Summary

• The recommended adult dose of XARELTO 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 XARELTO is 20 mg taken orally once daily with food, at approximately the same time each day.¹
• Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin (UFH) in patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.¹
• In the EINSTEIN-PE study, XARELTO demonstrated noninferiority compared to standard therapy in reducing the risk of symptomatic recurrent venous thromboembolism (VTE) in the intent-to-treat (ITT) population (2.1% vs 1.8%, respectively; P=0.003). The principal safety outcome of clinically relevant bleeding was 10.3% in the XARELTO group and 11.4% in the standard therapy group (P=0.23).²
• There are no recommendations on the treatment of recurrent VTE in patients receiving XARELTO for treatment of DVT, PE, and reduction in the risk of recurrence of DVT and of PE.
• Additional citations identified during a literature search have been included in the REFERENCES section for your review.^3-11

CLINICAL STUDIES

The EINSTEIN-PE Study

The EINSTEIN-PE Study² was a phase 3, randomized, open-label, event-driven, noninferiority study designed to evaluate the efficacy and safety of oral XARELTO (15 mg twice daily for 3 weeks followed by 20 mg once daily) vs subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral vitamin K antagonist (VKA) in patients with acute symptomatic PE with or without DVT.

Inclusion/Exclusion Criteria: Patients of legal age and who had an acute, symptomatic PE with objective confirmation, with or without symptomatic DVT, were included in this study. Patients who received a therapeutic dose of low-molecular-weight heparin (LMWH), fondaparinux, or UFH for more than 48 hours or if they had received more than a single dose of a VKA before randomization; if thrombectomy had been performed, a vena cava filter placed, or a fibrinolytic agent administered for treatment of the current episode; or if they had any contraindication listed in the local labeling of enoxaparin, warfarin, or acenocoumarol were excluded. Other exclusion criteria included: patients with another indication for a VKA; creatinine clearance (CrCl) <30 mL/min; clinically significant liver disease (eg, acute hepatitis, chronic active hepatitis, or cirrhosis) or alanine aminotransferase (ALT) level >3x upper limit of normal (ULN); bacterial endocarditis; active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; a systolic blood pressure (BP) >180 mm Hg or a diastolic BP >110 mm Hg; childbearing potential without proper contraceptive measures, pregnancy, or breast-feeding; concomitant use of a strong inhibitor of cytochrome P450 3A4 (CYP3A4) or a CYP3A4 inducer; participation in another experimental pharmacotherapeutic program within 30 days; or a life expectancy of <3 months.

Study Design: In this study, a total of 4832 patients (XARELTO, 2419; enoxaparin-VKA, 2413) were enrolled from March 2007 through March 2011. Patients were randomly assigned to either XARELTO 15 mg twice daily for 3 weeks, followed by 20 mg once daily, or subcutaneous enoxaparin (1.0 mg/kg twice daily) and a VKA, started within 48 hours after randomization. The VKA dose was adjusted to maintain an international normalized ratio (INR) of 2.0 to 3.0. Discontinuation of enoxaparin occurred when the patient’s INR was 2.0 or more for 2 consecutive days and the patient received at least 5 days of enoxaparin treatment. The use of nonsteroidal anti-inflammatory drugs and antiplatelet agents was discouraged. Aspirin (up to 100 mg/day), clopidogrel (75 mg/day), or both were allowed. The intended treatment duration of 3, 6, or 12 months was determined by the treating physician. Patients were followed for their intended treatment duration and assessed at fixed intervals. For the complete study design, see Figure: EINSTEIN-PE Study Design.

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 or clinically relevant nonmajor bleeding. Predefined secondary outcomes included major bleeding, death from any cause, vascular events (acute coronary syndrome, ischemic stroke, transient ischemic attack, or systemic embolism), and net clinical benefit (which was defined as a composite of the primary efficacy outcome and major bleeding).

