Summary

• ROCKET AF: Major bleeding occurred more frequently in XARELTO-treated patients than warfarin-treated patients (2.00 vs 1.24 events/100 patient-years [PY]; adjusted hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.34-2.05; P<0.0001).¹ Nonmajor clinical bleeding occurred more frequently in XARELTO-treated patients than warfarin-treated patients (1.75 vs 1.39 events/100 PY; adjusted HR, 1.28; 95% CI, 1.43-1.59; P=0.023). Results from a secondary analysis of the ROCKET AF study found that patients >75 years receiving XARELTO had a higher rate (event per 100 PY) of gastrointestinal (GI) bleeding compared with warfarin users (2.81 XARELTO vs 1.66 warfarin; P=0.0002).²
• J-ROCKET AF: Major bleeding from a GI site occurred in 1.3% of the XARELTO patients and 2.3% of the warfarin patients.³ In a subgroup analysis of the J-ROCKET AF study, the event rate (%/year) of major and nonmajor clinically relevant bleeding in patients aged >75 years was 25.05 for XARELTO-treated patients and 16.95 for warfarin-treated patients. The most frequent sites of major bleeding in the >75 years population were intracranial and GI.⁴
• X-VERT: GI bleeding occurred in 0.3% of patients in the XARELTO group compared to 0.2% in the vitamin K antagonist (VKA) group.⁵
• EINSTEIN-DVT: Of the patients who had a fatal treatment-emergent major bleeding event, GI bleeding occurred in 0.06% of XARELTO patients and 0.12% in the enoxaparin/VKA patients. Of the patients that had a nonfatal major bleeding event, GI bleeding occurred in 0.2% of XARELTO patients and 0.2% of in the enoxaparin/VKA patients.⁶
• EINSTEIN-PE: Of the patients who had a major bleeding event, GI bleeding occurred in 0.4% of the XARELTO group and 0.7% of the enoxaparin/VKA group.⁷
• EINSTEIN-Extension: Of the patients who had a major bleeding event, GI bleeding occurred in 0.5% of patients in the XARELTO group and no patients in the placebo group.⁸
• RECORD 1-4: A pooled analysis of these studies showed a fatal GI bleed in 0.02% of the XARELTO patients and 0% in the enoxaparin patients.⁹
• COMPASS: GI bleeding occurred in 1.5%, 1.0%, and 0.7% of patients in the XARELTO+aspirin group, XARELTO-alone group, and aspirin alone group, respectively.¹⁰
• Additional details about the specific site of GI bleeding for the following studies were not noted in the corresponding publications: EINSTEIN clinical program, J-EINSTEIN clinical program, RECORD program, COMPASS, ATLAS-ACS2-TIMI-51, MAGELLAN.
• Pharmacovigilance Study: An analysis of 2-year data from an ongoing observational, post-marketing safety surveillance study reported an incidence of major bleeding of 2.89 per 100 PY with XARELTO therapy. GI bleeding occurred in 87.2% of patients (N=846/970).^11,12
• XANTUS: The incidence rate of treatment-emergent GI bleeding in patients treated with XARELTO was 0.9 per 100 PY.¹³
• The mechanism by which XARELTO is associated with a greater risk of GI bleeding has not been determined.
• SENTINEL DATABASE: Data from the United States Food and Drug Administration (FDA) Sentinel database evaluated the incidence of major bleeding events in groups of patients stratified by age (<65 years and ≥65 years) receiving various DOACs.^14,15
• For patients aged <65 years¹⁵
  • In a comparison of XARELTO vs apixaban, the HR was 1.91 (95% CI 1.56-2.34 by inverse probability of treatment weighted pairwise comparison [IPTW]) for major GI bleeding.
  • In a comparison of XARELTO vs dabigatran, the HR was 1.32 (95% CI, 0.89-1.96 by IPTW) for major GI Bleeding.
• For patients aged ≥65 years¹⁴
  • In a comparison of XARELTO vs apixaban, the HR was 2.32 (95% CI, 2.07-2.59¹⁶ by propensity score matching [PSM]) and 2.35 (95% CI, 2.11-2.61 by IPTW) for major GI bleeding.
  • In a comparison of XARELTO vs dabigatran, the HR was 1.17 (95% CI, 1.08-1.28 by PSM) and 1.16 (95% CI, 1.07-1.25 by IPTW) for major GI bleeding.
• Additional citations are included for review.^17-43

