rivaroxaban and Uterine-Hemorrhage

Antithrombotic therapies are associated with an increased bleeding risk. Abnormal uterine bleeding data have been reported in clinical trials of patients with venous thromboembolism (VTE), but data are limited for patients with atrial fibrillation (AF).. Using real-world data from four US healthcare databases (October 2010 to December 2018), we compared the occurrence of severe uterine bleeding among women newly exposed to rivaroxaban, apixaban, dabigatran, and warfarin stratified by indication.. To reduce potential confounding, patients in comparative cohorts were matched on propensity scores. Treatment effect estimates were generated using Cox proportional hazard models for each indication, in each database, and only for pairwise comparisons that met a priori study diagnostics. If estimates were homogeneous (I. Data from 363,919 women newly exposed to a direct oral anticoagulant or warfarin with a prior diagnosis of AF (60.8%) or VTE (39.2%) were analyzed. Overall incidence of severe uterine bleeding was low in the populations exposed to direct oral anticoagulants, although 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). In the propensity score-matched AF population, a suggestive, moderately increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [hazard ratios and 95% confidence intervals from 0.83 (0.27-2.48) to 2.84 (1.32-6.23) across databases with significant heterogeneity], apixaban [pooled hazard ratio 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, a consistent increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [2.03 (1.19-3.27)] and apixaban [2.25 (1.45-3.41)], which were insensitive to the time-at-risk period.. For women who need antithrombotic therapy, personalized management strategies with careful evaluation of benefits and risks are required. CLINICALTRIALS.. NCT04394234; registered in May 2020.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Observational Studies as Topic; Pyridones; Risk Assessment; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism; Warfarin

Up to two-thirds of menstruating women experience abnormal uterine bleeding (AUB) when treated with oral anticoagulants. However, the true prevalence of AUB for specific agents remains uncertain, as many of these episodes, while interfering significantly with quality of life and overall health, are not captured by definitions of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) used in clinical trials. A 2017 systematic review determined that women taking rivaroxaban, but not edoxaban or apixaban, had a twofold higher risk of AUB than women taking warfarin. Since then, new data have become available from extension trials, cancer-associated venous thromboembolism trials, pediatric trials, and a few observational studies specifically examining AUB as an outcome. Reported rates of uterine CRNMB were low (around 1%) and similar for rivaroxaban and apixaban in all these studies, and no episodes of uterine bleeding meeting MB criteria were reported. Rates of AUB not meeting MB or CRNMB criteria were much higher, affecting up to 50% of women on rivaroxaban. Only 1 such study included women on apixaban, and no AUB was reported. In pediatric trials, 19% of girls experienced menorrhagia when treated with rivaroxaban. In conclusion, rates of uterine MB and CRNMB were low in all studies, but rates of other types of AUB not meeting these criteria ranged from 15.8% to 50%. We conclude that AUB is underreported due to the limitations of MB/CRNMB criteria despite its substantial impact on quality of life. We urge future investigators to include broader definitions of AUB to better capture the impact of this outcome in menstruating women treated with oral anticoagulants.

Topics: Administration, Oral; Adult; Anticoagulants; Female; Humans; Pyrazoles; Pyridones; Rivaroxaban; Uterine Hemorrhage

There have been reports of clinically relevant uterine bleeding events among women of reproductive age exposed to rivaroxaban.. The aim of this study was to compare the risk of severe abnormal uterine bleeding (SAUB) resulting in transfusion or surgical intervention among women on rivaroxaban versus apixaban, dabigatran and warfarin.. We conducted a retrospective cohort study in the FDA's Sentinel System (10/2010-09/2015) among females aged 18+ years with venous thromboembolism (VTE), or atrial flutter/fibrillation (AF) who newly initiated a direct oral anticoagulant (DOAC; rivaroxaban, apixaban, dabigatran) or warfarin. We followed women from dispensing date until the earliest of transfusion or surgery following vaginal bleeding, disenrollment, exposure or study end date, or recorded death. We estimated hazard ratios (HRs) using Cox proportional hazards regression via propensity score stratification. Four pairwise comparisons were conducted for each intervention.. Overall, there was an increased risk of surgical intervention with rivaroxaban when compared with dabigatran (HR 1.19; 95% CI 1.03-1.38), apixaban (1.23; 1.04-1.47), and warfarin (1.34; 1.22-1.47). No difference in risk for surgical intervention was observed for dabigatran-apixaban comparisons. Increased risk of transfusion was observed for rivaroxaban compared with dabigatran (1.49; 1.03-2.17) only. For patients with no gynecological history, rivaroxaban was associated with risk of surgical intervention compared with dabigatran (1.22; 1.05-1.42), apixaban (1.25; 1.04-1.49), and warfarin (1.36; 1.23-1.50).. Our study found increased SAUB risk with rivaroxaban use compared with other DOACs or warfarin. Increased risk with rivaroxaban was present among women without underlying gynecological conditions. Women on anticoagulant therapy should be aware of a risk of SAUB.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Uterine Hemorrhage; Warfarin

