Use of XARELTO in Reduction in the Risk of Recurrence of DVT and PE

Summary

• The recommended dose of XARELTO for the reduction in the risk of recurrence of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) after at least 6 months of standard anticoagulant treatment in adult patients at continued risk of DVT and/or PE is 10 mg taken orally once daily (OD) with or without food.¹
• There are no recommendations on the treatment of recurrent venous thromboembolism (VTE) in patients receiving XARELTOfor reduction in the risk of recurrence of DVT and of PE.¹
• ONCO PE²: In 178 patients with cancer and acute low-risk PE randomized to receive 18-month or 6-month XARELTO treatment, recurrent VTE occurred in 5/89 patients in the 18-month group vs 17/89 (19.1%) patients in the 6-month group (odds ratio, 0.25; 95% confidence interval [CI], 0.09-0.72).
  • The major secondary endpoint of major bleeding was reported in 7/89 (7.8%) patients vs 5/89 (5.6%) patients in the 18-month vs 6-month treatment group.
• In the EINSTEIN-Extension study, XARELTO demonstrated superiority compared to placebo in reducing the risk of symptomatic recurrent VTE in the intent-to-treat population (1.3% vs 7.1%; P<0.001, respectively).³
  • The principal safety outcome of major bleeding was 0.7% in the XARELTO group and 0% in the placebo group (P=0.11).
• EINSTEIN-Choice⁴: In 3365 patients with VTE who had completed 6-12 months of anticoagulation therapy and were in equipoise regarding the need for ongoing anticoagulation, XARELTO (at doses of 20 mg and 10 mg daily) significantly reduced the risk of a recurrent event compared to aspirin (100 mg daily) without a significant increase in major bleeding.
  • Fatal or nonfatal VTE occurred in 1.5% of patients receiving XARELTO 20 mg and 1.2% of patients receiving XARELTO 10 mg, as compared with 4.4% receiving aspirin (hazard ratio [HR]: 0.34 [95% CI, 0.20-0.59] and 0.26 [95% CI, 0.14-0.47], respectively; P<0.001 for both comparisons).
  • Rates of International Society on Thrombosis and Hemostasis (ISTH) major bleeding were 0.5% in the 20 mg XARELTO group, 0.4% in the 10 mg XARELTO group, and 0.3% in the aspirin group, while the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events (AEs) was similar in all 3 groups.
  • The study was designed to test the hypothesis that each dose of XARELTO would be superior to aspirin with respect to the primary efficacy outcome.
  • In prespecified subgroup analyses of the primary efficacy outcome and the composite outcome of major and clinically relevant nonmajor bleeding, results were consistent with the overall treatment effects.
• In a 2-center retrospective study that compared the efficacy and safety of XARELTO (single channel [SC]) vs XARELTO combined with aspirin (dual channel [DC]) for prevention of thrombotic events in patients with long-term inferior vena cava filter (IVCF) implantation (N=119), the incidence of combined VTE in the SC group (14/58  [24.1%]) was higher than that in the DC group (6/61 [9.8%]; HR, 0.38; 95% CI, 0.14-0.98; P=0.037). There were no significant differences in the incidence of DVT recurrence, PE, bleeding-related AEs, and all-cause mortality between the groups.⁵
• In a single-center, retrospective, observational study that compared the efficacy and safety of extended-duration and reduced-dose anticoagulation therapy in patients with cancer and VTE (N=299), recurrent VTE occurred in 12 (4%) patients; 83.3% of events were symptomatic. On-treatment recurrent VTE events occurred in 9/299 (3%) patients; 77.8% of events were symptomatic. A total of 4 (1.2%) and 10 (3.3%) patients experienced major bleeding and clinically relevant nonmajor bleeding events, respectively.⁶
• In a population-based cohort study that compared the efficacy and safety of apixaban, XARELTO, and warfarin in patients with VTE, patients on apixaban (HR, 0.67; 95% CI, 0.61-0.75) and XARELTO (HR, 0.77; 95% CI, 0.69-0.87) had a lower risk of recurrent VTE compared with those on warfarin. Patients on apixaban had a lower risk of major bleeding compared with those on warfarin (HR, 0.7; 95% CI, 0.64-0.76) and XARELTO (HR, 0.69; 95% CI, 0.63-0.75).⁷
• In a single-center, nonrandomized, observational, retrospective study that evaluated the efficacy and safety of low-intensity apixaban compared with XARELTO for extended-duration secondary prophylaxis of VTE, no statistically significant difference in the rate of VTE recurrence (99.3% vs 94.1%; P=0.176) and the rate of major bleeding (94.7% vs 92.6%; P=0.744) was found between the XARELTO vs apixaban group.⁸
• Additional citations have been included in the REFERENCES section for your review.^9-20