CLINICAL STUDIES

A summary of the incidence rates of GI bleeding from the ROCKET AF, J-ROCKET AF, X-VERT, RECORD 1-4, EINSTEIN-DVT, EINSTEIN-PE, EINSTEIN-Extension, J-EINSTEIN, COMPASS, ATLAS-ACS 2-TIMI-51, and MAGELLAN studies are presented in Table: Incidence of Treatment-Emergent GI Bleeding (Safety Population).

The following studies used a similar definition of major bleeding and nonmajor bleeding: ROCKET AF, J-ROCKET AF, X-VERT, EINSTEIN, J-EINSTEIN, MAGELLAN^3,5,45,47-50

• 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 packed red blood cells or whole blood, or permanent disability.
• Nonmajor clinically relevant bleeding was defined as overt bleeding not meeting criteria for major bleeding but required medical intervention, unscheduled contact with a physician, temporary interruption of study drug, pain, or impairment of daily activities.

For the RECORD program: Major bleeding was defined as bleeding that was fatal, occurred into a critical organ, required re-operation, or was clinically overt from an extra-surgical site and associated with a fall in hemoglobin of ≥2 g/dL or a transfusion of ≥2 units of blood.^51-54

COMPASS used the modified International Society on Thrombosis and Hemostasis criteria for major bleeding defined as: the composite of fatal bleeding, symptomatic bleeding in a critical organ, or bleeding into the surgical site requiring reoperation, and bleeding leading to hospitalization (including presentation to an acute care facility without overnight stay).¹⁰

ATLAS-ACS 2-TIMI 51⁵⁵ defined Thrombolysis in Myocardial Infarction (TIMI) major bleeding as any intracranial bleeding or clinically overt bleeding event that is associated with a decrease in hemoglobin of ≥5 g/dL or an absolute drop in hematocrit of ≥15%. Nonmajor bleeding was defined as an overt bleeding event that does not meet the criteria for a major bleeding event but is associated with medical intervention.

Additional Clinical Study Results: ROCKET AF and RECORD

Sherwood et al (2015)¹ conducted a post-hoc subgroup analysis of the ROCKET AF study to investigate the incidence and outcomes of adjudicated GI bleeding reported during the safety period (from first dose of study medication to last dose + 2 days). All bleeds were adjudicated by a multispecialty clinical events committee blinded to the patients’ treatment assignments. In the outcomes analyses, only the first GI bleed of each type for each patient was considered. Due to differing length of follow-up among patients, event rates were presented as events per 100 PY.

Of the 14,236 patients enrolled in ROCKET AF, 684 (42% warfarin and 58% XARELTO) had major and nonmajor clinically relevant GI bleeds during follow-up. There were significantly more GI bleeding events in XARELTO-treated patients vs warfarin-treated patients. For the rates of GI bleeding, see Table: ROCKET AF Rates of GI Bleeding.

Piccini et al (2014)⁵⁶ conducted an analysis of the safety population within the ROCKET AF study to describe the management and outcomes of major bleeding. A clinical events committee was blinded to treatment assignment and adjudicated all bleeding events using the primary source data and documents. The committee adjudicated both the anatomic site and severity of the bleed using the International Society on Thrombosis and Hemostasis (ISTH) criteria. A total of 779 patients experienced a major bleeding event (395 XARELTO and 384 warfarin). Major bleeding in XARELTO patients was more frequently located in the upper GI tract (hematemesis or melena) than warfarin patients (38.1% vs 25.7%). The location of major bleeding was lower GI tract (11.8% XARELTO patients and 8.1% warfarin patients) and rectal (6.5% XARELTO patients and 2% warfarin patients). See Table: ROCKET AF Rates of GI Bleeding below.

