Summary

• XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.¹
• In ROCKET AF, macroscopic hematuria, categorized as major bleeding occurred in 0.37% of the XARELTO group and 0.29% of the warfarin group. Treatment-emergent hematuria occurred more in XARELTO patients than warfarin patients (P<0.05).²
• In the VENTURE-AF study, hematuria was reported in 1.6% of XARELTO-treated patients.³
• From the Dresden NOAC registry, 6 of the 67 patients who discontinued XARELTO due to bleeding complications reported hematuria (2.7%).⁴
• In the EINSTEIN-EXTENSION study in patients with pulmonary embolism (PE) or deep venous thrombosis (DVT), non-major, clinically relevant hematuria occurred in 9 XARELTO patients and no patients in the placebo group.⁵
• A post hoc analysis of the MAGELLAN and MARINER trials observed hematuria in 27 (20.5%) of all patients with a nonmajor clinically relevant bleed (NMCRB) and in 2 (7.7%) of all patients with a major bleed in the MARINER trial. In the MAGELLAN trial, urogenital bleeding was observed in 48 (30.4%) of all patients with a NMCRB, in 3 (5.4%) of all patients with a major bleed, and in 61 (10.8%) of all patients with trivial bleeding.^6,7
• In a retrospective study to assess the efficacy and safety of XARELTO and apixaban in obese patients with an acute venous thromboembolism (VTE), hematuria was reported in 26.1% of all patients who had a bleeding event with XARELTO compared to 0% of all patients who had a bleeding event with apixaban.⁸
• Hematuria was reported in 5/24 (3.0%) patients of which 2 (4.1%) had a trough concentration (C_trough) <12 ng/mL and 3 (2.5%) had a C_trough ≥12 ng/mL in a retrospective study to assess the efficacy and safety of XARELTO in patients with non-valvular atrial fibrillation (NVAF).⁹
• Additional citations identified are included for your review.^10-23

CLINICAL STUDIES

Stroke Prevention in Nonvalvular Atrial Fibrillation

ROCKET AF Trial

The ROCKET AF trial was a phase 3, randomized, double-blind, double-dummy, multicenter, event-driven, noninferiority study to evaluate the efficacy and safety of XARELTO 20 mg once daily (15 mg for patients with creatinine clearance [CrCl] 30-49 ml/min) and dose-adjusted warfarin (target international normalized ratio [INR]: 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular AF at moderate-to-high risk for stroke.²⁴

• The incidence of treatment-emergent hematuria was higher in XARELTO-treated patients (296/7111) compared to warfarin-treated patients (242/7125) (4.16% vs 3.40%, P<0.05).²
• Macroscopic hematuria, within the major bleeding category, occurred in 26 XARELTO-treated patients and 21 warfarin-treated patients (0.37% vs 0.29%).
  • Major bleeding was defined as clinically overt bleeding associated with any of the following: Fatal outcome, involvement of a critical anatomical site, fall in hemoglobin concentration ≥2 g/dL, transfusion ≥2 units of whole blood or packed red blood cells, or permanent disability.²

VENTURE AF

VENTURE AF (ActiVe-controlled multicENTer stUdy with blinded-adjudication designed to evaluate the safety of uninterrupted Rivaroxaban and uninterrupted vitamin K antagonists [VKA] in subjects undergoing cathEter ablation for nonvalvular Atrial Fibrillation) was a  phase 3b, randomized, open-label study comparing XARELTO 20 mg once daily and dose-adjusted VKA (target INR: 2.0 to 3.0).³

• Hematuria was reported as a non-major bleeding event in 2/123 XARELTO-treated patients (1.6%) and in 0/121 VKA-treated patients.

Beyer-Westendorf et al (2015)⁴ conducted a study using prospective data from a non-interventional, oral anticoagulation registry (Dresden NOAC) to determine XARELTO (15-20 mg daily) medication persistence in 1204 patients with AF.

• During the median follow-up period of 544 days, 223 patients (18.5%) discontinued XARELTO, with bleeding complications as the most common reason (30%).
  • Of the 67 patients who discontinued XARELTO due to bleeding complications, 6 reported hematuria (2.7%).

Stepanyan et al (2014)²⁵ conducted a retrospective analysis to evaluate the risk of bleeding and thromboembolic complications associated with new oral anticoagulants during and after an ablation procedure in patients with paroxysmal (71%), persistent (26%), or long-lasting persistent (3%) AF.

• Patients were grouped according to their peri-procedural anticoagulation regimen: uninterrupted warfarin with therapeutic INR (n=114; 37.9%), dabigatran (n=89; 29.5%), or XARELTO (n=98; 32.6%).
• Bleeding complications were defined as any bleeding event requiring transfusion or prolonging hospital stay. One of 17 patients from the XARELTO treatment group with a bleeding event reported persistent hematuria (1.0%).

Mao (2013)²⁶ evaluated the efficacy and safety of XARELTO 20 mg once daily (15 mg once daily for patients with CrCl 30-49 mL/min) and dose-adjusted warfarin (target INR: 2.0 to 3.0) for prevention of stroke and systemic embolism in Chinese patients with AF.

• Treatment-emergent hematuria occurred in 4/177 XARELTO-treated patients and 5/176 warfarin-treated patients.
• Macroscopic hematuria, within the major bleeding category, occurred in 1 XARELTO-treated patient and 2 warfarin-treated patients (0.6% vs 1.1%).
  • Major bleeding included bleeding associated with any of the following: decrease in hemoglobin ≥2 g/dL, transfusion, critical bleeding, fatal bleeding, or intracranial hemorrhage.

