Adverse Event of XARELTO - Epistaxis

SUMMARY

• In ROCKET AF, the incidence of major bleeding by site, including epistaxis, was comparable and was reported in 13 of 7111 (0.18%) XARELTO-treated patients and 14 of 7125 (0.20%) warfarin-treated patients.¹ Epistaxis was reported in 303 of 7111 (4.3%) XARELTO-treated patients and 275 of 7125 (3.9%) warfarin-treated patients.²
• In EINSTEIN-DVT, in the safety population, the rates of drug-related treatment-emergent epistaxis were 3.9% (67/1718) and 3.3% (56/1711) in the XARELTO and enoxaparin/vitamin K antagonist (VKA) groups, respectively.³
• In EINSTEIN-PE, in the safety population, the rates of drug-related treatment-emergent epistaxis were 7.2% (173/2412) and 6.6% (159/2405) in the XARELTO and enoxaparin/VKA groups, respectively.⁴
• In EINSTEIN-Extension, in the safety population, the rates of drug-related treatment-emergent epistaxis were 2.8% (17/598) and 1.5% (9/590) in the XARELTO and placebo groups, respectively.⁵
• In RECORD 1, epistaxis was observed in 12 of 2209 (0.54%) XARELTO-treated patients and 9 of 2224 (0.40%) enoxaparin-treated patients.⁶ In RECORD 2, epistaxis was observed in 3 of 1228 (0.24%) XARELTO-treated patients and 5 of 1229 (0.41%) enoxaparin-treated patients.⁷ In RECORD 3, epistaxis was observed in 2 of 1220 (0.16%) XARELTO-treated patients and 2 of 1239 (0.16%) enoxaparin-treated patients.⁸ In RECORD 4, epistaxis was observed in 28 of 1526 (1.83%) XARELTO-treated patients and 20 of 1508 (1.33%) enoxaparin-treated patients.⁹
• In UNIVERSE, there was one patient (2%) in the XARELTO part B (N=64) group with a major bleeding event of epistaxis. The rates of epistaxis classified as trivial bleeding were 11% (7/64) and 9% (3/34) in the XARELTO and aspirin part B groups respectively.¹⁰
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^11-29

CLINICAL DATA

Stroke Prevention in Nonvalvular Atrial Fibrillation (NVAF)

ROCKET AF was a phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, event-driven, noninferiority study designed to evaluate the efficacy and safety of oral fixed-dose XARELTO 20 mg once daily (15 mg for patients with a creatinine clearance (CrCl) of 30 to 49 mL/min) and dose-adjusted warfarin (target international normalized ratio: 2.0-3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate to high risk for stroke.³⁰

• Treatment-emergent epistaxis occurred more frequently in the XARELTO-treated patients (721 of 7111 [10.14%]) as compared to warfarin-treated patients (609/7125 [8.55%]).¹

Goodman et al (2014)

Goodman et al (2014)² investigated factors associated with major bleeding in 14,264 patients with atrial fibrillation in the ROCKET AF trial who were randomized to either XARELTO or dose-adjusted warfarin.

• The incidences of major or nonmajor clinically relevant bleeding by site, including epistaxis, were similar between groups, with reports in 1475 of 7111 (20.7%) XARELTO-treated patients and 1449 of 7125 (20.3%) warfarin-treated patients.
• Adverse event of epistaxis was reported more frequently in the XARELTO-treated patients (6.9%) than the warfarin-treated patients (5.7%; P≤0.001).

J-ROCKET AF

J-ROCKET AF was a prospective, randomized, double-blind comparison to confirm the noninferiority of XARELTO to warfarin for the prevention of stroke in regard to the primary safety outcome in Japanese patients with NVAF.³¹

• In patients with CrCl of 30-49 mL/min, epistaxis was reported in 19.1% of patients treated with XARELTO 10 mg once daily (n=141) and in 11.2% of patients treated with warfarin (n=143).
• In patients with CrCl of ≥50 mL/min, epistaxis was reported in 15.5% of patients treated with XARELTO 15 mg once daily (n=498) and in 8.9% of patients treated with warfarin (n=496).

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

EINSTEIN-DVT

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 VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE.³²

• In the safety population, the rates of drug-related treatment-emergent epistaxis were 3.9% (67/1718) and 3.3% (56/1711) in the XARELTO and enoxaparin/VKA groups, respectively.³

EINSTEIN-PE

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) vs subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT.³³

• In the safety population, the rates of drug-related treatment-emergent epistaxis were 7.2% (173/2412) and 6.6% (159/2405) in the XARELTO and enoxaparin/VKA groups, respectively.⁴

EINSTEIN-Extension

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.³²

• In the safety population, the rates of drug-related treatment-emergent epistaxis were 2.8% (17/598) and 1.5% (9/590) in the XARELTO and placebo groups, respectively.⁵

RECORD

The RECORD clinical development program, a comprehensive program of 4 phase III studies with over 12,000 patients, studied XARELTO^® (rivaroxaban tablets) for the prophylaxis of venous thromboembolism (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 h after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12-24 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.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

As part of the phase 3 RECORD clinical trial program, 4 randomized, double-blind, double-dummy, multinational, active comparator-controlled studies compared efficacy and safety between oral XARELTO 10 mg once daily and subcutaneous enoxaparin 40 mg once daily or 30 mg every 12 hours for VTE prevention in patients undergoing elective total hip arthroplasty or total knee arthroplasty.^34-37

• RECORD 1 (N=4541) and RECORD 2 (N=2509) compared efficacy and safety between oral XARELTO 10 mg once daily and subcutaneous enoxaparin in patients who underwent total hip arthroplasty.
• RECORD 3 (N=2531) and RECORD 4 (N=3148) compared efficacy and safety between oral XARELTO 10 mg once daily and subcutaneous enoxaparin in patients who underwent total knee arthroplasty.
• Efficacy and safety outcome measures were the same for all trials.

