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 with or without food.¹
• There are no recommendations on the treatment of recurrent VTE in patients receiving XARELTOfor reduction in the risk of recurrence of DVT and of PE.¹
• In the EINSTEIN-Extension study, XARELTO demonstrated superiority compared to placebo in reducing the risk of symptomatic recurrent venous thromboembolism (VTE) in the intent-to-treat population (1.3% vs 7.1%; P<0.001, respectively).²
  • The principal safety outcome of major bleeding was 0.7% in the XARELTO group and 0% in the placebo group (P=0.11).
• EINSTEIN-Choice³: 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% confidence interval [CI], 0.20-0.59 and HR, 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 single-center, non-randomized, observational, retrospective study that evaluated efficacy and safety of low-intensity apixaban compared to 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 and apixaban groups, respectively.⁴
• Additional citations have been included in the REFERENCES section for your review.^5-12

CLINICAL STUDIES

PROSPECTIVE RANDOMIZED STUDIES

The EINSTEIN-Extension Study

The EINSTEIN-Extension Study² was a phase 3, randomized, double-blind, event-driven, superiority study comparing XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6 to 12 months with XARELTO or 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.¹³

EINSTEIN-CHOICE

EINSTEIN CHOICE³ was a phase 3, randomized, double-blind study that compared the efficacy and safety of 2 doses of XARELTO (20 mg and 10 mg, once daily) with aspirin (100 mg, once daily) 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 once daily 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 STUDY

Lagana et al (2024)

Lagana et al (2024)⁴ conducted a single-center, non-randomized, observational, retrospective study that evaluated efficacy and safety of low-intensity apixaban compared to 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 inferior vena cava filter 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 21 August 2024.