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 patients at continued risk of DVT and/or PE is 10 mg taken orally once daily with or without food.¹
• EINSTEIN-Choice: In 3365 patients with venous thromboembolism (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 lowered the risk of a recurrent event compared to aspirin (100 mg daily), without a significant increase in major bleeding.²
  • Fatal or nonfatal VTE occurred in 1.5% of patients receiving XARELTO 20 mg and in 1.2% of patients receiving XARELTO 10 mg, as compared with 4.4% of patients 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% with XARELTO 20 mg, 0.4% with XARELTO 10 mg, and 0.3% with aspirin, while rates of clinically relevant nonmajor (CRNM) bleeding were 2.7%, 2.0%, and 1.8%, respectively. 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 CRNM bleeding, results were consistent with the overall treatment effects.
• A benefit-risk analysis of the EINSTEIN-Choice study found that compared to aspirin, extended anticoagulation with once daily XARELTO reduced recurrent VTE with a favorable benefit-risk profile.³

PRODUCT LABELING

Please refer to the following sections of the enclosed XARELTOFull Prescribing Information that are relevant to your inquiry: INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES.

The recommended dose of XARELTO for the reduction in the risk of recurrence of DVT and/or PE after at least 6 months of standard anticoagulant treatment in patients at continued risk of DVT and/or PE is 10 mg taken orally once daily with or without food.¹

CLINICAL STUDy

EINSTEIN-Choice

EINSTEIN-Choice was a phase 3, randomized, double-blind, double-dummy, event-driven, superiority 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 patients with VTE who had completed 6 to 12 months of anticoagulation therapy and for whom there was equipoise with respect to the need for ongoing anticoagulation.²

Study Design/Methods

• 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 vitamin K antagonist [VKA] or a direct oral anticoagulant [DOAC]), and had not interrupted therapy for >7 days prior to randomization; patients were excluded if they required extended anticoagulant therapy at therapeutic dosages or antiplatelet therapy, had a creatinine clearance (CrCl) <30 mL/min, or had hepatic disease associated with a coagulopathy.
• Patients were enrolled at least 24 hours after they received 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 index diagnosis (DVT or PE) and country, and then assigned to 1 of 3 groups: XARELTO 20 mg, XARELTO 10 mg, or aspirin 100 mg.
  • All study medications were given once daily with food.
• The primary efficacy outcome was symptomatic recurrent fatal or nonfatal VTE, and the principal safety outcome was ISTH major bleeding.

Results

Baseline Characteristics

• Of the 3396 patients that were enrolled, 3365 were analyzed; of these, 1107 patients were treated with XARELTO 20 mg, 1127 patients were treated with XARELTO 10 mg, and 1131 patients were treated with aspirin.
• Baseline characteristics of the patients in the EINSTEIN-Choice study are summarized in Table: EINSTEIN-Choice Baseline Demographics and Clinical Characteristics.

Efficacy/Safety

• 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 in 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 XARELTO 20 mg group, 0.4% in the XARELTO 10 mg group, and 0.3% in the aspirin group, while rates of CRNM bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of AEs was similar in all 3 groups. 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.

Benefit-Risk Analysis of EINSTEIN-Choice

Prandoni et al (2018)³ evaluated data from EINSTEIN-Choice to compare the benefit-risk profiles of extended XARELTO treatment (20 mg or 10 mg once daily) and extended aspirin treatment (100 mg once daily) in patients with VTE who had completed 6 to 12 months of anticoagulation.

• One-year cumulative incidences of recurrent VTE and major bleeding were estimated, and benefits and risks were calculated by determining between-group differences in a hypothetical population of 10,000 VTE patients treated for 1 year.
• Baseline characteristics were similar among the 3 treatment groups.
• The cumulative incidences of recurrent VTE were 1.9%, 1.6%, and 5.0% in the XARELTO 20 mg, XARELTO 10 mg, and aspirin groups, respectively.
• The cumulative incidences of major bleeding were 0.7%, 0.4%, and 0.5% in the XARELTO 20 mg, XARELTO 10 mg, and aspirin groups, respectively.
• The incidences of the combined outcome of recurrent VTE and major bleeding were 2.8% and 3.4% lower in the XARELTO 20 mg and XARELTO 10 mg groups, respectively, than in the aspirin group.
• For 10,000 patients treated for 1 year, there would be 284 (95% CI: 106-462) and 339 (95% CI: 165-512) fewer events with XARELTO 20 mg and XARELTO 10 mg, respectively, than with aspirin.
  • The number needed to treat (NNT) to prevent 1 episode of DVT or PE with XARELTO rather than with aspirin was 33 for XARELTO 20 mg and 30 for XARELTO 10 mg.
• The cumulative incidence of recurrent VTE was lower with XARELTO vs aspirin across all subgroups, while the cumulative incidence of major bleeding varied between subgroups. Net clinical benefit and NNT to number needed to harm ratio favored XARELTO across all subgroups, except for comparison of XARELTO 20 mg with aspirin in patients with cardiac disease.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases), conducted on 26 August 2024, did not identify any relevant citations pertaining to this topic.