PRODUCT LABELING

Please refer to the following sections of the enclosed full Prescribing Information that are relevant to your inquiry: WARNINGS AND PRECAUTIONS and OVERDOSAGE.

Warnings and Precautions

Risk of Bleeding

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

Reversal of Anticoagulant Effect

An agent to reverse the anti-factor Xa activity of XARELTO is available. Because of high plasma protein binding, XARELTO is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of XARELTO. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate or recombinant factor VIIa has not been evaluated.¹

Use in Specific Populations

Females and Males of Reproductive Potential

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants, including XARELTO, should be assessed in females of reproductive potential and those with abnormal uterine bleeding.¹

Drug Interactions

Anticoagulants and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)/Aspirin

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.¹

CLINICAL STUDIES

EINSTEIN-Extension

The Continued Treatment Study (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 pulmonary embolism (PE) or deep vein thrombosis (DVT) who had been treated for 6 to 12 months with XARELTO or vitamin K antagonist (VKA).²

• The primary efficacy outcome was symptomatic, recurrent venous thromboembolism (VTE; a composite of DVT or nonfatal or fatal PE).²
• The principal safety outcome was major bleeding, which was defined as if it was clinically overt and associated with a fall in the hemoglobin level of 20 g per liter or more, or if it led to transfusion of 2 or more units of red cells, or if it was retroperitoneal, intracranial, occurred in a critical site, or contributed to death.²⁵
  • The primary safety outcome occurred in 4 (0.7%) of the patients in the XARELTO group and none in the placebo group (P=0.11).²
  • One of the 4 reported major bleeds was identified as menorrhagia and led to treatment discontinuation.²
• Clinically relevant nonmajor bleeding outcomes was also observed in the safety population, which was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study treatment, or associated with any other discomfort such as pain or impairment of activities of daily life.²⁵
• The incidence of uterine bleeding, classified under clinically relevant nonmajor bleeding, was observed in 3 XARELTO treated patients and 2 placebo treated patients (0.50% vs 0.34% of respectively).²

Dzhenina et al (2020)

Dzhenina et al (2020)⁴ conducted a real-world study using EINSTEIN-DVT/-PE data to assess the incidence of uterine bleeding during XARELTO therapy.

• Over a period of 3 years, 72 female patients of reproductive age, with regular menstruation, and with DVT were observed. The duration of thrombosis ranged between 3 and 36 months.
• All patients received XARELTO 20 mg/day.
• At baseline, a total of 19 patients had gynecological disorders such as endometriosis, uterus myoma, and endometrial polyps, 6 had hypermenorrhea, and all patients denied the presence of active menometrorrhagia until venous thrombosis development.
• During XARELTO therapy, 32 (44.4%) patients experienced new-onset hypermenorrhea or progression of hypermenorrhea. Of these patients, 7 experienced menometrorrhagia.
• XARELTO was reduced to 10 mg/day in 3 patients with a positive effect. The dose was reduced in 15 patients only for menstruation, with 9 patients noting a decrease in blood loss by flexible mode of anticoagulation.
• XARELTO was replaced with apixaban 5 mg/day in 2 patients, with apixaban 10 mg/day in 2 patients, and with enoxaparin 40 mg/day in 1 patient. The reduced dose of alternative anticoagulant had a positive effect in all patients. There was no recurrence of DVT in these patients during the observation period.
• Anticoagulation was completed prematurely in 9 patients. Following cessation of XARELTO therapy, 1 patient, who had a history of recurrent DVT, developed thrombosis again.

Martinelli et al (2016)

Martinelli et al (2016)³ conducted a post hoc analysis of the EINSTEIN-DVT and -PE study cohort to compare the incidences of recurrent VTE and abnormal uterine bleeding in female patients who did and did not utilize concomitant hormonal therapy while taking XARELTO or enoxaparin/VKAs for confirmed symptomatic DVT and/or PE. A total of 1888 female patients <60 years of age were eligible for participation in these analyses. After excluding those who had undergone a hysterectomy, 1737 were evaluated in the uterine bleeding analysis.

