Summary

• The recommended dose of XARELTO in adults for the initial treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) is 15 mg taken orally twice daily with food for the first 21 days. After this initial treatment period, the recommended dose of XARELTOis 20 mg taken orally once daily with food, at approximately the same time each day.¹
• In the EINSTEIN-DVT study, XARELTO demonstrated noninferiority to the standard therapy group in reducing the risk of symptomatic recurrent venous thromboembolism (VTE) in the intent-to-treat population (2.1% vs 3.0%, respectively; P<0.001). The principal safety outcome of clinically relevant bleeding was 8.1% in both groups (P=0.77).²
• There are no recommendations on the treatment of recurrent VTE in patients receiving XARELTO for reduction in the risk of recurrence of DVT and of PE.
• Additional citations were identified during a literature search and are included in the REFERENCES section for your review.^3,4

CLINICAL STUDIES

The EINSTEIN-DVT Study

The EINSTEIN-DVT Study² was a phase 3, randomized, open-label, event-driven, noninferiority trial that compared oral XARELTO alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (1.0 mg/kg twice daily) in combination with a vitamin K antagonist (VKA) in patients with confirmed symptomatic DVT without symptomatic PE.

Inclusion/Exclusion Criteria

Patients of legal age for consent and with acute, symptomatic, objectively-confirmed proximal DVT, without symptomatic PE, were included in the study. Patients were excluded if they received therapeutic doses of low-molecular-weight heparin, fondaparinux, or unfractionated heparin for more than 48 hours, or if they had received more than a single dose of a VKA before randomization; if they had been treated with thrombectomy, a vena cava filter, or a fibrinolytic agent for the current episode of thrombosis; or if they had any contraindication listed in the labeling of enoxaparin, warfarin, or acenocoumarol. Patients with another indication for a VKA; creatinine clearance <30 mL/min; clinically significant liver disease (eg, acute hepatitis, chronic active hepatitis, or cirrhosis) or an alanine aminotransferase level that was >3x upper limit of normal; bacterial endocarditis; active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; systolic blood pressure (BP) >180 mm Hg or diastolic BP >110 mm Hg; childbearing potential without proper contraceptive measures; pregnancy or breast-feeding; concomitant use of strong cytochrome P-450 3A4 inhibitors or inducers; participation in another experimental pharmacotherapeutic program within 30 days before screening; or a life expectancy of <3 months were also excluded from this study.

Study Design

The study consisted of treatment duration from March 2007 to September 2009 and enrolled a total of 3449 patients (XARELTO: 1731; enoxaparin-VKA: 1718). 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 VKA started within 48 hours of randomization, for a treatment duration of 3, 6, or 12 months in patients with confirmed symptomatic DVT without symptomatic PE. Enoxaparin was discontinued when the patients’ international normalized ratio (INR) was 2.0 or more for 2 consecutive days and they received at least 5 days of enoxaparin treatment. 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. For the number of patients enrolled in the study and included in the efficacy and safety analysis, see Figure: EINSTEIN-DVT Study-Patient Disposition. In both the 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 clinically relevant bleeding, defined as the composite of major or clinically relevant nonmajor bleeding (CRNM). Predefined secondary outcomes included all-cause mortality, vascular events (acute coronary syndrome, ischemic stroke, transient ischemic attack, or systemic embolism), and net clinical benefit (defined as the composite of the primary efficacy outcome or major bleeding [MB]).

Of the patients taking enoxaparin-VKA, the median duration of enoxaparin treatment was 8 days (interquartile range [IQR], 6-11), and the INR at end of treatment was at least 2.0 in 80.8% of patients. INR was in therapeutic range 57.7% of the time during the study. Baseline characteristics were similar between the XARELTO and enoxaparin-VKA groups, which are displayed in Table: Demographic and Clinical Characteristics. Characteristics of treatment and reasons for premature discontinuation of treatment are shown in Table: Characteristics of Treatment.