CLINICAL STUDIES

PROSPECTIVE RANDOMIZED STUDIES

ONCO PE Study

The ONCO PE Study² was a multicenter, open-label, adjudicator-blinded, randomized clinical study comparing 18-month XARELTO treatment with 6-month XARELTO treatment in patients with cancer and acute low-risk PE.

Key Inclusion/Exclusion Criteria:

Adult patients with active cancer who were newly diagnosed with acute low-risk PE confirmed by contrast computed tomography examination were eligible. Active cancer was defined as cancer meeting one of the following criteria: newly diagnosed cancer within 6 months of randomization; cancer treatment performed within 6 months of randomization; current cancer treatment; recurrence, local invasion, or distant metastases; and a hematopoietic malignancy that has not achieved complete remission. The key exclusion criteria were patients on anticoagulation therapy at the time of diagnosis, patients with a contraindication to rivaroxaban, and patients who were expected to have a life prognosis of ≤6 months by the treating physicians.

Study Design:

Eligible patients were randomly assigned in a 1:1 ratio to the 18-month XARELTO treatment group or the 6-month XARELTO treatment group. The XARELTO dose in both groups was 15 mg twice daily for the first 3 weeks, followed by 15 mg OD thereafter. The study included 179 patients, 178 of whom were included in the intention-to-treat analysis (18-month group, n=89; 6-month group, n=89).

Outcomes:

The primary endpoint was recurrent VTE at 18 months. The major secondary endpoint was a major bleeding event at 18 months. Other secondary endpoints were death resulting from all causes, symptomatic recurrent VTE events, and all clinically relevant bleeding events at 18 months.

Baseline characteristics are listed in Table: Select Baseline Characteristics.

Clinical outcomes are presented in Table: Clinical Outcomes at 18 Months.

The EINSTEIN-Extension Study

The EINSTEIN-Extension Study³ was a phase 3, randomized, double-blind, event-driven, superiority study comparing XARELTO 20 mg OD with placebo in patients with confirmed symptomatic PE or DVT who had been treated for 6 to 12 months with XARELTO or a vitamin K antagonist (VKA). The use of nonsteroidal anti-inflammatory drugs and antiplatelet agents was discouraged. If indicated, aspirin (up to 100 mg/day), clopidogrel (75 mg/day), or both were allowed.

Key inclusion/Exclusion Criteria: Patients with objectively confirmed, symptomatic DVT or PE, who had been treated for 6-12 months with acenocoumarol or warfarin (in the EINSTEIN studies or from routine care) or XARELTO (in the EINSTEIN studies), and who had equipoise with respect to the need for continued anticoagulation were included in the study. Patients with another indication for a VKA; creatinine clearance (CrCl) <30 mL/min; clinically significant liver disease or an alanine aminotransferase level that was >3x upper limit (ULN) of normal; bacterial endocarditis; active bleeding or a high risk of bleeding; systolic blood pressure (BP) >180 mm Hg or diastolic BP >110 mm Hg; concomitant use of strong cytochrome P450 3A4 inhibitors or inducers; or a life expectancy of <3 months were excluded from this study.

Study Design: In this study, a total of 1197 (XARELTO 602; placebo 595) patients were enrolled from February 2007 through March 2009. Of these patients, 34.1% had completed the EINSTEIN-DVT Study and 19.1% had completed the EINSTEIN-PE Study, with the remaining 560 patients (47.5%) from outside routine care. For the complete study design see Figure: EINSTEIN-Extension Study Design. In both XARELTO alone and enoxaparin-VKA treatment groups, patients were followed for their intended treatment duration and seen at fixed intervals.

Outcomes: The primary efficacy outcome was symptomatic, recurrent VTE (a composite of DVT or nonfatal or fatal PE). The principal safety outcome was major bleeding. Predefined secondary outcomes included all-cause mortality, vascular events (acute coronary syndrome, ischemic stroke, transient ischemic attack, or systemic embolism), and net clinical benefit (the composite of the primary efficacy outcome or major bleeding).