• In the EINSTEIN-DVT and -PE trials, patients were followed for the desired treatment period and assessed at identical fixed intervals for both treatment groups. At visits, patients were evaluated systematically to determine whether they had experienced any signs or symptoms of recurrent VTE and bleeding, including uterine bleeding.
• Female patients of childbearing potential were instructed to use sufficient methods of contraception. The protocol did not specify a specific contraceptive method or hormonal replacement therapy.
• Abnormal uterine bleeding occurred more frequently in the XARELTO treatment arm than in the enoxaparin/VKA treatment arm (hazard ratio [HR]: 2.13; 95% confidence interval [CI]: 1.57-2.89).
  • The incidence density of abnormal uterine bleeding during hormonal therapy for patients treated with XARELTO and enoxaparin/VKA were 29.8%/year and 15.5%/year, respectively, whereas the values were 30.7%/year and 13.4%/year for those without hormonal therapy (P_interaction=0.68).
• Uterine bleeding leading to transfusion occurred more frequently in the XARELTO treatment arm (n=19) than in the enoxaparin/VKA treatment arm (n=3).
  • Twenty of the 22 patients with uterine bleeding leading to transfusion had concomitant anemia at baseline, and 9 had uterine fibroids and/or adenomyosis.

REGISTRY STUDIES

Myers and Webster (2016)

Myers and Webster (2016)⁵ conducted a small, real-world, prospective, observational study, reporting on personal experience with both XARELTO and apixaban. The East Midlands database was utilized for the analysis. Side effects, including heavy menstrual bleeding (HMB), were reported in all patients either beginning or changing to a direct oral anticoagulant (DOAC) between January 2012 and October 2015. A total of 139 female patients, aged 55 or younger, were studied.

• Of the 139 female patients examined, 96 reported taking XARELTO and 43 reported taking apixaban. HMB was reported in 28 patients, 24 of whom received XARELTO.
• Most patients treated in the short-term completed the regimen (8/10).
  • The 2 patients that stopped taking XARELTO had to stop due to severe menorrhagia, one of whom required transfusion.
• Among patients requiring long-term anticoagulation, 9 with HMB discontinued XARELTO, 7 switched to apixaban therapy, and 5 reported symptom resolution.
• Four of the 43 patients taking apixaban reported HMB. Of these patients, 1 had a diagnosis of polycystic ovary syndrome, 1 reported HMB that was comparable to when on warfarin, and another reported more severe menstrual bleeding as compared to warfarin.
• A calculated HR of the likelihood of menorrhagia was 2.688 (95% CI: 0.989-7.273).

Beyer-Westendorf et al (2016)

Beyer-Westendorf et al (2016)⁶ investigated the management and outcomes of vaginal bleeding complications in a case series of female patients of reproductive age during therapy with direct oral factor Xa inhibitors. Individuals identified for inclusion in the study came from 2 sources of prospectively collected data: the noninterventional Dresden Novel Oral Anticoagulant (NOAC) Registry (NCT01588119), and all locally archived data from phase 3 trials of direct oral factor Xa inhibitors done at University Hospital Carl Gustav Carus Dresden, which consisted of EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY, AMPLIFY-EXT, and Hokusai-VTE covering a time period from March, 2007, to October, 2012.