• The decision to re-start or permanently withdraw the study drug after resolution of a bleeding event was left to the discretion of the investigator according to local practice. Permanent discontinuation of study drug was defined as the last dose received on the day of, or 1 or 2 days after, the patient’s last GI bleed. Patients who died within this timeframe were not considered discontinuations. In the setting of GI bleeding, 34% of patients remained on the study drug and 27% permanently discontinued the study drug either at the time of bleeding or 1 to 2 days previously. A total of 39% of patients stopped the study drug at or near the time of GI bleed and re-started the study drug afterward, with a median duration of interruption of 9 days.
• The study identified the following independent factors for GI bleeding: previous GI bleeding, age, decreasing creatinine clearance (CrCl), and anemia at baseline. Potentially modifiable risk factors identified: concomitant use of aspirin and other antiplatelet agents.

Turpie et al (2011)⁹ conducted a pooled analysis of RECORD1-4 studies. Of the 12,729 patients randomized across the 4 pivotal studies, 12,383 were included in the safety population.

• There were 2 fatal bleeding events in the XARELTO group. One of the events was an upper GI bleeding event that occurred in a patient that was taking non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin (ASA) and had multiple gastric ulcers.
• In the total treatment duration pool, 9 patients (8 XARELTO, 1 enoxaparin) had major bleeding. All 9 cases were associated with GI bleeding.

Elderly Population

Halperin et al (2014)² conducted a prespecified secondary analysis of the ROCKET AF study to compare the safety and efficacy results between XARELTO and warfarin in patients ≥75 years versus <75 years.

• Of the 14,264 randomized patients, 6229 (44%) were aged ≥75 years at study entry, of which the median age was 79 years.
• The rates of major bleeding were higher in the older group (4.63 [4.21-5.09] per 100 PY) than in the younger group <75 years old (2.74 [2.47-3.04]; P<0.0001) but there were no significant differences in patients receiving XARELTO compared with warfarin.
• GI bleeding results by age group and treatment group are presented below in Table: ROCKET AF – Subgroup Analysis: Rates of GI Bleeding in Elderly.

• Patients receiving XARELTO had a higher rate of GI bleeding compared with warfarin, regardless of age.

Hori et al (2014)⁴ conducted a subgroup analysis of the J-ROCKET AF study to assess the safety and efficacy of XARELTO and warfarin in relation to age.

• In the 39.0% of patients aged ≥75 years, the event rate (%/year) of the principal safety outcome was 25.05 for XARELTO-treated patients and 16.95 for warfarin-treated patients. In nonelderly patients, the event rate was 14.18 for patients treated with XARELTO and 16.13 for patients treated with warfarin (P=0.04).
• The most frequent major bleeding sites in patients aged >75 are shown in Figure 1.
• Patients >75 years receiving XARELTO had higher rates of GI bleeding compared to those <75 years.

Study Characteristics

Stroke Prevention in Nonvalvular Atrial Fibrillation

The ROCKET AF⁵⁷ study was a phase 3, double-blind, double-dummy, parallel-group, event-driven, noninferiority study designed to evaluate the efficacy and safety of oral XARELTO 20 mg once daily (15 mg for patients with 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 (SE) in patients with nonvalvular atrial fibrillation (NVAF) at moderate-to-high risk for stroke. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days.

The J-ROCKET AF study³ was a double-blind comparison study to confirm noninferiority of XARELTO versus warfarin with regard to the principal safety outcome (major or nonmajor clinically relevant bleeding) for the prevention of stroke in patients in Japan with NVAF. Doses of XARELTO were optimized for the pharmacokinetic and pharmacodynamic profile of Japanese patients. Patients were randomized to either 15 mg XARELTO once daily (10 mg in patients with CrCl 30-49 mL/min) or warfarin (target INR 2.0-3.0 for patients aged <70, or 1.6-2.6 for those aged ≥70).

The X-VERT study⁵ was a prospective, randomized, open-label, parallel-group, phase 3b study that compared the efficacy and safety of XARELTO to dose-adjusted VKA for the prevention of cardiovascular (CV) events in patients with NVAF scheduled for cardioversion. The primary safety endpoint was major bleeding.