Baseline characteristics of the patients in the EINSTEIN-Extension study are shown in Table: Demographic and Clinical Characteristics. Characteristics of treatment and reasons for premature discontinuation of treatment are shown in Table: Characteristics of Treatment.

The clinical outcomes are presented in Table: Clinical Outcomes in the EINSTEIN-Extension Study. The net clinical benefit occurred in 2.0% of patients in the XARELTO group and 7.1% of patients in the placebo group (HR, 0.28; 95% CI, 0.15-0.53; P<0.001). The relative efficacy and safety outcomes were consistent across the prespecified subgroups. The combination of alanine aminotransferase level >3x ULN and bilirubin level >2x ULN was not seen in either group.

In EINSTEIN-Extension, the investigator assessed patients who were suspected of having a DVT or PE. If the investigator confirmed the diagnosis, study treatment was discontinued and standard anticoagulation was initiated at the discretion of the treating physician.²¹

EINSTEIN-CHOICE

EINSTEIN CHOICE⁴ was a phase 3, randomized, double-blind study that compared the efficacy and safety of 2 doses of XARELTO (20 mg and 10 mg, OD) with aspirin (100 mg, OD) in 3365 patients with VTE who had completed 6-12 months of anticoagulation therapy and for whom there was equipoise with respect to the need for ongoing anticoagulation. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal VTE and the principal safety outcome was ISTH major bleeding.

Key Inclusion/Exclusion Criteria: Patients were included if they had objectively confirmed, symptomatic proximal DVT or PE, were treated for 6 to 12 months with an anticoagulant including a VKA or a direct oral anticoagulant (DOAC) and had not interrupted therapy for more than 7 days prior to randomization. Patients were excluded if they required extended anticoagulant therapy at therapeutic dosages or antiplatelet therapy, had a CrCl >30 mL/min, or had hepatic disease associated with a coagulopathy.

Study Design: Patients were enrolled at least 24 hours after receiving the last dose of DOAC or, if they were receiving a VKA, when the international normalized ratio (INR) was ≤2.5. Patients were stratified according to the index diagnosis (DVT or PE) and country, and then assigned to 1 of 3 groups:

• XARELTO 20 mg
• XARELTO 10 mg
• Aspirin 100 mg
  • All study medications were given OD with food.

Outcomes: Baseline characteristics of the patients for the EINSTEIN-Choice Study are shown in Table: EINSTEIN-Choice Baseline Demographics and Clinical Characteristics.

The clinical outcomes are presented in Table: EINSTEIN-Choice Efficacy Outcomes. The primary efficacy outcome occurred in 17 of the 1107 patients (1.5%) receiving XARELTO 20 mg and 13 of the 1127 patients (1.2%) receiving XARELTO 10 mg, as compared with 50 of the 1131 patients (4.4%) receiving aspirin (HR, 0.34; 95% CI, 0.20-0.59 and HR, 0.26; 95% CI, 0.14-0.47, respectively; P<0.001 for both comparisons).

Rates of ISTH major bleeding were 0.5% in the 20-mg XARELTO group, 0.4% in the 10-mg XARELTO group, and 0.3% in the aspirin group, while rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of AEs was similar in all 3 groups. The safety outcomes are presented in Table: EINSTEIN-Choice Safety Outcomes.

For rates of recurrent VTE and major bleeding, please refer to Table: Rates of Recurrent VTE and Major Bleeding, According to Risk Profile and Duration of Anticoagulation Before Randomization.

RETROSPECTIVE STUDIES

Wang et al (2026)

Wang et al (2026)⁵ conducted a 2-center retrospective cohort study to evaluate the efficacy and safety of XARELTO combined with aspirin in the prevention of thrombotic events in patients with long-term IVCF implantation. The primary endpoint was the incidence of combined VTE. Secondary endpoints were the recurrence rate of DVT, incidence of IVCF thrombosis (IVCFT), incidence of PE, incidence of bleeding-related AEs, all-cause mortality, Venous Clinical Severity Score (VCSS), and Chronic Venous Insufficiency Questionnaire (CIVIQ-20) score.

Key Inclusion Criteria

Patients were included if they were ≥18 years old, had an IVCF implantation time of ≥12 months (defined as “long-term implantation”) with 12 months of follow-up, had been regularly administered XARELTO or a combination of XARELTO and aspirin in accordance with the doctor’s instructions, and had complete clinical data.