• A total of 178 female patients of reproductive age who received direct oral factor Xa inhibitor therapy were identified, of whom 57 had vaginal bleeding events, including 50 who received XARELTO, 6 who received apixaban, and 1 who received edoxaban.
  • These 57 patients had 72 vaginal bleeding events, including 59 cases of HMB and 13 bleeding events unrelated to the menstrual cycle.
    • Fifty-one (86%) of these HMB events (2 major bleeding events, 17 clinically relevant nonmajor bleeding events, 32 minor bleeding events) were treated conservatively (eg, change of oral hormone therapy or reduction, temporary interruption, or discontinuation of direct oral factor Xa inhibitor).
    • The remaining 8 (14%) events (3 major bleeding events and 5 clinically relevant nonmajor bleeding events) required elective surgical or interventional treatment (hysterectomy, curettage, ovary excision, or excision of ovarian cysts).
    • Thirteen (23%) patients had a second bleeding event and 2 (4%) had a third bleeding event.
    • Nine patients had underlying anatomical abnormalities; compared with patients without abnormalities, these patients had more intense bleeding, more had recurrent bleeding (5 [56%] of 9 patients with abnormalities vs 8 [17%] of 48 patients without abnormalities), and more needed surgical treatment for bleeding (8 [89%] of 9 vs 0 of 48).

PROSPECTIVE STUDIES

Boonyawat et al (2021)

Boonyawat et al (2021)⁷ conducted a subanalysis of the EINSTEIN-CHOICE study, prospectively collecting data on the duration and intensity of menstrual bleeding in female patients who reported having menstrual cycles, as well as on the actions taken to manage the bleeding.

• EINSTEIN-CHOICE was a 3-arm, parallel-group, multicenter, double-blind, double-dummy, randomized study that compared once-daily XARELTO 20 mg, XARELTO 10 mg, and aspirin 100 mg for extended treatment of VTE in patients who had completed 6 to 12 months of anticoagulant therapy.
• Of the 1500 female patients enrolled in EINSTEIN-CHOICE, 377 (25.1%) reported having menstrual cycles. Data on menstrual flow duration and intensity were collected from 362 (96.0%) of these patients, of whom 134 (37.0%) received XARELTO 20 mg, 120 (33.1%) received XARELTO 10 mg, and 108 (29.8%) received aspirin. Menstrual flow duration and intensity were assessed at days 30, 90, 180, 270, and 360 and were compared with duration and intensity observed prior to starting anticoagulant therapy. A baseline history of HMB was reported in 2 (1.5%), 3 (2.5%), and 0 patients in the XARELTO 20 mg, XARELTO 10 mg, and aspirin groups, respectively.
• Over the 5 follow-up assessments, menstrual flow duration was longer than usual in 12-18% of the patients given XARELTO 20 mg, in 6-12% of the patients given XARELTO 10 mg, and in 9-12% of the patients given aspirin. Corresponding increases in flow intensity were 19-24%, 14-21%, and 13-20%, respectively.
• Comparisons among treatment groups:
  • XARELTO 20 mg vs aspirin: The frequency of increased menstrual flow duration (odds ratio [OR], 1.36; 95% CI, 0.62-2.96; P=0.63) and intensity (OR, 1.41; 95% CI, 0.67-2.99; P=0.52) was numerically (but not statistically significantly) higher in patients treated with XARELTO 20 mg vs those treated with aspirin.
  • XARELTO 10 mg vs aspirin: The frequency of increased menstrual flow duration (OR, 0.77; 95% CI, 0.33-1.81; P=0.76) and intensity (OR, 1.07; 95% CI, 0.49-2.34; P=0.98) was numerically (but not statistically significantly) lower in patients treated with XARELTO 10 mg vs those treated with aspirin.
  • XARELTO 10 mg vs XARELTO 20 mg: The frequency of increased menstrual flow duration (OR, 0.57; 95% CI, 0.26-1.25; P=0.21) and intensity (OR, 0.76; 95% CI, 0.37-1.57; P=0.64) was numerically (but not statistically significantly) lower in patients treated with XARELTO 10 mg vs those treated with XARELTO 20 mg.
• There were no statistically significant differences in menstrual hemorrhage patterns between patients treated with 10 or 20 mg of XARELTO and aspirin. Compared with XARELTO 10 mg and aspirin, XARELTO 20 mg was more often associated with increased menstrual flow duration and intensity.
• Overall, 21 (15.7%), 15 (12.5%), and 15 (13.9%) patients treated with XARELTO 20 mg, XARELTO 10 mg, and aspirin, respectively, had an action taken. Actions could be change in hormonal therapy, stopping study medication, referral to gynecologist, blood transfusion, prohemostatic/antifibrinolytic therapy, or iron supplementation. Stopping or interrupting study medication, use of blood transfusion, and use of prohemostatic/antifibrinolytic therapy were reported 9 times in the XARELTO 20mg group vs 2 times in the other 2 groups. There were no statistical differences between groups.

