SUMMARY

• In ROCKET-AF, major bleeding was defined as clinically overt bleeding associated with any of the following: fatal outcome, involvement of a critical anatomic site (intracranial, intraspinal, intraocular, pericardial, intra-articular, retroperitoneal, or intramuscular with compartment syndrome), fall in hemoglobin concentration ≥2 g/dL, transfusion of ≥2 units of whole blood or packed red blood cells, or permanent disability. Nonmajor clinically relevant bleeding was defined as overt bleeding not meeting criteria for major bleeding but requiring medical intervention, unscheduled contact with a physician, temporary interruption of study drug, pain, or impairment of daily activities.¹
• In the EINSTEIN program, major bleeding was defined as overt bleeding and associated with a fall in hemoglobin of 2 g/dL or more or leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or occurring in a critical site, or contributing to death. Other clinically relevant nonmajor bleeding is defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, or associated with any other discomfort such as pain, or impairment of activities of daily life.^2-4
• In all four RECORD trials, major bleeding was defined as bleeding that was fatal, occurred into a critical organ, required reoperation, or clinically overt extra-surgical site bleeding that was associated with a fall in hemoglobin of ≥2 g/dL or a transfusion of ≥2 units of blood. Nonmajor bleeding was defined as multiple-source bleeding, unexpected hematoma (>25 cm²), excessive wound hematoma, nose bleeding (>5 minutes), gingival bleeding (>5 minutes), macroscopic hematuria, rectal bleeding, coughing or vomiting blood, vaginal bleeding, blood in semen, intra-articular bleeding with trauma, or surgical-site bleeding.^5-8
• In ATLAS-ACS TIMI-51, 3 bleeding event scales including the Thrombolysis in Myocardial Infarction (TIMI) scale, XARELTO Program Scale (utilized the International Society on Thrombosis and Haemostasis [ISTH] classification) and the GUSTO scale were utilized to assess bleeding events in this study.⁹
• In COMPASS, a modified ISTH bleeding criteria was used to assess safety outcomes. These criteria were defined as a composite of fatal bleeding, symptomatic bleeding in a critical organ, or bleeding into the surgical site requiring reoperation, and bleeding leading to hospitalization (includes presentation to an acute care facility without overnight stay).¹⁰
• In VOYAGER PAD, major bleeding was defined according to TIMI major bleeding as¹¹:
  • Non-CABG-related bleeding (any one of the following)
    • Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo magnetic resonance imaging [MRI])
    • Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL; if hemoglobin not available, drop in hematocrit ≥15% (corrected for transfusion)
    • Fatal bleeding (bleeding that directly results in death within 7 days)
  • CABG-related major bleeding (any one of the following)
    • Fatal bleeding (bleeding that directly results in death)
    • Perioperative intracranial bleeding
    • Reoperation after closure of the sternotomy incision for the purpose of controlling bleeding
    • Transfusion of ≥5 units whole blood or red blood cells within a 48-hour period (cell saver products not counted)
    • Chest tube output >2L within a 24-hour period
• In MAGELLAN¹² and MARINER¹³ major bleeding was defined as decrease in hemoglobin ≥2 g/dL, or leading to transfusion of ≥2 units of packed red blood cells or whole blood, or bleeding that occurs in a critical site (eg intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal) or fatal bleeding. Nonmajor clinically relevant bleeding was defined as overt bleeding not meeting the criteria for major bleeding, but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment or associated with discomfort for the subject, such as pain or impairment of activities of daily life. Other bleeding was defined as overt bleeding that did not meet criteria for major or nonmajor clinically relevant bleeding.
• In UNIVERSE, major bleeding events was defined by the ISTH criteria: overt bleeding and associated with a decrease in hemoglobin of ≥2 g/dL, leading to a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood in adults, occurring in a critical site (intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal), or contributing to death. Clinically relevant nonmajor bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, discomfort for the patient, such as pain, or impairment of activities of daily life. Trivial (minimal) bleeding event was defined as any other overt bleeding event that does not meet criteria for clinically relevant nonmajor bleeding.^14-16

CLINICAL DATA

ROCKET AF

The ROCKET AF (Rivaroxaban, Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial evaluated the efficacy and safety of XARELTO and warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at moderate-to-high risk for stroke.¹⁷

In ROCKET AF, the primary safety endpoint was the composite of both major bleeding and nonmajor clinically relevant bleeding.

EINSTEIN

EINSTEIN-DVT

The 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 (SC) 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).¹⁸

In EINSTEIN-DVT, the principal safety outcome was clinically relevant bleeding, defined as the composite of major or clinically relevant nonmajor bleeding.