Reduction in the Risk of Recurrence of DVT and of PE

EINSTEIN-Extension Study

The EINSTEIN-Extension⁵ 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. 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.

• Hematuria occurred in 9/598 XARELTO-treated patients and in no patients on placebo.
• Hematuria was classified as clinically relevant non-major bleeding if it was macroscopic, and either spontaneous or lasts for more than 24 hours after instrumentation (e.g. catheter placement or surgery) of the urogenital tract.⁵

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients

Pooled Analysis from MAGELLAN AND MARINER

Spyropoulos et al (2022)⁶ conducted a post hoc analysis of the MAGELLAN and MARINER trials to evaluate the risk of all-cause mortality in patients with major bleeding or nonmajor clinically relevant bleeding. Patients were followed for all-cause mortality through day 90 in MAGELLAN and day 75 in MARINER. All bleeding events in patients taking at least 1 dose of study drug from randomization until 2 days after the last dose were evaluated. Patients were grouped into 1 of 4 categories (patients with no bleeding event, patients whose first event was a nonmajor clinically relevant bleed, major bleed, or trivial bleed).

A total of 20,125 patients overall were randomized in both trials. The safety population in MAGELLAN and MARINER included 7,998 (pooling together XARELTO and enoxaparin/placebo arms) and 11,962 (pooling together the XARELTO and placebo arms) patients respectively. Patients in the major bleeding group across both studies (MAGELLAN: n=56; MARINER: n=26) included a higher percentage of males and a history of anemia. Nonmajor clinically relevant bleeding (MAGELLAN: n=158; MARINER: n=132) and trivial bleeding (MAGELLAN: n=567; MARINER: n=85) were also reported in both studies.

• In the MARINER trial, hematuria was reported in 27 (20.5%) patients with a NMCRB and in 2 (7.7%) patients with a major bleed.^6,7
• In the MAGELLAN trial, urogenital bleeding was reported in 48 (30.4%) patients with a NMCRB, in 3 (5.4%) patients with a major bleed, and in 61 (10.8%) patients with trivial bleeding.^6,7

Retrospective Study

Anusim et al (2022)⁸ conducted a retrospective study to assess efficacy and safety of XARELTO or apixaban in obese patients with an acute VTE admitted between January 2013 to January 2020 to any Beaumont Health facility in Michigan.

• Age, sex, race, body mass index (BMI), and post-admission diagnoses of VTE or bleeding was collected from electronic medical records.
• Patients prescribed anticoagulants other than direct oral anticoagulants (DOACs) or had a chronic VTE were excluded.
• Primary outcomes included development of a new VTE event (PE, DVT, or both) or prior VTE progression within 60 days of starting XARELTO or apixaban.
• Bleeding events (major bleeding or clinically relevant minor bleeding), length of hospital stay, and mortality were included for secondary outcomes.
• A total of 499 patients were assessed for 60 days. Patient characteristics included a mean age of 57.4 years-old, 67.9% were female, median BMI (range) was 44.6 (39.5, 88.4), and Xarelto was prescribed in 296 (59.3%) of patients compared to 203 (40.7%) prescribed apixaban.
• Overall, there were 23 (7.8%) bleeding events reported for XARELTO compared to 12 (5.9%) events reported for apixaban.
  • Hematuria was reported in 7/23 (26.1%) patients who had a bleeding event with XARELTO compared to 0/12 (0%) patients who had a bleeding event with apixaban.

Gao et al (2022)⁹ conducted a retrospective study to assess the efficacy and safety of XARELTO in patients with NVAF admitted between October 2017 to October 2020 at the Fujian Provincial Hospital with a C_trough <12 ng/mL (n=49) or C_trough ≥12 ng/mL (n=118).

• Age, sex, height, weight, biochemical parameters, and medication status was collected from electronic medical records.
• Patients were included in the study if they were ≥18 years old, had a high risk of stroke, transient ischemic attack (TIA), or systemic embolism, and a CHA2DS2-VASc (congestive heart failure [CHF], hypertension, age ≥75 years [doubled], diabetes mellitus, stroke/TIA [doubled], vascular disease, age 65–74 years of age, and sex) score ≥1 for men and ≥2 for women, receiving long-term oral XARELTO due to NVAF (persistent or paroxysmal), provided written informed consent, and agreed to 1-year follow-up visits after the first dose of XARELTO.
• Clinicians selected XARELTO doses based on the age of the patient, renal function, and the HAS-BLED [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ration, elderly, drugs/alcohol concomitantly] score.
• The primary safety end point was bleeding events (principal and nonmajor bleeding events). The nonmajor bleeding events included subcutaneous bleeding, gastrointestinal bleeding, hematuria, epistaxis, or similar events.
• A total of 167 patients (113 men and 54 women) were followed for 1 year after the first dose of XARELTO. Patient characteristics included a mean age of 70.40 ± 12.46 years, 38.8% were female with a C_trough <12 ng/mL, and 29.7% were female with a C_trough ≥12 ng/mL.
• Overall, 24 patients (14.4%) experienced bleeding events where only nonmajor bleeding events occurred.
  • Hematuria was reported in 5/24 (3%) patients of which 2 (4.1%) had a C_trough <12 ng/mL and 3 (2.5%) had a C_trough ≥12 ng/mL.

Management of Hematuria

There are no specific recommendations on XARELTO reinitiate after a patient has developed hematuria. The decision to reinitiate treatment with XARELTO should be based on clinical judgement.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 01 August 2024.