Outcomes: Of the patients taking enoxaparin-VKA, the median duration of enoxaparin treatment was 8 days (interquartile range, 6-11), and the INR at end of treatment was at least 2.0 in 83% of patients. INR was in therapeutic range 62.7% of the time during the study. In the XARELTO group, adherence to therapy was about 80% in 94.2% of patients. Baseline characteristics were similar between the XARELTO and enoxaparin-VKA groups, which are displayed in Table: Demographic and Clinical Characteristics of the Patients. Treatment characteristics and reasons for premature discontinuation are presented in Table: Characteristics of Treatment.

The clinical outcomes are presented in Table: Clinical Outcomes in the EINSTEIN-PE Study. At 21 days after XARELTO administration, the primary efficacy outcome occurred in 0.7% of patients in the XARELTO group and 0.9% of patients in the enoxaparin-VKA group. The net clinical benefit occurred in 3.4% of patients in the XARELTO group and 4.0% of patients in the enoxaparin-VKA group (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.63-1.14; P=0.28). The combination of ALT level >3x ULN and bilirubin level >2x ULN was seen in 5 XARELTO patients (0.2%) and 4 enoxaparin/VKA patients (0.2%).

In the EINSTEIN-PE 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.¹²

Fermann et al (2015)¹³ conducted a post hoc analysis of EINSTEIN-PE data to assess the efficacy and safety of XARELTO in patients with PE. Adverse outcomes were assessed in relation to the simplified Pulmonary Embolism Severity Index (PESI) score in patients treated with XARELTO or standard therapy. The PESI scoring system is a validated prognostic tool for predicting death and adverse outcome events in patients with PE. Patients considered low risk may be able to be discharged from the hospital.

To determine PESI score, 1 point was assigned for each of the following: age >80 years; history of cancer; chronic cardiopulmonary disease; pulse ≥110 beats/minute; systolic BP <100 mmHg; and arterial oxyhemoglobin saturation <90%. Patients were assigned a PESI score of 0 if they had none of the above variables.

Outcomes included recurrent VTE, fatal PE, major bleeding, and all-cause mortality at 7, 14, 30, and 90 days and at the end of the full intended treatment period.

Of the 4832 randomized patients in the EINSTEIN PE study, the simplified PESI score could be calculated for 4831 patients. A total of 53.6%, 36.7%, and 9.7% of patients had PESI scores of 0, 1, and ≥2, respectively. There were no patients with a simplified PESI score higher than 3. For recurrent VTE, fatal PE, all-cause mortality, and major bleeding, there was a significant association between simplified PESI, with a higher score corresponding to increased risk of the adverse outcome. During the first 7, 14, and 30 days of treatment, patients with simplified PESI scores of 0 or 1 had low incidences of major adverse outcomes. At all measured time points, patients with simplified PESI scores of ≥2 had more frequent events of recurrent VTE, fatal PE, all-cause mortality, and major bleeding than those with simplified PESI scores of 0 and 1. Patients in the XARELTO group (simplified PESI score 1 or ≥2) had a lower incidence of major bleeding compared with the standard therapy group.

The J-EINSTEIN-PE Study

The J-EINSTEIN-PE Study¹⁴ was an open-label, double-blind, randomized study comparing oral XARELTO therapy with standard of care (SOC) therapy in Japanese patients with acute symptomatic PE with or without DVT.

Inclusion/Exclusion Criteria: Patients >20 years of age with an acute, objectively confirmed symptomatic proximal DVT and/or PE were included in the study. Patients who had received heparin or fondaparinux for >48 hours or >1 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 UFH or warfarin or another indication for the use of UFH or warfarin; a CrCl <30 ml/min; significant hepatic disease or ALT >3x ULN; bacterial endocarditis; active bleeding or a high risk of bleeding contraindicating treatment with UFH 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 CYP3A4 inhibitors; and a life expectancy of less than 3 months were excluded from the study.

Study Design: A total of 35 patients with a PE were randomized, with 28 patients assigned to receive XARELTO therapy and 7 assigned to receive SOC therapy. Patients were randomized to receive either XARELTO or SOC in a 4:1 ratio. The XARELTO-treated patients received 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 SOC group received intravenous UFH for >5 days (dose adjusted to prolong activated partial thromboplastin time to 1.5-2.5-fold), overlapping with and followed by INR-adjusted warfarin (range 1.5-2.5). UFH 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.