EINSTEIN-PE

The EINSTEIN-PE study 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 SC enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT.³

In EINSTEIN-PE, the principal safety outcome was clinically relevant bleeding, which was defined as a composite of major or clinically relevant nonmajor bleeding.

EINSTEIN-Extension

The EINSTEIN-Extension study 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.¹⁸

In EINSTEIN-Extension, the principal safety outcome was major bleeding.

In the EINSTEIN program, all suspected bleedings were to be classified by the Central Independent Adjudication Committee (CIAC) as major, clinically relevant nonmajor, trivial, or no bleeding.²

All other overt bleeding episodes not meeting the criteria for clinically relevant bleeding will be classified as trivial bleed.²

EINSTEIN-Choice

The EINSTEIN-Choice was a phase 3, randomized, double-blind 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 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.¹⁹

In EINSTEIN-Choice, the primary safety outcome was ISTH major bleeding.

EINSTEIN-Junior

The EINSTEIN-Junior study was a phase 3, randomized, open-label study that evaluated the efficacy and safety of a body weight-adjusted 20 mgequivalent dose of XARELTO compared with standard anticoagulants in pediatric patients aged ≤17 years with acute VTE.²⁰

The principal safety outcome was the composite of overt major and clinically relevant nonmajor bleeding.²⁰

RECORD

The RECORD clinical development program, a comprehensive program of four phase 3 studies with over 12,000 patients, studied XARELTO (XARELTO tablets) for the prophylaxis of VTE in patients undergoing knee (RECORD 3 and 4) or hip (RECORD 1 and 2) replacement surgery. The data from the RECORD program were submitted to the Food and Drug Administration (FDA). XARELTO was approved on July 1, 2011, by the FDA for the indication studied in the RECORD program.

In the RECORD 4 study, patients received either oral XARELTO 10 mg once daily, beginning at least 6-8 hours after surgery, or SC enoxaparin 30 mg every 12 hours, starting 1224 hours after surgery. Data from RECORD 4 are not included in the approved product labeling for XARELTO.

Since publication of RECORD 4 findings, the sponsor company conducted a verification of the data for all patients in this clinical trial. With respect to study findings, additional adverse events/serious adverse events were identified; however, the distribution of those was balanced between study groups. In the company’s view, verification findings did not appreciably change the conclusions of the study. Thus, the RECORD 4 findings reported in the publication remain consistent with the overall results from the total RECORD program.

RECORD

As part of the phase 3 RECORD (REgulation of Coagulation in major ORthopaedic surgery reducing the risk of DVT and PE) clinical trial program, 4 randomized, double-blind, double-dummy, multinational studies, compared efficacy and safety between oral XARELTO 10 mg once daily and SC enoxaparin 40 mg once daily (RECORD 1, 2, and 3) or 30 mg every 12 hours (RECORD4) for VTE prevention in patients undergoing elective total hip arthroplasty (RECORD 1 and 2) or total knee arthroplasty (RECORD3 and 4).^5-8 XARELTO was started 68 hours after surgery (RECORD1, 2, 3, and 4) while enoxaparin was started 12 hours before surgery and restarted 6-8 hours after wound closure for RECORD1, 2, and 3 and was started 12 to 24 hours after wound closure in RECORD4. Efficacy and safety outcome measures were the same for all trials.

The major safety outcome was the incidence of on-treatment major bleeding that occurred after the first dose of study drug and up to 2 days after the last dose of study drug. Patients were ineligible if they had active bleeding or a high risk of bleeding.

ATLAS-ACS TIMI-51

ATLAS-ACS TIMI-51 (Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with/without thienopyridine therapy in Subjects with Acute Coronary Syndrome ─ Thrombolysis In Myocardial Infarction 51) was a randomized, multicenter, double-blind, event-driven trial to determine whether XARELTO (2.5 mg twice daily or 5 mg twice daily), when added to standard care, was safe and reduced the risk of the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke in patients with acute coronary syndrome (ACS) compared with placebo. Standard medical therapy included low-dose aspirin. Patients were stratified by the investigator’s intention to administer a thienopyridine (clopidogrel or ticlopidine) or not at the time of enrollment.²¹

The primary safety endpoint was TIMI major bleeding not related to coronary artery bypass graft (CABG). A total of 3 bleeding event scales were utilized to assess bleeding events: TIMI scale, XARELTO Program Scale (utilized the ISTH classification) and the GUSTO scale.⁹

TIMI Scale

The TIMI scale included categories of major, minor, requiring medical attention, and insignificant bleeding events. A TIMI major bleeding event was defined as:

• Any symptomatic intracranial hemorrhage, or
• Clinically overt signs of hemorrhage (including imaging) associated with a drop in hemoglobin of ≥5 g/dL (or when the hemoglobin concentration is not available, an absolute drop in hematocrit of ≥15%)

A TIMI minor bleeding event was defined as any clinically overt sign of hemorrhage (including imaging) that is associated with a fall in hemoglobin concentration of 3 to <5 g/dL (or, when hemoglobin concentration is not available, a fall in hematocrit of 9 to <15%).

