2.5 mg XARELTO twice daily, 5 mg XARELTO twice daily, or aspirin 100 mg daily in patients with chronic atherosclerotic vascular disease. In this subanalysis, the impact of frailty on the outcomes for XARELTO plus aspirin compared to aspirin monotherapy were evaluated in 3515 frail patients (mean age, 68 years; 65% male) and 23,880 nonfrail patients (mean age 68.3 years; 80% male). Frailty was defined by the frail index, a ratio of age-related deficits identified over the total list of age-related deficits, where nonfrail patients scored ≤-0.2 and frail were >2.

• There was a significant difference between frail and nonfrail groups. Adding XARELTO to aspirin in nonfrail patients reduced the primary efficacy outcome (composite of MI, stroke, or CV death) and increased the primary safety outcome (major bleeding defined by ISTH criteria). However, the impact of these outcomes among frail patients was not evident.
• Composite of MI, stroke, or CV death; nonfrail vs frail, P interaction=0.011
  • Nonfrail group: aspirin alone (n=7939) vs XARELTO plus aspirin (n=7992): 5.1% vs 3.6% (HR, 0.69; 95% CI, 0.59-0.80); P<0.0001.
  • Frail group: aspirin alone (n=1187) vs XARELTO plus aspirin (n=1160): 7.4% vs 8.1% (HR, 1.06; 95% CI, 0.79-1.42); P=0.70.
• Major bleeding; nonfrail vs frail, P interaction=0.032
  • Nonfrail group: aspirin alone (n=7939) vs XARELTO plus aspirin (n=7992): 1.7% vs 3.1% (HR, 1.87; 95% CI, 1.51-2.31); P<0.0001.
  • Frail group: aspirin alone (n=1187) vs XARELTO plus aspirin (n=1160): 3.2% vs 3.6% (HR, 1.10; 95% CI, 0.71-1.70); P=0.68

Use in NVAF

Retrospective Studies

Coleman et al (2022)⁶ conducted a subanalysis of a retrospective study (RIVA-DM) that used data from the United States (US) Optum^® De-Identified electronic health record database from November 2010 to December 2019 to evaluate the impact of age (<80 vs ≥80 years) on the effectiveness and safety of XARELTO vs warfarin in patients with NVAF and T2DM.

• Adult patients with NVAF and T2DM who were newly initiated on XARELTO or warfarin were stratified into 2 subgroups, <80 and ≥80 years.
• The primary outcomes included the incidence rates of developing SSE (effectiveness outcome) and hospitalization due to major or CRNMB (safety outcome).
• Overall, 32,078 XARELTO and 83,971 warfarin users were identified and included in the main analysis.
  • A total of 25,472 XARELTO and 58,636 warfarin users were <80 years old, and 6606 XARELTO and 25,335 warfarin users were ≥80 years old.
• After propensity score-overlap weighting in the <80 vs ≥80 years subgroups (XARELTO group), the mean age was 67 (standard deviation [SD], 9) vs 83 (SD, 2) years, the mean CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥75 [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 and sex category [female]) score was 3.8 (SD, 1.3) vs 4.4 (SD, 1.2) , and the modified HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio [INR], elderly, drugs/alcohol concomitantly) score was 1.4 (SD, 0.8) vs 1.7 (SD, 0.7), respectively.
• After propensity score-overlap weighting in the <80 vs ≥80 years subgroups (warfarin group), the mean age was 67 (SD, 8) vs 83 (SD, 2) years, the mean CHA₂DS₂-VASc score was 3.8 (SD, 1.3) vs 4.4 (SD, 1.2), and the modified HAS-BLED score was 1.4 (SD, 0.8) vs 1.7 (SD, 0.7), respectively.
• Both the XARELTO and warfarin groups had a hospital frailty score of 38.0 (intermediate risk) and 15.9 (high risk) in the <80 year subgroup and 38.7 (intermediate risk) and 25.6 (high risk) in the ≥80 year subgroup.
• The mean duration of follow-up for XARELTO and warfarin was 2.9 (SD, 1.9) and 2.9 (SD, 2.0) years, respectively.
• Incidence rates of SSE, hospitalization for major or CRNMB are referenced in Table: XARELTO and Warfarin Comparisons in Patients Aged <80 vs ≥80 Years.

Kim et al (2022)⁷ conducted a retrospective analysis, based on the national health claims database in Korea, to evaluate the efficacy and safety of OAC vs non-OAC therapy and compare the clinical outcomes of DOACs, including XARELTO, dabigatran, apixaban, and edoxaban, with those of warfarin therapy in frail patients with AF.

• The Hospital Frailty Risk Score was determined retrospectively using the available International Classification of Disease, Tenth Revision (ICD-10) diagnostic codes that were documented before the index date.
• Among 28,547 fragile patients with AF undergoing OAC therapy, 7519 (26.3%) and 9808 (34.4%) received XARELTO and warfarin therapies, respectively; the mean duration of follow-up was 12.3 months. XARELTO treatment was associated with lower risks of NACE, ischemic stroke, major bleeding, and CV death compared with warfarin. Clinical outcomes of XARELTO vs warfarin therapy in fragile patients with AF are presented in the Table: Outcomes of DOAC Treatment Compared With Warfarin Treatment After Inverse Probability of Treatment Weighting.

Kim et al (2021)⁸ conducted a retrospective, observational study using Medicare data to evaluate the impact of frailty on the clinical outcomes of DOACs, including XARELTO, dabigatran, and apixaban, vs warfarin in older patients with AF.