Bryk et al (2016)

Bryk et al (2016)⁸ conducted a single-center, prospective study investigating the incidence of HMB in female patients aged 18-55 years treated with XARELTO compared to those on VKAs. Between May 2013 and June 2016, 210 female patients referred to the Center for Coagulation Disorders at the John Paul II Hospital in Cracow, Poland for suspected thrombophilia were identified. Among these, 121 patients were eligible for inclusion in the analysis, including 76 (63%) patients treated with XARELTO and 45 (37%) patients treated with a VKA (26 on warfarin and 20 on acenocoumarol).

• Patients on XARELTO more commonly reported HMB compared with those on VKA (31 [41%] vs 8 [18%], P=0.009).
• Patients treated with XARELTO more frequently needed interventions to reduce menstruation compared with those on VKA (29 [38%] vs 6 [13%], P=0.004).
• During the median follow-up time of 13 months, there were 8 (11%) recurrent VTEs on XARELTO and 3 (7%) on VKA (P=0.5).
• XARELTO treatment predisposed to HMB (OR, 3.2; 95% CI, 1.4-8.2; P=0.007) and the interruption of anticoagulant treatment for 2-3 days (OR, 3.2; 95% CI, 1.1-11.6; P=0.033).
• HMB during XARELTO treatment predisposed to recurrent VTE (OR, 5.3; 95% CI, 1.1-33.3; P=0.038).

RETROSPECTIVE STUDIES

Corrales-Medina (2022)

Corrales-Medina et al (2022)⁹ conducted an observational cohort study to evaluate the safety and effectiveness of DOACs, including XARELTO, apixaban, dabigatran, and edoxaban, to treat VTE in pediatric patients.

• The study reported results from the American Thrombosis and Hemostasis Network 15 (ATHN 15) study (from January 2015 to June 2021) conducted in 15 ATHN-affiliated pediatric centers across the US.
• Patients were divided into 2 cohorts: the retrospective cohort, which included patients who had completed DOAC treatment at least 6 months before the study, and the prospective cohort, which included patients who started DOAC treatment at the start of the study.
• A total of 233 patients were enrolled in the study (male: 46.4%, median age at initial VTE: 16.5 years); of these, most were enrolled retrospectively (79.3%).
• XARELTO was the highest prescribed DOAC (59.1%), followed by apixaban (38.8%), dabigatran (1.3%), and edoxaban (0.9%).
• In the evaluation of DOAC-related HMB in female patients (n=98; age: >12 years), worsening menstrual bleeding was reported in 35.7% (35/98) of patients.
  • Majority of the patients reported HMB at only 1-time point (85.7%) compared to patients who reported HMB multiple times (14.3%).
  • XARELTO was administered to 58.2% (57/98) of patients, apixaban to 37.8% (37/98) of patients, and dabigatran and edoxaban to 2% (2/98) of patients each.
  • Heavy menstrual bleeding on at least 1 follow-up was reported by 45.6% of patients treated with XARELTO vs 18.9% of patients treated with apixaban.
  • In patients who reported HMB, a lower percentage were taking apixaban vs XARELTO (CI, -46.99% to -6.40%; P=0.02).
  • Follow-up action to address DOAC-related HMB, including modification of hormonal therapy, further consultation with a gynecologist, or both, was required by 37.1% (13/35) of patients.
  • None of the patients who reported DOAC-related HMB required switching of anticoagulation therapy.