A bleeding event requiring medical attention was defined as any bleeding event that requires medical treatment, surgical treatment, or laboratory evaluation and does not meet criteria for a major or minor bleeding event, as defined above.

An insignificant bleeding event was defined as a reported blood loss or bleeding event episode not meeting any of the above criteria.

XARELTO Program Scale

ISTH major bleeding event classification criteria was utilized which included categories of major, clinically relevant nonmajor, and minimal bleeding events.

Major bleeding event was defined as clinically overt bleeding that is associated with:

• A fall in hemoglobin of 2 g/dL or more, or
• A transfusion of 2 or more units of packed red blood cells or whole blood, or
• A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or
• A fatal outcome

A clinically relevant nonmajor bleeding event was defined as an overt bleeding event not meeting the criteria for a major bleeding event, but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study drug treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life.

Minimal bleeding events were defined as all other overt bleeding events not meeting the criteria for major or clinically relevant nonmajor bleeding events.

GUSTO Scale

GUSTO scale included 3 classes: mild, moderate, and severe/life threatening. Mild bleeding was defined as bleeding that does not meet criteria for either severe or moderate bleeding. Moderate bleeding was defined as bleeding that requires blood transfusion but does not result in hemodynamic compromise. Severe/life threatening was defined as either an intracranial hemorrhage or bleeding that causes hemodynamic compromise and required intervention.

COMPASS

COMPASS (Rationale, Design and Baseline Characteristics of Participants in the Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) was a double-blind, event-driven superiority trial that compared XARELTO 2.5mg twice daily in combination with aspirin 100mg once daily or XARELTO 5mg twice daily versus aspirin 100mg once daily for prevention of MI, stroke, or CV death in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD).¹⁰

The primary safety outcome was based on a modification of the ISTH major bleeding criteria and is the composite of: fatal bleeding, symptomatic bleeding in a critical organ, or bleeding into the surgical site requiring reoperation, and bleeding leading to hospitalization (includes presentation to an acute care facility without overnight stay).¹⁰

VOYAGER PAD

VOYAGER PAD was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily is more effective than aspirin 100 mg once daily alone for the risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing lower extremity revascularization.²²

The primary safety outcome was TIMI major bleeding. Secondary safety outcomes included ISTH major bleeding and BARC (grade ≥3b) major bleeding.²²

MAGELLAN

MAGELLAN was a phase 3, randomized, controlled study designed to evaluate the safety and efficacy of extended-duration XARELTO compared to enoxaparin/placebo for the prevention of VTE in acutely ill medical patients both during hospitalization and post-discharge.²³ XARELTO 10 mg once daily for up to 39 days was compared to enoxaparin 40mg daily for up to 14 days.

The primary safety outcome is the incidence of the composite of treatment-emergent major bleeding and nonmajor clinically relevant bleeding.¹²

MARINER

MARINER was a phase 3, randomized, double-blind, event-driven study that evaluated the efficacy and safety of XARELTO 10 mg once daily (7.5 mg once daily if creatinine clearance [CrCl] ≥30 to <50 mL/min) compared with placebo in the prevention of symptomatic VTE and VTE-related death after hospital discharge in high-risk, medically ill patients for a period of 45 days post-hospital discharge. ^13,24

The primary safety outcome was based on the ISTH major bleeding criteria.

UNIVERSE

UNIVERSE was a prospective, randomized, multicenter, 2-part, open-label study in pediatric patients 2 to 8 years of age with single-ventricle physiology, who had completed the Fontan procedure within 4 months prior to enrollment. Part A was designed to characterize the single- and multiple-dose pharmacokinetic and pharmacodynamic profiles following oral XARELTO administration while part B evaluated the safety and efficacy of XARELTO compared to aspirin for thromboprophylaxis. XARELTO was dosed twice daily by body weight using a 0.1% [1 mg/mL] oral suspension for 12 months in parts A and B. Aspirin was given ~5 mg/kg once daily for up to 12 months in part B.^14,15

The primary safety outcome was major bleeding events, as defined by the ISTH. The secondary safety outcomes were clinically relevant nonmajor bleeding and trivial (minimal) bleeding events.^14,15

Literature Search

A literature search of MEDLINE^® EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 December 2023.