Efficacy/Safety Results

The clinical outcomes are presented in Table: Clinical Outcomes in the EINSTEIN-DVT Study. By day 21, the primary efficacy outcome occurred in 1.2% of patients in the XARELTO group and 1.7% of patients in the enoxaparin/VKA group. The net clinical benefit occurred in 2.9% of patients in the XARELTO group and 4.2% of patients who received enoxaparin/VKA (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.47-0.95; P=0.03). The relative efficacy and safety outcomes were consistent across the prespecified subgroups. The combination of alanine aminotransferase level >3x upper limit of normal and bilirubin level >2x upper limit of normal was seen in 2 XARELTO patients (0.1%) and 4 enoxaparin/VKA patients (0.2%).²

In the EINSTEIN-DVT study, 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.⁵

The J-EINSTEIN-DVT Study

The J-EINSTEIN-DVT Study⁶ was an open-label, double-blind, randomized trial comparing oral XARELTO therapy with the standard of care in Japan that included patients with a confirmed symptomatic DVT without PE. A separate PE study was performed.

Inclusion/Exclusion Criteria

Patients >20 years of age with an acute, objectively-confirmed symptomatic proximal DVT were included in the trial. Patients who had received heparin or fondaparinux for >48 hours or more than a single dose of warfarin; those who underwent a thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent for the current episode; who had any contraindication listed in the local labeling of unfractionated heparin or warfarin or another indication for the use of unfractionated heparin or warfarin; a creatinine clearance <30 mL/min; significant hepatic disease or alanine aminotransferase >3 times the upper limit of normal; bacterial endocarditis; active bleeding or a high risk of bleeding contraindicating treatment with unfractionated heparin or warfarin; a systolic BP >180 mm Hg or a diastolic BP >110 mm Hg; childbearing potential without proper contraceptive measures, pregnancy, or breast-feeding; concomitant use of strong cytochrome P450 3A4 inhibitors; and a life expectancy of less than 3 months were excluded from the study.

Study Design

A total of 55 patients with a DVT were randomized, with 43 patients assigned to receive XARELTO therapy and 12 assigned to receive standard of care therapy. Patients were randomized to receive either XARELTO or standard of care in a 4:1 ratio. The XARELTO-treated patients were allocated in a 1:1 ratio to receive either XARELTO 10 mg twice daily or XARELTO 15 mg twice daily for the first 3 weeks in a double-blind fashion, followed by XARELTO 15 mg once daily in an open-label fashion. The standard of care group received intravenous unfractionated heparin (dose adjusted to prolong activated partial thromboplastin time to 1.5-2.5-fold) for >5 days, overlapping with and followed by INR-adjusted warfarin (range 1.5-2.5). Unfractionated heparin was discontinued once the INR maintained a level of 1.5 or more for 2 consecutive measurements. Treatment duration varied from 3, 6, or 12 months as determined by the treating physician. Venous compression ultrasound and spiral computed tomography was repeated at day 22 and at end of intended treatment period.

Outcomes

The primary efficacy outcome of this study was the occurrence of symptomatic recurrent VTE or asymptomatic deterioration. Symptomatic VTE was defined as symptomatic DVT or symptomatic fatal or nonfatal PE. Bleeding was defined as major if it was clinically overt and associated with a decrease in hemoglobin levels of 2.0 g/dL or more or a transfusion of 2 or more units of red blood cells; or if bleeding was intracranial or retroperitoneal in nature, occurred in another critical site, or contributed to death. The definition of CRNM was overt bleeding that did not meet the criteria for MB but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of a study drug, or discomfort or impairment of activities of daily life.

Efficacy/Safety Results

The mean treatment duration was 195 days in the XARELTO group and 200 days in the standard of care group. At day 22, 1 patient (4.2%) in the XARELTO group (15 mg twice daily) developed symptomatic recurrent VTE and 1 patient (4.3%) in the XARELTO group (10 mg twice daily) developed asymptomatic recurrent VTE. No events were reported in the standard of care group. At the end of the treatment period, 1 patient (4.3%) in the XARELTO group (15 mg twice daily) developed symptomatic recurrent VTE compared with none in the standard of care group.

There were no MB events among both treatment groups during the study. In the DVT and PE studies, CRNM occurred in 6 (7.8%) patients in the XARELTO group and in 1 (5.3%) patient in the standard of care group. Between both of the studies, 3 patients (3.9%) from the XARELTO group died, 2 from cardiac failure and 1 from gastrointestinal bleeding. None of the patients in the standard of care group died during the treatment period.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 27 May 2024.