Study Design

All participants underwent IVCF implantation. Starting from the first day after the operation, in the SC group, XARELTO was administered at a loading dose of 15 mg twice daily for the first 21 days, followed by a maintenance dose of 20 mg OD. The dual-channel (DC) group received, in addition to the SC group regimen, enteric-coated aspirin at a daily dose of 100 mg. The study included 119 patients (SC, n=58; DC, n=61). The mean (standard deviation) age of the patients was 73.47 (7.92) years in the SC group and 72.18 (6.83) years in the DC group (P=0.343).  

Outcomes

• Efficacy outcomes: The incidence of combined VTE was 24.1% (14/58) in the SC group and 9.8% (6/61) in the DC group (HR, 0.38; 95% CI, 0.14-0.98; P=0.037). The DVT recurrence rate was 12.1% (7/58) in the SC group vs 8.2% (5/61) in the DC group (P=0.483). The incidence of IVCFT was 10.3% (6/58) in the SC group vs 1.6% (1/61) in the DC group (P=0.044). The incidence of nonfatal PE was 1.7% (1/58) in the SC group and 0% (0/61) in the DC group (P=0.303). No fatal PE event occurred in either group.
• Safety outcomes: The incidence of minor bleeding was 3.4% (2/58) in the SC group and 4.9% (3/61) in the DC group (P=0.690). No major bleeding or clinically relevant nonmajor bleeding was reported in either group. One individual died in each group (1.7%, SC group; 1.6%, DC group; P=0.971), with both deaths attributed to malignant tumors. At 12 months, the VCSS decreased in both groups compared with baseline. The mean (SD) 12-month VCSS was 4.23±1.01 in the SC group and 2.34±1.54 in the DC group (P<0.001). Additionally, at 12 months, the SC group exhibited higher scores in the total, physical, and pain dimensions of CIVIQ-20 compared with the DC group (P<0.001), while no statistically significant differences were found in scores in the social and psychological dimensions between the 2 groups.

Ogunbiyi et al (2025)

Ogunbiyi et al (2025)⁶ conducted a retrospective, single-center, observational study to compare the efficacy and safety of extended-duration and reduced-dose anticoagulation in patients with cancer and VTE.

Key Inclusion Criteria

Patients with active cancer and VTE who were switched to a prophylactic dose of anticoagulants at the discretion of their treating physician after completing at least 6 months of full-dose anticoagulation therapy were included. A prophylactic dose of anticoagulation therapy was defined as apixaban 2.5 mg twice daily, XARELTO 10 mg OD, or enoxaparin 40 mg OD (20 mg OD for weight <50 kg).

Study Design

Data on recurrent VTE, bleeding events, and mortality in the 12-month period after anticoagulant dose reduction were collected. The data were pulled from electronic health records and were manually curated. Recurrent VTE was defined as all imaging-proven PE or DVT events occurring during the 12-month study period. Major bleeding and clinically relevant nonmajor bleeding were defined based on ISTH criteria. The study included 299 patients, with anticoagulant dose reduction occurring at median of 6.2 months (interquartile range [IQR], 6-7.5) from the time of index VTE. The average age was 63 years (IQR, 53-72); 56% of patients were female.

Outcomes

• Efficacy outcomes: Recurrent VTE events occurred in 12/299 (4%) patients; 83.3% of events were symptomatic. Of these, 33.3% of recurrent VTE events occurred in the first 3 months of anticoagulant stepdown, 50% occurred during 3 to 6 months, and 16.7% occurred during 6 to 12 months. On-treatment recurrent VTE events occurred in 9/299 (3%) patients; 77.8% of events were symptomatic. Additionally, 44.4% of on-treatment recurrent VTE events occurred in the first 3 months of anticoagulant stepdown, 44.4%  occurred during 3 to 6 months, and 11.1% occurred during 6 to 12 months.
• Safety outcomes: Overall, 4/299 (1.2%) patients experienced major bleeding and 10/299 (3.3%) patients experienced clinically relevant nonmajor bleeding. The rate of all-cause mortality over the 12-month study period was 26%.

Bea et al (2025)

Bea et al (2025)⁷ conducted a population-based cohort study using 2 United States private and Medicare health insurance databases to compare the efficacy and safety of apixaban, XARELTO, and warfarin in patients with VTE, covering the period from 2016 to 2024. The primary efficacy outcome was hospitalization for recurrent VTE, and the primary safety outcome was major bleeding.

