Summary

• The EINSTEIN program:
• EINSTEIN-DVT 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) followed by dose-adjusted oral vitamin K antagonist (VKA) (warfarin or acenocoumarol) in patients with confirmed symptomatic deep vein thrombosis (DVT) without symptomatic pulmonary embolism (PE).¹
• EINSTEIN-PE was a phase 3, randomized, open-label, event-driven, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg twice daily for 3 weeks followed by 20 mg once daily) versus subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT.²
• EINSTEIN-Extension 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.¹
• EINSTEIN CHOICE was a Phase 3, randomized, double-blind study, that compared the efficacy and safety of two doses of XARELTO (20 mg and 10 mg, once-daily) with aspirin (100 mg, once-daily) in patients with venous thromboembolism (VTE) who had completed 6-12 months of anticoagulation therapy and for whom there was equipoise with respect to the need for ongoing anticoagulation.³
• EINSTEIN Junior phase 3 was a randomized, open-label, active-controlled study that evaluated efficacy and safety of bodyweight-adjusted XARELTO in a 20 mg-equivalent dose compared with standard-of-care for treatment of children with acute venous thromboembolism (VTE).⁴

CLINICAL STUDIES

EINSTEIN-DVT and EINSTEIN-PE

Inclusion criteria for each study are listed below:^{1, 2, 5}

• Patients with an acute, symptomatic, objectively confirmed proximal DVT, without symptomatic PE were included in the DVT study.
• Patients with an acute, symptomatic, objectively confirmed PE with or without symptomatic DVT were included in the PE study.

Patients could be included in the study if they had recent trauma.  It was at the investigator’s discretion to enroll patients with recent trauma or surgery. There were no specified timelines associated with the term recent trauma.

Exclusion criteria for both studies are listed below:^{1, 2, 5}

• More than 48 hours pre-randomization treatment with therapeutic dosages of low-molecular-weight heparin, fondaparinux, or unfractionated heparin or more than a single dose of VKA prior to randomization
• Treatment with a thrombectomy, insertion of a cava filter, use of a fibrinolytic agent to treat the current episode of DVT and/or PE
• Indicated for treatment with a VKA for a condition other than DVT/PE
• Creatinine clearance (CrCl) <30 ml/min
• Significant liver disease or alanine aminotransferase (ALT) >3x the upper limit of normal (ULN)
• Bacterial endocarditis
• Active bleeding or high risk for bleeding contraindicating treatment with enoxaparin or VKA
• Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg
• Concomitant use of strong CYP3A4 inhibitors or CYP3A4 inducers

Nonsteroidal anti-inflammatory drugs and antiplatelet agents were discouraged. However, if indicated, aspirin up to a dosage of 100 mg/day as well as clopidogrel (75 mg/day) were allowed.

Treatment populations for both studies are listed below:^{1, 2, 5}

• Patients in the XARELTO treatment group received oral XARELTO 15 mg twice daily for the first three weeks of treatment, followed by XARELTO 20 mg once daily for 3, 6, or 12 months. Treatment duration was at the investigator's discretion, but was based on the patient's risk factors and potential for bleeding. XARELTO was discontinued at the final assessment.
• Patients in the standard therapy group received enoxaparin 1.0 mg/kg twice daily, and either warfarin or acenocoumarol, started within 48 hours after randomization. Enoxaparin was discontinued when the international normalized ratio (INR) was ≥ 2.0 for 2 consecutive days (target INR: 2.0 to 3.0) and the patient had received enoxaparin treatment for at least 5 days. Once stabilized, the INR was measured at least once a month.
• Patients were followed up at fixed intervals during the treatment duration, and during an 30 day observational period at the end of treatment.

Outcomes for both studies are listed below:^{1, 2}

• Primary efficacy outcome: Symptomatic, recurrent VTE (a composite of DVT or nonfatal or fatal PE).
• Principal safety outcome: Clinically relevant bleeding, defined as the composite of major or clinically relevant nonmajor bleeding.
• Predefined secondary outcomes: 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). Analyses of the treatment effects and bleeding were also performed in prespecified subgroups.

Analysis populations for both studies are listed below:^{1, 2, 5}

• All efficacy analyses were performed on the intention-to-treat (ITT) population, which consists of all patients who were randomized. A supportive analysis of the primary efficacy outcome was also assessed in the per-protocol (PP) population, which consisted of all randomized patients without any major deviation from the protocol.
• The safety analysis was performed on the valid-for-safety-analysis population, which consisted of all patients who were randomized and received at least one dose of anticoagulant treatment after randomization. Bleeding events were analyzed during treatment or within two days after treatment was discontinued. An analysis of the bleeding events and mortality was also done on the ITT population.

EINSTEIN-Extension

The treating physician must have deemed that there was clinical equipoise with respect to continued anticoagulation. Placebo was chosen as the appropriate control due to the uncertainty of the need for continuation of anticoagulation. The intended treatment duration in the EINSTEIN-Extension study was 6 to 12 months.¹

Inclusion criteria for the EINSTEIN-Extension study are listed below:^{1, 5}

• Patients with objectively confirmed, symptomatic DVT or PE who had been treated for 6 to 12 months with acenocoumarol or warfarin (in the EINSTEIN studies or from routine care) or XARELTO (in the EINSTEIN studies) and equipoise with respect to the need for continued anticoagulation

Patients could be included in the study if they had recent trauma.  It was at the investigator’s discretion to enroll patients with recent trauma or surgery. There were no specified timelines associated with the term recent trauma.