Weaver et al (2021)

Weaver et al (2021)¹⁰ conducted a retrospective, observational cohort study using real-world data from 4 US healthcare databases to compare the incidence of severe uterine bleeding among female patients newly exposed to XARELTO, apixaban, dabigatran, and warfarin, stratified by indication. Severe uterine bleeding was defined as vaginal bleeding requiring same-day transfusion or surgical management within 60 days, in relation to treatment.

• Analyses were conducted to assess whether individual DOACs (XARELTO, apixaban, and dabigatran) were associated with a risk of severe uterine bleeding compared with warfarin and with each other among patients with prior diagnoses of atrial fibrillation (AF) and VTE.
• The study was conducted using patient data (from October 2010 to December 2018) from the following 4 US administrative claims databases: IBM MarketScan^® Commercial Database, IBM MarketScan^® Multistate Medicaid, IBM MarketScan^® Medicare Supplemental Beneficiaries, and Optum’s Clinformatics^® Data Mart Database.
• Cohorts of adult, female new users of XARELTO, apixaban, dabigatran, and warfarin with ≥183 days of prior continuous database observation were identified. A total of 12 new user cohorts were constructed for 3 indications across 4 treatments.
• A total of 363,919 female patients newly exposed to a DOAC or warfarin with a prior diagnosis of AF (60.8%) or VTE (39.2%) were included in the study.
• In patients treated with DOACs, the overall incidence of severe uterine bleeding was relatively higher in the younger VTE population vs the AF population (unadjusted incidence rates: 2.8-33.7 vs 1.9-10.0 events/1000 person-years, respectively).
• In the propensity score-matched AF population, XARELTO was associated with a moderately increased risk of severe uterine bleeding vs warfarin (HRs and 95% CIs from 0.83 [0.27-2.48] to 2.84 [1.32-6.23] across databases with significant heterogeneity), apixaban (pooled HR, 1.45 [0.91-2.28]), and dabigatran (2.12 [1.01-4.43]), which were sensitive to the time-at-risk period.
• In the propensity score-matched VTE population, XARELTO was associated with a consistently increased risk of severe uterine bleeding vs warfarin (2.03 [1.19-3.27]) and apixaban (2.25 [1.45-3.41]), which were insensitive to the time-at-risk period.

Eworuke et al (2021)

Eworuke et al (2021)¹¹ conducted a retrospective cohort study using the FDA Sentinel System to compare the risk of severe abnormal uterine bleeding resulting in transfusion or surgical intervention among female patients on rivaroxaban vs apixaban, dabigatran, and warfarin. Severe abnormal uterine bleeding was defined as vaginal bleeding requiring same-day red blood cell transfusion and vaginal bleeding requiring surgery (hysteroscopic/laparoscopic/abdominal polypectomy or myomectomy, dilation/curettage, hysterectomy, endometrial ablation, other hysteroscopy, or uterine artery embolization) within 60 days.