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

The EINSTEIN program consisted of 3 phase 3, event-driven, randomized studies of XARELTO.

1. EINSTEIN-DVT⁸ - Open-label, noninferiority study that compared oral XARELTO alone (15 mg twice daily [BID] for 3 weeks, followed by 20 mg once daily) with subcutaneous (SC) enoxaparin (1.0 mg/kg BID) followed by dose-adjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE
2. EINSTEIN-PE⁵⁰ - Open-label, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg BID for 3 weeks followed by 20 mg once daily) versus SC enoxaparin (1.0 mg/kg BID) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT
3. EINSTEIN-Extension⁸ - Double-blind 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 J-EINSTEIN Program consisted of 2 open-label, double blinded, randomized studies of XARELTO in Japanese patients.⁴⁵

1. J-EINSTEIN-DVT - Compared XARELTO (XARELTO 10 mg BID or XARELTO 15 mg BID for the first 3 weeks, followed by XARELTO 15 mg once daily) with the Japanese standard of care (intravenous unfractionated heparin [UFH] for >5 days, overlapping with and followed by INR-adjusted warfarin [range 1.5-2.5]) in patients with a confirmed symptomatic DVT without PE.
2. J-EINSTEIN-PE - Compared XARELTO therapy (XARELTO 15 mg BID for 3 weeks, followed by 15 mg once daily) with the Japanese standard of care in patients with acute symptomatic PE with or without DVT.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

<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 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 (SC) 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.>

The RECORD clinical study program consisted of 4 double-blind, double-dummy, multi-national studies that compared efficacy and safety of oral XARELTO 10 mg once daily and SC enoxaparin 40 mg once daily (RECORD1-3) or 30 mg BID (RECORD4) for VTE prevention in patients undergoing total hip replacement (THR) (RECORD1-2) or total knee replacement (TKR) (RECORD3-4). In both RECORD1 and 2, patients undergoing THR were given XARELTO for 35±4 days. In RECORD3 and 4, patients undergoing TKR were given XARELTO for 12±2 days. Enoxaparin was given for 13±2 days in RECORD3 or 12±2 days in RECORD4. All patients were followed up for 30-35 days after the last dose of study medication.^51-54

Coronary Artery Disease

COMPASS¹⁰ (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) 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 (MI), stroke, or CV death in patients with stable coronary artery disease or peripheral artery disease.

Dosing interventions are as follows:

• XARELTO 2.5 mg BID and aspirin 100 mg once daily
• XARELTO 5 mg BID and placebo once daily
• Placebo BID and aspirin 100 mg once daily

Acute Coronary Syndrome

ATLAS-ACS TIMI-51⁵⁵ was a multi-center, double-blind, event-driven study designed to determine whether XARELTO (2.5 mg BID or 5 mg BID), when added to standard care, was safe and reduced the risk of the composite of CV death, MI, or stroke compared with placebo in stabilized patients after an acute coronary syndrome ACS event. Standard medical therapy included low dose aspirin (75-100 mg) with or without a thienopyridine. Patients were stratified by the investigator’s intention to administer a thienopyridine (clopidogrel or ticlopidine) at the time of enrollment. A total of 93% of patients received a thienopyridine.

Prevention of VTE in Medically Ill Patients Requiring Hospitalization

MAGELLAN⁴⁷ was a phase 3 double-blind study to evaluate the efficacy and safety of once daily oral XARELTO, compared to standard-duration once daily SC 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.

