SummarY

• A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies was conducted to provide a more detailed analysis of the efficacy and safety of XARELTO in key clinical subgroups, including patients presenting with a large clot burden. Both studies used the same protocol to ascertain outcomes.¹
• In patients with limited clot burden, recurrent venous thromboembolism (VTE) occurred in 1.3% and 2.3% of XARELTO and standard therapy patients, respectively (hazard ratio [HR]: 0.51; 95% confidence interval [CI]: 0.24-1.10). In patients with intermediate clot burden, recurrent VTE occurred in 2.2% and 2.6% of XARELTO and standard therapy patients, respectively (HR: 0.82; 95% CI: 0.54-1.24). In patients with extensive clot burden, recurrent VTE occurred in 2.6% and 2.0% of XARELTO and standard therapy patients, respectively (HR: 1.29; 95% CI: 0.78-2.15).¹
• In the limited clot burden group, a first major or nonmajor clinically relevant bleeding event occurred in 9.2% and 9.3% of XARELTO and standard therapy patients, respectively (HR: 0.97; 95% CI: 0.70-1.34). In the intermediate clot burden group, a first major or nonmajor clinically relevant bleeding event occurred in 9.7% and 10.1% of XARELTO and standard therapy patients, respectively (HR: 0.95; 95% CI: 0.78-1.17). In the extensive clot burden group, a first major or nonmajor clinically relevant bleeding event occurred in 9.3% and 10.1% of XARELTO and standard therapy patients, respectively (HR: 0.90; 95% CI: 0.71-1.15).¹
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^2-7

CLINICAL STUDIES

EINSTEIN-DVT and EINSTEIN-PE Pooled Analysis

A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies¹ was conducted in various subgroups, including patients presenting with a large clot burden. In these studies, patients were randomized to either oral XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily, or subcutaneous (SC) 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 deep vein thrombosis (DVT) or pulmonary embolism (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.

Clot burden was defined as limited if thrombosis was not above the popliteal vein or PE was confirmed to a single lobe involving ≤25% of the vasculature of that lobe. Extensive clot burden was defined by thrombosis involving the common femoral and/or iliac vein or a PE involving multiple lobes and affecting >25% of the entire pulmonary vasculature. All other results for thrombosis and PE were classified as intermediate.

There were 8282 patients enrolled; 4151 were assigned to receive XARELTO and 4131 received standard therapy (enoxaparin/VKA). Efficacy outcomes in all patients and in the selected patient subgroup are presented below in Table: Efficacy Outcomes in All Patients and Selected Patient Subgroup.

Safety outcomes in all patients and the selected patient subgroup are presented in Table: Safety Outcomes in All Patients and Selected Patient Subgroup.

EINSTEIN-DVT Dose-Ranging Study

The EINSTEIN-DVT Dose-Ranging study⁸ was a randomized, phase 2 study (N=543) that compared double-blinded oral XARELTO 20, 30, or 40 mg once daily with open-label, parenteral unfractionated heparin (started with 5000-IU bolus and 1250-IU/hour infusion) or low-molecular-weight heparin (SC tinzaparin 175 IU/kg once daily or SC enoxaparin 1.5 mg/kg once daily or SC enoxaparin 1 mg/kg twice daily) followed by an oral VKA for treatment of symptomatic acute DVT. The primary efficacy endpoint was the composite of symptomatic recurrent DVT, symptomatic fatal and nonfatal PE, and asymptomatic deteriorations in thrombotic burden (assessed by compression ultrasound and perfusion lung scan at baseline and day 84). Treatment was continued for 12 weeks.

• The primary efficacy endpoint occurred in 6.1%, 5.4%, and 6.6% of the respective XARELTO dose groups and in 9.9% of patients in the heparin/VKA group.
• Major bleeding and clinically relevant nonmajor bleeding (primary safety outcome) occurred in 5.9%, 6.0%, and 2.2% of the respective XARELTO dose groups and in 8.8% of patients in the heparin/VKA group.

ODIXa-DVT Study

The Oral, DIrect factor Xa inhibitor (ODIXa)-DVT study⁹ was a randomized, phase 2, dose-finding study (N=613) that compared double-blinded doses of XARELTO (10, 20, or 30 mg twice daily OR 40 mg once daily) with open-label standard anticoagulation (SC enoxaparin 1 mg/kg twice daily [for at least 5 days] followed by VKA) for treatment of acute proximal DVT. The primary efficacy endpoint was an improvement in thrombotic burden at day 21 (range, 18-26 days), defined as ≥4-point reduction in thrombus score (measured by complete compression ultrasound) without VTE recurrence or VTE-related death. Treatment continued for 12 weeks.

• The primary efficacy endpoint was achieved in 53%, 59.2%, 56.9%, and 43.8% of the respective XARELTO dose groups and in 45.9% of patients in the enoxaparin/VKA group.
• After 3 months, the primary efficacy endpoint was achieved in 71%, 71.4%, 73.4%, and 68.8% of the respective XARELTO dose groups and in 71.6% of patients in the enoxaparin/VKA group.
• Major bleeding rates (primary safety outcome) were 1.7%, 1.7%, 3.3%, and 1.7% in the respective XARELTO dose groups and 0% in the enoxaparin/VKA group.
• Rates of any bleeding were 5.0%, 9.4%, 10.7%, and 11.6% in the respective XARELTO dose groups and 6.3% in the enoxaparin/VKA group.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) conducted on 19 July 2024.