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 per deciliter 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. Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding, 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.

Outcomes: The mean treatment duration was 195 days in the XARELTO group and 200 days in the SOC group. At day 22, 1 patient (3.6%) in the XARELTO group developed asymptomatic recurrent VTE compared with none in the SOC group. At the end of the treatment period, 1 patient (14.3%) in the SOC group developed asymptomatic recurrent VTE compared with none in the XARELTO group.

There were no major bleeding events amongst both treatment groups during the study. The composite of clinically relevant nonmajor bleeding from the DVT and PE studies occurred in 6 (7.8%) patients in the XARELTO group and 1 (5.3%) patient in the SOC group. Between both 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 SOC group died during the treatment period.

MulticEnter trial of XARELTO for early disCharge of pUlmonaRY embolism from the Emergency Department (MERCURY PE)

MERCURY PE was a randomized, open-label, parallel-group, multicenter, prospective, phase 4 study designed to determine if patients diagnosed with PE and identified as being at low risk of clinical deterioration may be safely discharged from the Emergency Department (ED) and treated with XARELTO as outpatients. The study evaluated whether these patients require fewer hospital days and lower costs compared to those on SOC therapy.^15,16

Inclusion/Exclusion Criteria: Adult patients presenting to the ED with objectively confirmed, low-risk PE were eligible for enrollment. Low-risk PE was defined by the absence of any Hestia criteria, adapted for emergency medicine by removing 24-hour requirements. Although Hestia criteria exclude hemodynamically unstable patients, instability was not defined and was determined per the physician’s judgment.¹⁶

Study Design: The Hestia criteria was used to identify patients with PE who were at low risk for subsequent clinical deterioration and who were candidates for anticoagulant treatment on an outpatient basis. Upon ED discharge, patients were randomized in a 1:1 ratio to the following treatment arms: XARELTO (15 mg taken twice daily with food for the first 21 days, followed by 20 mg once daily with food for approximately 69 days, for a total treatment duration of 90 days) or SOC as per local protocol (if receiving warfarin, target INR was 2.0 to 3.0, with testing per local protocol). The primary efficacy outcome was the total amount of time (expressed in hours) spent in the hospital (including the index admission) for VTE or bleeding-related events during the first 30 days following randomization. The primary safety outcome was major bleeding within 90 days. Prespecified secondary efficacy outcomes included 90-day rates of new/recurrent VTE, VTE-related death, and total costs of care (direct medical care costs and costs of anticoagulation and related monitoring). Clinical and safety endpoints were adjudicated by a panel blinded to treatment allocation.¹⁶

Outcomes: Of the 114 patients that were randomized, 51 received XARELTO and 63 received SOC. Of these, 99 (86.8%) patients completed the study. Demographic characteristics were similar between groups. Median treatment duration was 90 days; XARELTO, 91 days and SOC, 89 days. Greater than 75% of patients received some type of direct-acting oral anticoagulant.¹⁶

The mean duration of initial and subsequent hospitalizations for bleeding and/or VTE events was shorter with XARELTO than with SOC: 4.8 hours vs 33.6 hours, respectively (P<0.0001), with a mean difference (95% CI) of 28.8 hours (-41.5 to -16.2). At 90 days, XARELTO was associated with fewer mean total hospital days (for any reason) compared with SOC (19.2 hours vs 43.2 hours, respectively, with a mean difference [95% CI] of 26.4 hours [-47.0 to -3.3]). At 90 days, there were no bleeding events (International Society on Thrombosis and Hemostasis [ISTH] major bleeding), recurrent VTE events, or deaths. The composite safety endpoint (ISTH major bleeding, clinically relevant nonmajor bleeding, and mortality) was similar among both treatment arms, with a difference in proportions of 0.005 (95% CI: -0.18 to 0.19). Total costs were $1496 for XARELTO and $4234 for SOC, with a median difference of $2496 (95% CI: -$2999 to -$2151).¹⁶

The Home Treatment of Pulmonary Embolism (HoT-PE) Study

The HoT-PE Study was a prospective, international, multicenter, single-arm, phase 4 management study designed to evaluate whether early discharge and ambulatory treatment with XARELTO is effective and safe in patients with acute low-risk PE.^17,18