FDA SENTINEL REPORTS

• As part of its pharmacovigilance Sentinel Initiative, the United States Food and Drug Administration (FDA conducts retrospective analyses of safety data collected from electronic health records of patients receiving FDA-regulated drugs. The results of these analyses are published in Sentinel reports.⁵⁸
• Data from the FDA Sentinel database has evaluated the incidence of major bleeding events in groups of patients stratified by age (<65 years and ≥65 years) receiving various DOACs.^14,15
  • Each study evaluated new users of standard-dose apixaban, dabigatran, and XARELTO with a diagnosis of NVAF in the preceding 183 days.
• For patients aged <65 years, the HR (95% CI) for GI bleeding was¹⁵
  • XARELTO vs apixaban, 1.91 (1.56-2.34 by IPTW)
  • XARELTO vs dabigatran, 1.32, 95% CI (0.89-1.96 by IPTW)
• For patients aged ≥65 years, the HR (95% CI) for GI bleeding was¹⁴
  • XARELTO vs apixaban, 2.32 (2.07-2.59 by PSM) and 2.35 (2.11-2.61 by IPTW)
  • XARELTO vs dabigatran, 1.17 (1.08-1.28 by PSM) and 1.16 (1.07-1.25 by IPTW)

POSTMARKETING STUDIES

Pharmacovigilance Study

An ongoing 5-year observational, post-marketing safety surveillance study will provide longitudinal safety data on XARELTO in patients with NVAF. Peacock et al (2015)¹¹ published data collected between January 1, 2013-December 31, 2014. Electronic medical records from the United States (US) Department of Defense database were reviewed to assess patients for major bleeding hospitalizations among XARELTO users. The types of serious bleeding events considered included GI bleeding, hemorrhagic strokes and other intracranial bleeds, genitourinary bleeding, and bleeding at other sites. Major bleeding events were included if they occurred during and up to 7 days post-discontinuation of XARELTO use.

• A total of 970 patients experienced at least 1 major bleed event, representing an incidence of 2.89 per 100 person-years.
• GI bleeding was the most common site of bleeding (87.2%, n=846).¹²
• Of the 35 patients that had a fatal outcome during hospitalization, 9 (25.7%) had GI bleeding.

Tamayo et al (2015)⁵⁹ data is consistent with the data from Peacock et al (2015).

XANTUS

The XANTUS study was a prospective, international, observational study designed to assess the safety and efficacy of XARELTO for stroke prevention in NVAF in routine clinical practice.¹³

• Adjudicated treatment-emergent GI bleeding occurred in 52 (0.8%) of the 6,784 patients treated with XARELTO, representing an incidence rate of 0.9 per 100 PY (95% CI 0.6–1.1).

RETROSPECTIVE STUDIES

ANALYSIS OF POST-MARKETING CASE REPORTS

McDonald et al (2014)⁷¹ analyzed spontaneous adverse event reports associated with XARELTO from Australia, Canada and the US. Spontaneous adverse event reports for XARELTO were obtained from the Australian Therapeutic Goods Administration’s Database of Adverse Event Notifications for Medicines, Health Canada’s Vigilance Adverse Reaction Online Database and the US Food and Drug Administration Adverse Events Reporting System (FAERS) from August 1, 2005 to March 31, 2013. The authors calculated the frequency of adverse events by Medical Dictionary for Regulatory Activities (MedDRA) term as a proportion of all adverse event reports for XARELTO within each of the data sets.

There were 244 spontaneous adverse event reports associated with XARELTO from Australia, 536 from Canada and 1,638 from the US. Reporting of hemorrhage (any type) was common, ranging from 30.7 % for Australia to 37.5 % for Canada. GI hemorrhage was the most commonly reported hemorrhage, accounting for 13.9 % of Australian, 16.4 % of Canadian and 11.1 % of US adverse event reports.

The FDA acknowledges that FAERS data has limitations. For example, there is no certainty that a reported adverse event was actually due to the product. FDA does not require a causal relationship between a product and an event be proven, and reports do not always contain enough detail to properly evaluate an event. Therefore, the FDA states that FAERS data cannot be used to calculate the incidence of an adverse event or medication error in the U.S. population. A full description of FAERS can be accessed at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm

An analysis of FAERS 2016 third-quarter data was conducted to identify predictors of GI bleed among older adults (>65 years of age) who had a documented adverse event caused by a nonsteroidal anti-inflammatory drug; among those reports, XARELTO was observed to increase the risk of GI bleed.⁷²

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 29 July 2024.