• Female patients ≥18 years of age, who had a diagnosis of VTE or AF and were newly initiated on a DOAC (XARELTO, apixaban, dabigatran) or warfarin from October 19, 2010 to September 30, 2015, were identified within the Sentinel Distributed Database and included in the analysis.
• Patients with joint replacement surgery, hysterectomy, vaginal bleeding, use of oral contraception/antifibrinolytics/vaginal packing, insertion of intrauterine device, or any of the study outcomes within 183 days were excluded.
• Study outcomes were severe abnormal uterine bleeding by management and included: vaginal bleed and same-day transfusion (transfusion outcome); vaginal bleed followed by gynecological surgeries within 60 days (surgical outcome).
• Patients were followed from the dispensing date until the first transfusion or surgery following vaginal bleeding, disenrollment from health plan, initiation of another anticoagulant, recorded death, or end of available data, whichever was earliest.
• Cox proportional hazards regression via propensity score stratification was used to estimate the HRs overall and by age (18-50 years and ≥51 years), presence or absence of gynecological disorder, low (dabigatran 75 mg, XARELTO 10 mg, apixaban 2.5 mg) vs high (dabigatran 150 mg, XARELTO 15 and 20 mg, apixaban 5 mg) DOAC dose, and DOAC indication (AF vs VTE). Four pairwise comparisons were conducted for each intervention: XARELTO-dabigatran, XARELTO-apixaban, dabigatran-apixaban, and XARELTO-warfarin.
• A total of 194,400 XARELTO, 80,074 dabigatran, 97,784 apixaban, and 722,772 warfarin new users were identified.
• An increased risk of surgical intervention was observed with XARELTO when compared to dabigatran (HR, 1.19; 95% CI, 1.03-1.38), apixaban (HR, 1.23; 95% CI, 1.04-1.47), and warfarin (HR, 1.34; 95% CI, 1.22-1.47). No difference in risk was observed for the dabigatran-apixaban comparison.
  • Hysteroscopic polypectomy and hysterectomy accounted for more than half of the gynecological surgeries across all treatment groups.
• An increased risk of transfusion was observed with XARELTO when compared to dabigatran (HR, 1.49; 95% CI, 1.03-2.17) and warfarin (HR, 1.12; 95% CI, 0.95-1.33). No difference in risk was observed for the XARELTO-apixaban and dabigatran-apixaban comparisons.
• Among patients with no underlying gynecological conditions, XARELTO was associated with risk of surgical intervention compared to dabigatran (HR, 1.22; 95% CI, 1.05-1.42), apixaban (HR, 1.25; 95% CI, 1.04-1.49), and warfarin (HR, 1.36; 95% CI, 1.23-1.50). No difference in risk was observed for the XARELTO-dabigatran, XARELTO-apixaban, and dabigatran-apixaban comparisons, when stratified by age and dose, for both outcomes.

Anderson et al (2020)

Anderson et al (2020)¹² conducted a retrospective cohort study using the FDA Sentinel System to determine the incidence of abnormal uterine bleeding (defined as vaginal bleeding requiring medical, transfusion, or surgical intervention) among oral anticoagulant users in the US.

• Female patients who had a diagnosis of VTE or AF (in the 183 days prior to [baseline] and including the index date) and were newly initiated on an oral anticoagulant, including a NOAC (XARELTO, apixaban, dabigatran) or warfarin, from October 2010 to September 2015, were identified within the Sentinel Database and included in the analysis.
• Patients with joint replacement, hysterectomy, or outcome of interest (vaginal bleeding management) during the baseline period were excluded.
• Patients were followed from oral anticoagulant dispensing date until the earliest of end of treatment exposure, disenrollment from medical or prescription drug coverage, death, end of study period, or study outcome.
• The 3 abnormal uterine bleeding outcomes of interest included vaginal bleeding diagnosis followed by one of the following within 30 days:
  • 1) Same-day medical intervention (insertion of intrauterine device, vaginal packing, initiation of an oral contraceptive or antifibrinolytic)
  • 2) Same-day red blood cell transfusion
  • 3) Gynecologic surgery (hysterectomy, polypectomy, myomectomy, dilation and curettage, endometrial ablation, or uterine artery embolization)
• Incidence rates of these outcomes were estimated overall and stratified by age group.
• At baseline, overall, 2.8% of patients had a reported gynecologic disorder (adenomyosis, endometrial hyperplasia, endometriosis, gynecologic cancers, ovarian cyst, uterine fibroids, uterine or cervical polyp).
• Among 1,050,192 oral anticoagulant new users, the overall abnormal uterine bleeding incidence rates were 0.6, 1.7, and 5.0 per 1,000 person-years for outcomes with medical, transfusion, and surgical management, respectively.
  • When stratified by age group, the abnormal uterine bleeding incidence rates in female patients ≤50 years increased to 11.8, 13.7, and 33.0 per 1,000 person-years, respectively. All estimates were consistently higher vs those observed in female patients ≥51 years (0.2, 1.2, and 3.9, respectively).
• Across all ages, abnormal uterine bleeding requiring surgical management was more common than abnormal uterine bleeding requiring medical or transfusion management.