Key Inclusion Criteria

Patients were included if they were ≥18 years old with at least 1 year of continuous insurance enrollment prior to oral anticoagulant (OAC) initiation. Patients were required to initiate OAC therapy within 30 days of discharge from the initial VTE hospitalization and have no history of VTE in the year before cohort entry.

Study Design

Patients were followed up from the date after OAC initiation until the occurrence of outcome, treatment discontinuation or switch, disenrollment from insurance plan, death, or end of the study period, whichever occurred first. To adjust for confounding, propensity score-matched weights were applied to balance baseline characteristics across the 3 treatment groups. Weighted Cox hazard models were used to estimate HRs and 95% CIs. The study included a total of 163,593 patients (apixaban, n=95,734 [58.5%]; XARELTO, n=42,006 [25.7%]; warfarin, n=25,853 [15.8%]). The mean age of the patients was 71.4 years, and 56.7% were female.

Outcomes

• Efficacy outcomes: Overall, 3270 recurrent VTE events occurred. Patients on apixaban (HR, 0.67; 95% CI, 0.61-0.75) and XARELTO (HR, 0.77; 95% CI, 0.69-0.87) had a lower risk of recurrent VTE compared with those on warfarin. Apixaban showed a further decrease in recurrent VTE risk compared with XARELTO (HR, 0.87; 95% CI, 0.78-0.96).
• Safety outcomes: A total of 4229 bleeding events occurred. Patients on apixaban had a lower risk of major bleeding compared with those on warfarin (HR, 0.70; 95% CI, 0.64-0.76) and XARELTO (HR, 0.69; 95% CI, 0.63-0.75). No difference in bleeding risk was observed between XARELTO and warfarin (HR, 1.02; 95% CI, 0.92-1.12).

Lagana et al (2024)

Lagana et al (2024)⁸ conducted a single-center, nonrandomized, observational, retrospective study that evaluated efficacy and safety of low-intensity apixaban compared with XARELTO for extended-duration secondary prophylaxis of VTE in patients with a follow-up of ≥12 months. The primary efficacy outcome was the symptomatic recurrence of VTE (including fatal and nonfatal PE and DVT) and the primary safety outcome was major bleeding.

Key Inclusion Criteria

Patients were included if they were ≥18 years old, had an objectively confirmed, provoked, or unprovoked proximal DVT, PE, or both, had started extended prophylaxis with a low dose apixaban or XARELTO because of high risk of VTE recurrence due to unprovoked VTE, recurrence of VTE, residual vein obstruction, presence of a permanent IVCF or VTE with major thrombophilia.

Study Design

Acute VTE phase was treated with LMWH, VKAs or DOACs as per the clinician’s choice and the secondary extended prophylaxis was started with low-intensity apixaban 2.5 mg or XARELTO 10 mg daily. Patients were then assessed every 3-6 months during the treatment period. The median follow-up period was 25.4 months. A total of 323 patients were treated with one of the following:

• XARELTO (N=135): median age, 56.74 years; 59.3% were male; index event: 66.7% had DVT, 4.4% had PE, 28.9% had both.
• Apixaban (N=188): median age, 56.17 years; 59.0% were male; index event: 63.8% had DVT, 5.3% had PE, 30.9% had both.

Outcomes

• Efficacy outcome: A total of 3.7% VTE recurrence events were observed during the low dose therapy post which these patients were switched to full dose DOAC therapy. Thrombotic event-free-survival (tEFS) for patients on low dose DOACs was 99.4% at 1 year, 98.1% at 2 years, and 96.9% at 5 years. Four patients died but none of the deaths were related to VTE. There was no statistically significant difference in the rate of VTE recurrence between the XARELTO and apixaban groups, respectively (1/135 vs 11/188, with tEFS of 99.3% vs 94.1%, P=0.176).
• Safety outcome: During the low dose therapy, after a median treatment period of 13.6 months, 21 patients experienced bleeding events. Of them, 1 was major bleeding, 8 clinically relevant nonmajor bleeding and 12 minor bleeding. There was no statistically significant difference in the rate of bleeding events between the XARELTO and apixaban groups, respectively (7/135 vs 14/188, with bleeding event free survival of 94.7% vs 92.6%, P=0.744).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 03 August 2026.