Exclusion criteria for the EINSTEIN-Extension study are listed below:¹

• Indicated for treatment with a VKA for a condition other than DVT/PE
• Participation in another pharmacotherapeutic study within 30 days
• CrCl <30 ml/min
• Significant liver disease or ALT >3x ULN
• Bacterial endocarditis
• Active bleeding or high risk for bleeding contraindicating treatment with enoxaparin or VKA
• Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg
• Concomitant use of strong CYP3A4 inhibitors or CYP3A4 inducers

Outcomes for the EINSTEIN-Extension study are listed below:¹

• Primary efficacy outcome: Symptomatic recurrent VTE, which was defined as a composite of fatal or nonfatal PE or DVT.
• Principal safety outcome: Major bleeding.
• Predefined secondary outcomes: 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). Analyses of the treatment effects and bleeding were also performed in prespecified subgroups.

Analysis populations for the EINSTEIN-Extension study are listed below:^{1, 5}

• All efficacy analyses were performed on the ITT and PP populations. The primary efficacy outcome was performed in the ITT population and repeated in the PP population. The ITT population consisted of all subjects who had been randomized, and the PP population consisted of all randomized subjects without any major deviations from the protocol.
• All safety analyses were performed on the valid-for-safety-analysis population, which consisted of all subjects who were randomized and received at least one dose of study treatment. Bleeding events were analyzed during treatment or within two days after treatment was discontinued.

EINSTEIN CHOICE

Inclusion criteria for the EINSTEIN CHOICE study are listed below:³

• Objectively confirmed, symptomatic proximal DVT or PE
• Treated for 6 to 12 months with an anticoagulant including a VKA or a direct oral anticoagulant
• No interrupted therapy for more than 7 days prior to randomization

Exclusion criteria for the EINSTEIN CHOICE study are listed below:³

• Extended anticoagulant therapy at therapeutic dosages or antiplatelet therapy required
• Calculated CrCl of less than 30 ml/min
• Hepatic disease associated with a coagulopathy

Study Design: Patients were enrolled at least 24 hours after they received the last dose of DOAC or, if they were receiving a VKA, when the INR was ≤ 2.5. Patients were stratified according to the index diagnosis (DVT or PE) and country, then assigned to one of 3 groups:

• XARELTO 20 mg
• XARELTO 10 mg
• Aspirin 100 mg
  • All study medications were given once daily with food

Outcomes for the EINSTEIN CHOICE study are listed below:³

• Primary efficacy outcome: Symptomatic recurrent fatal or nonfatal VTE
• Primary safety outcome: ISTH major bleeding

Analysis populations for the EINSTEIN CHOICE study are listed below:³

• The efficacy and safety analyses included all the patients who had undergone randomization with valid informed consent and who had received at least one dose of a study medication (ITT population).
• The PP population excluded patients who had a rate of adherence to the study drug regimen of less than 80% or who had other major protocol violations.
• Efficacy outcomes were considered during the individual intended treatment period, whereas safety outcomes were considered during the time from administration of the first dose of a study drug to 48 hours after the administration of the last dose.

EINSTEIN JUNIOR

Inclusion criteria for the EINSTEIN JUNIOR study are listed below:⁴

• Children 0-17 years if they had objectively-confirmed acute VTE.

Exclusion criteria for the EINSTEIN JUNIOR study are listed below:⁴

• Active bleeding or high risk for bleeding contraindicating anticoagulant therapy.
• Hepatic disease associated with a coagulopathy.
• Estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m².

Study Design for the EINSTEIN JUNIOR study:⁴

• Patients were randomized 2:1 to XARELTO or standard anticoagulation (heparins/vitamin K antagonist [VKA]) for a treatment duration of 3 months (except for those with catheter-related thrombosis <2 years of age who had a main treatment period of 1 month). Patients had the option to continue treatment in 3-month increments for up to a maximum study treatment duration of 12 months (children <2 years of age with catheter-related thrombosis had the option to prolong treatment in 1-month increments for up to a total of 3 months).
  • XARELTO was administered as a body weight-adjusted 20 mg-equivalent total daily dose regimen using either immediate release film-coated tablets (dose of 5, 10, 15, or 20 mg) or an oral suspension (1 mg/mL). Children with body weight of ≥20 kg received tablets or oral suspension and those with body weight of <20 kg received oral suspension.
  • XARELTO was administered once daily in children with a body weight of ≥30 kg, while those with a body weight of <30 kg required a substantially higher XARELTO dose (mg/kg basis) to achieve a similar exposure compared to young adults treated with XARELTO 20 mg once daily.
    • Those with a body weight of 12 to <30 kg received a twice-daily regimen and those with a body weight of <12 kg received a thrice-daily regimen to avoid increased peak XARELTO plasma concentration.
• A repeat imaging test obtained at the end of the main treatment period was compared with the baseline test and was classified as normalized, improved (ie, thrombus still present, but partly recanalized or involving less venous segments), no relevant change (ie, not recanalized and similar in extent), or deteriorated (ie, new venous segment involved).

Outcomes for the EINSTEIN JUNIOR study:⁴

• The primary efficacy objective was to document efficacy of XARELTO regimens at a 20 mg-equivalent dose for prevention of fatal or symptomatic nonfatal recurrent VTE.
• The secondary efficacy objective was to assess incidence of symptomatic recurrent VTE and asymptomatic deterioration on repeat imaging.
• The primary safety objectives were to document the incidence of major and clinically relevant nonmajor bleeding.

LITERATURE SEARCH

A literature search of MEDLINE^® EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 20 June 2023.