Key Inclusion/Exclusion Criteria: Patients ≥18 years of age with an objectively confirmed diagnosis of acute PE (with or without symptomatic DVT), absence of right ventricular enlargement or dysfunction, and absence of free-floating thrombi in the right atrium or right ventricle were eligible for inclusion. Key exclusion criteria included hemodynamic instability at presentation, active bleeding or known significant bleeding risk, other medical conditions/comorbidities requiring hospitalization, and noncompliance or inability to adhere to treatment or to the follow-up visits.^17,18

Study Design: Treatment with an approved parenteral or oral anticoagulant (UFH, LMWH, fondaparinux, XARELTO, or apixaban) could be started before enrollment upon clinical suspicion of PE and no later than 3 hours after confirmation of PE. The first dose of study drug (XARELTO) was given in hospital (≤2 hours before the second dose of LMWH, fondaparinux, XARELTO, or apixaban would have been due) or at the time of discontinuation of intravenous UFH. Echocardiography and compression ultrasonography of the leg veins were recommended before discharge, but not required. Patients were discharged within 48 hours of presentation. Patients were to receive XARELTO 15 mg twice daily for 3 weeks, followed by 20 mg once daily for at least 3 months. A reduction of the maintenance dose to 15 mg once daily was considered if the patient’s assessed risk for bleeding outweighed risk for recurrent VTE.^17,18

The primary efficacy outcome was symptomatic recurrent VTE or recurrent PE-related death within 3 months of enrollment. Secondary efficacy outcomes included all-cause mortality and the number of rehospitalizations due to PE or a bleeding event within 3 months. Safety outcomes included major bleeding (defined by ISTH criteria), clinically relevant nonmajor bleeding, and serious adverse events. All efficacy and safety outcomes were adjudicated by an independent clinical events committee.^17,18

Outcomes: Of the 2854 patients that were enrolled in the study, 525 were included in the primary (ITT) analysis, 519 in the safety population, and 497 in the per-protocol population. Mean age was 56.7 years, 45.7% of patients were female, 5.5% had a CrCl of <50 mL/min, 15.9% had prior DVT, 7.5% had prior PE, 7.1% had recent major surgery, 4.4% had recent major trauma, 96.0% spent ≤2 nights in the hospital, 94.2% completed study treatment, and median length of hospitalization was 34 hours.¹⁸

XARELTO was given at the standard maintenance dosage of 20 mg once daily over a mean period of 68 days; 4 patients received the reduced dosage of 15 mg once daily.¹⁸

The primary efficacy outcome of symptomatic recurrent VTE or fatal recurrent PE within 3 months occurred in 3/525 (0.6%; all 3 were recurrent PE [95% CI: 0.1-1.7]) patients in the ITT population and in 2/497 (0.4%) patients in the per-protocol population. Twelve out of 525 (2.3%) patients experienced rehospitalization due to suspected recurrent PE or bleeding (final diagnosis: pneumonia, n=4; recurrent PE, n=2; major bleeding, n=4; clinically relevant nonmajor bleeding, n=1; other, n=1). A total of 54/525 (10.3%) patients required either prolongation of the initial hospital stay (n=11) or rehospitalization (n=43) due to serious adverse events, which occurred a median of 14 days after the initial presentation. Major bleeding (defined by ISTH criteria) occurred in 6/519 (1.2%) patients (95% CI: 0.4-2.5) and clinically relevant nonmajor bleeding occurred in 31/519 (6.0%) patients (95% CI: 4.1-8.4). At least 1 serious adverse event occurred in 58/519 (11.2%) patients (95% CI: 8.6-14.2). Death from any cause within 3 months occurred in 2/525 (0.4%; both due to advanced cancer) patients (95% CI: 0.1-1.4). Study results demonstrated that early discharge and home treatment with XARELTO was effective and safe in patients with acute low-risk PE.¹⁸

LITERATURE SEARCH

A literature search of MEDLINE^® Embase^®, BIOSIS Previews^®, Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 26 June 2024.