DeCrem et al (2015)

DeCrem et al (2015)¹³ was a single-center, retrospective study evaluating abnormal uterine bleeding in female VTE patients of reproductive age who were treated with XARELTO or VKAs. The objective of this study was to evaluate the impact of XARELTO compared to VKAs on abnormal uterine bleeding in acute symptomatic VTE. All patients between ages of 14 and 55 who were enrolled in the VTE care program from September 2007 until September 2014 were assessed for eligibility. Patients were excluded if they did not have an acute symptomatic VTE, but suffered from asymptomatic thrombosis, thrombophilia or superficial thrombophlebitis, as well as patients who were treated with an alternative anticoagulant other than XARELTO or VKAs.

• Three hundred nineteen female patients of reproductive age suffered from a VTE during this timeframe. Of these patients, 111 were treated with VKAs and 81 received XARELTO. A small portion (n=35) received both treatments.
• Patients were assessed by filling out a questionnaire. Fifty-two patient questionnaires from the XARELTO treatment arm, 52 questionnaires from the VKA treatment arm, and 16 questionnaires from patients who had received both treatments were available for assessment.
• Approximately two thirds of all patients reported abnormal uterine bleeding after starting anticoagulant therapy. Patients in the XARELTO treatment arm were reported to be more likely to experience prolonged (>8 days) of menstrual bleeding (27% vs 8.3%, P=0.017). XARELTO treatment increased the duration of menstrual bleeding from a median of 5 (interquartile range [IQR], 3.5-6.0) days before treatment initiation to 6 (IQR, 4.1-8.9) days (P<0.001). VKA did not lead to significant prolongation of the menstrual period. The start of VKA treatment increased intermenstrual bleeding rates (26% vs 7.8%, P=0.018), but did not have a significant effect on the duration of menstrual blood loss or on prolonged bleeding rates.
• Patients on XARELTO more often reported an unscheduled contact with a medical practitioner (41% vs 25%, P=0.096), more medical or surgical intervention (25% vs 7.7%, P=0.032), and had more adaptations of anticoagulant therapy (15% vs 1.9%, P=0.031) for abnormal uterine bleeding than those utilizing VKAs.

Ferreira et al (2016)

Ferreira et al (2016)¹⁴ reviewed the clinical course of female patients between the ages of 16 and 55 who were treated with XARELTO between September 2012 and September 2014.

• Of 128 analyzed patients, HMB was documented in 26 (20%), with a mean age of 38.7 years.
  • Forty-seven (37%) patients were treated with an anticoagulant other than XARELTO, of whom 5 (11%) had previously documented HMB. Of the 47 patients who received XARELTO, 10 reported experiencing HMB, of whom only 2 had previously reported experiencing HMB.
  • Anemia was reported in 23% (n=6) of those with HMB, with a mean drop in hemoglobin from 18 g/L and mean hemoglobin of 114 g/L (range, 72-140 g/L). One episode of major bleeding required hospitalization, blood transfusion, and tranexamic acid due to severe HMB.
  • Uterine fibroid disease was found in 12 of the 15 patients with reported HMB who had a pelvic scan, with an average age of 43.2 years.
  • Surgery was planned in 3 patients (1 hysterectomy and 2 myomectomies), all of whom had to discontinue anticoagulation with XARELTO. Only 7 patients without HMB had reported fibroid disease.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 25 November 2024.