Risk Reduction of Major CV Events in Stable Coronary Artery Disease (CAD) and Peripheral Artery Disease (PAD)

COMPASS was a phase 3, event-driven, double-blind, randomized, controlled study designed to evaluate whether treatment with XARELTO and aspirin versus aspirin alone or XARELTO alone versus aspirin alone is more effective for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD.³⁸

• The incidence of epistaxis was not identified in the published literature regarding this trial.

Acute Coronary Syndrome (ACS)

ATLAS-ACS TIMI-51 was a randomized, multicenter, double-blind, event-driven trial to determine whether XARELTO, when added to standard care, was safe and reduced the risk of the composite of cardiovascular death, myocardial infarction, or stroke in patients with ACS compared with placebo.³⁹

• The incidence of epistaxis was not identified in the published literature regarding this trial.

Prevention of VTE in Medically Ill Patients Requiring Hospitalization

The phase 3 MAGELLAN trial was an international, randomized, double-blind, active-comparator-controlled study to evaluate the efficacy and safety of once-daily oral XARELTO, compared to standard-duration once-daily subcutaneous enoxaparin, and to evaluate the role of extended-duration XARELTO (up to 39 days) for the prevention of VTE in acutely ill medical patients who required hospitalization.⁴⁰

• The incidence of epistaxis was not identified in the published literature regarding this trial.

The MARINER study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 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 posthospital discharge.⁴¹

• The incidence of epistaxis was not identified in the published literature regarding this trial.

Prevention of Thrombotic Events in Pediatric Patients Post Fontan Procedure

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 PK and PD 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.¹⁰

• There was one patient (2%) in the XARELTO part B (N=64) group with a major bleeding event of epistaxis. The epistaxis was in a noncritical site and was considered a major bleeding event because the patient required a blood transfusion. The rates of epistaxis classified as trivial bleeding were 11% (7/64) and 9% (3/34) in the XARELTO and aspirin part B groups respectively.
• No cases of epistaxis were reported in the XARELTO part A group.

Case Series/Report

Duran et al (2024)⁴² reported a single-center case series of pediatric patients with congenital heart disease (CHD) treated with XARELTO (N=27).

• The study included patients who were aged <18 years; diagnosed with CHD; and treated with XARELTO between May 1, 2020, and July 30, 2022.
• There were 9/27 (33%) female patients. The median age at XARELTO initiation was 42 months (interquartile range [IQR], 11-56 months), with the youngest patient being 4 months old at the time.
• A total of 19/27 (70%) patients were initiated on XARELTO treatment for single-ventricle CHD, 12/27 (44%) patients for VTE (treatment group), and 15/27 (56%) patients for prophylaxis (prophylaxis group).
• Of the 12 patients who were initiated on XARELTO treatment for VTE, 8 (75%) patients experienced VTE resolution, and 2 others (83%) had no further VTE propagation.
• New VTE formation was reported in 2 patients (17% of treatment group; 7% of total); these patients had multiple significant thrombus risk factors.
• No thrombus formation was reported in patients who were treated with XARELTO for VTE prophylaxis.
• Bleeding was reported in 2 patients, 1 each in the treatment and prophylaxis groups.
  • After 29 days of treatment, the treatment-group patient had recurrent episodes of prolonged epistaxis that were ultimately treated with a transfusion of packed red blood cells (RBCs) and XARELTO discontinuation. The patient had a history of prolonged epistaxis before XARELTO initiation and did not seek medical evaluation in a timely manner as recommended.
  • The prophylaxis-group patient had hematochezia on treatment day 2 that resolved itself without a significant decrease in hematocrit. XARELTO was stopped and restarted safely.
• The overall event rate of bleeding was 12.9 events per 100 patient-years.
• No intracranial bleeds were reported in the cohort.
• Overall, 3 deaths were reported due to complex CHD-related complications. No deaths were deemed related to XARELTO treatment.

Utkewicz et al (2015)⁴³ reported a case of an 82-year-old man with right-sided anterior epistaxis in a XARELTO-treated patient that was managed with topical tranexamic acid.

• His physical exam revealed point bleeding over the right anterior nasal septum, which was initially treated with silver nitrate and then with thrombin solution via a nasal tampon.
• Reassessment revealed additional bleeding in the left nare. The packing was removed and a cotton pledget soaked with 500 mg tranexamic acid was applied and removed without obvious bleeding.
• Another nasal tampon was placed, but continued to ooze, at which point a double-balloon catheter was placed and eventually resulted in cessation of bleeding. The double-balloon catheter was maintained in place and only aspirin therapy was advised until the patient’s follow-up office visit the following day. The patient completed follow-up with no additional bleeding.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 August 2026.