• Frailty was measured using a validated claims-based frailty index (CFI). Using accepted cutpoints, patients were classified as frail if the CFI was ≥0.25. Nonfrailty and prefrailty corresponded to the CFIs of <0.15 and 0.15-0.24, respectively.
• In the propensity score-matched cohort of patients treated with XARELTO (n=137,972) and warfarin (n=137,972), the mean age was 76.8 (SD, 7.2) years in the XARELTO group and 76.8 (SD, 7.3) years in the warfarin group; 49.9% of patients were female in both the groups. The mean CHA₂DS₂-VASc and HASBLED scores were 4.1 (SD, 1.6) and 2.1 (SD, 0.7), respectively, for both the groups.
• Clinical outcomes associated with XARELTO vs warfarin therapy in frail patients are presented in the Table: Outcomes of DOAC Treatment Compared With Warfarin in Propensity Score-Matched Clinical Care Frail Population⁷.

Lip et al (2020)⁹ conducted a 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 stroke or SE and major bleeding amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants or warfarin.

• Data were pooled from the US Centers for Medicare and Medicaid Services (CMS) Medicare database and 3 US commercial claims databases: the commercial section of IQVIA PharMetrics Plus™ Database, the Optum Clinformatics™ Data Mart, and the Humana Research Database between January 1, 2013, and September 30, 2015. These databases account for over 123 million beneficiaries.
  • A total of 150,487 patients were included in this study (35,780 apixaban, 9324 dabigatran, 42,228 XARELTO, and 63,155 warfarin). Following 1:1 propensity-score matching, a total of 39,898 XARELTO-warfarin, 34,138 apixaban-XARELTO, and 9235 dabigatran-XARELTO pairs were matched.
• Frailty was defined with an algorithm previously described by Segel et al based on the Fried phenotype for frailty. In the final model, 21 variables were included in the predicted probability of frailty (range: 0-1) over a 12-month baseline period. A probability cut-off of 0.20 was utilized to classify individuals as frail, yielding a sensitivity of 35% and specificity of 91%.
• Among elderly frail NVAF patients, XARELTO use was associated with a lower risk of the combined outcome of stroke and SE compared to warfarin (HR, 0.79; 95% CI, 0.72-0.87; P<0.001), including a lower risk of the components of ischemic (HR, 0.82; 95% CI, 0.73-0.92; P<0.001) and hemorrhagic stroke (HR, 0.68; 95% CI, 0.55-0.83; P<0.001), but not SE alone (HR, 1.02; 95% CI, 0.66-1.58; P<0.001), compared to warfarin. XARELTO was associated with a higher risk of major bleeding (HR, 1.14; 95% CI, 0.1.08-1.21; P<0.001) and gastrointestinal bleeding (HR, 1.31; 95% CI, 1.21-1.43; P<0.001), but a lower risk of intracranial hemorrhage (HR, 0.70; 95% CI, 0.61-0.81; P<0.001), compared with warfarin.
  • Apixaban was the only other nonvitamin K oral anticoagulant (NOAC) associated with a lower risk of the combined outcome of stroke and SE (HR, 0.61; 95% CI, 0.550.69; P<0.001) compared with warfarin, as well as the components of ischemic (HR, 0.70; 95% CI, 0.62-0.79; P<0.001) and hemorrhagic stroke (HR, 0.39; 95% CI, 0.29-0.53; P<0.001), and SE (HR, 0.42; 95% CI, 0.23-0.76; P=0.004).
• Compared with XARELTO, apixaban was associated with a lower risk of the combined outcome of stroke and SE (HR, 0.80; 95% CI, 0.70-0.90; P<0.001), as well as the individual components of the combined outcome. Apixaban was also associated with a lower risk of major bleeding (HR, 0.53; 95% CI, 0.50-0.57; P<0.001), gastrointestinal bleeding (HR, 0.46; 95% CI, 0.42-0.50; P<0.001), and intracranial hemorrhage (HR, 0.55; 95% CI, 0.49-0.69; P<0.018).
• Compared with XARELTO, dabigatran was associated with a similar risk of stroke and SE (HR, 1.03; 95% CI, 0.83-1.28; P=0.795) and the components of ischemic stroke and SE, but a lower risk of hemorrhagic stroke (HR, 0.55; 95% CI, 0.31-0.98; P<0.041). Dabigatran was also associated with a lower risk of major bleeding (HR, 0.71; 95% CI, 0.63-0.80; P<0.001), gastrointestinal bleeding (HR, 0.77; 95% CI, 0.66-0.89; P=0.001), and a similar rate of intracranial hemorrhage (HR, 0.74; 95% CI, 0.50-1.10; P=0.134).
• An additional subgroup analysis by dose (standard-dose: apixaban 5 mg twice a day (BID), dabigatran 150 mg BID, XARELTO 20 mg once a day (QD); lower-dose: apixaban 2.5 mg BID, dabigatran 75 mg BID, XARELTO 15 mg/10 mg QD) showed generally consistent results with the main analysis.

Martinez et al (2018)¹⁰ evaluated US Truven MarketScan administrative claims data from November 2011 to December 2016, regarding patients identified as frail. The effectiveness and safety of XARELTO, apixaban, or dabigatran vs warfarin was assessed in NVAF patients.

• Frailty status was determined using the Johns Hopkins Claims-Based Frailty Indicator scoring algorithm (score ≥0.20 indicating frailty).
• A total of 5270, 2700, and 2784 patients were included in the XARELTO, apixaban, and dabigatran propensity-score matched analyses, respectively, to warfarin.
• At 2 years, XARELTO was associated with a reduced hazard of SE (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 stroke SE 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.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 04 September 2024.