Topics: Anticoagulants; Dabigatran; Female; Humans; Incidence; Pyrazoles; Pyridones; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism

This is a case report of a 48-year-old woman who presented with heavy per vaginal bleeding to the emergency department after being commenced on direct oral anticoagulants (DOACs) for venous thromboembolism. She had significant bleeding which initially required resuscitation and stabilisation. Her symptoms were ultimately managed by changing her anticoagulation agent to therapeutic low molecular weight heparin with Clexane

Topics: Administration, Oral; Anticoagulants; Contraceptives, Oral; Diagnosis, Differential; Enoxaparin; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Middle Aged; Rivaroxaban; Treatment Outcome; Uterine Hemorrhage; Venous Thromboembolism

Massive pulmonary embolism (PE) is defined by acute PE with sustained systemic arterial hypotension that is below 90 mm Hg for at least 15 min or requires inotropic agents (Jaff et al., 2011). For patients with absolute contraindications to thrombolysis, interventional treatment requires the removal of obstructing thrombi from the main pulmonary arteries to facilitate RV recovery and improve symptoms and survival (European Respiratory Society et al., 2014). For patients with acute PE, anticoagulation is recommended, with the objective of preventing both early death and recurrent symptomatic or fatal VTE. Rivaroxaban, an oral factor Xa inhibitor and a new oral anticoagulants, shows effective anticoagulation within hours of administration. It has a fixed-dose regimen, and requires no laboratory monitoring (EINSTEIN-PE Investigators et al., 2012). However, the efficacy and safety of rivaroxaban plus catheter-directed treatment for massive PE and bleeding is unknown. This case demonstrated that a combination of catheter-directed treatment and rivaroxaban was safe and effective in for the treatment of severe PE with vaginal bleeding.

Topics: Administration, Oral; Catheterization; Computed Tomography Angiography; Electrocardiography; Factor Xa Inhibitors; Female; Heparin; Humans; Infusions, Intravenous; Middle Aged; Pulmonary Embolism; Rivaroxaban; Tachycardia; Thrombolytic Therapy; Treatment Outcome; Uterine Hemorrhage

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration.

Topics: Adult; Anticoagulants; Contraceptives, Oral, Hormonal; Drug Synergism; Enoxaparin; Estrogen Replacement Therapy; Estrogens; Female; Humans; Middle Aged; Progestins; Proportional Hazards Models; Randomized Controlled Trials as Topic; Recurrence; Retrospective Studies; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism; Young Adult

In this issue of Blood, Martinelli et al provide reassuring data that women taking oral anticoagulant therapy for venous thromboembolism (VTE) may use estrogen or progestin hormonal therapy to control the menstrual bleeding without increased risk for recurrent thromboembolism.

Topics: Anticoagulants; Enoxaparin; Estrogens; Female; Humans; Progestins; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism

Topics: Administration, Oral; Anticoagulants; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Pyridones; Rivaroxaban; Treatment Outcome; Uterine Hemorrhage

Observational data and results from post-hoc analyses in clinical trials suggest that direct oral factor Xa inhibitors might increase menstrual bleeding intensity in women of reproductive age, but the extent of this effect is unknown. We aimed to investigate the management and outcomes of vaginal bleeding complications during therapy with direct oral factor Xa inhibitors in a case series of women of reproductive age.. To identify individuals for inclusion in this case series, we searched two sources of prospectively collected data from women of reproductive age treated with direct oral factor Xa inhibitors: the non-interventional Dresden NOAC Registry (NCT01588119), which is based in the administrative district of Dresden (Saxony, Germany), and all locally archived data from phase 3 trials of direct oral factor Xa inhibitors done at University Hospital Carl Gustav Carus Dresden. Vaginal bleeding events were defined as any vaginal bleeding complications as reported by the patient. We collected data on type and dosage of anticoagulation; suspected or confirmed bleeding events, hospital admissions, and mortality; and pattern and management of vaginal bleeding events. For all cases of bleeding identified, we reviewed all available source data to identify examination results suggesting potential underlying anatomical causes of bleeding.. We identified 178 women of reproductive age who received direct oral factor Xa inhibitor therapy, of whom 57 had vaginal bleeding events, including 50 who received rivaroxaban, six who received apixaban, and one who received edoxaban. These 57 women had 72 vaginal bleeding events, including 59 cases of heavy menstrual bleeding and 13 bleeding events unrelated to the menstrual cycle. 51 (86%) of these heavy menstrual bleeding events (two major bleeding events, 17 clinically relevant non-major 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) and the remaining eight (14%) events (three major bleeding events and five clinically relevant non-major bleeding events) required elective surgical or interventional treatment (hysterectomy, curettage, ovary excision, or excision of ovarian cysts). Of the 57 women, 13 (23%) had a second bleeding event and two (4%) had a third event. Nine patients had underlying anatomical abnormalities; compared with patients without abnormalities, these patients had more intense bleeding, more had recurrent bleeding (five [56%] of nine patients with abnormalities vs eight [17%] of 48 patients without abnormalities), and more needed surgical treatment for bleeding (eight [89%] of nine vs zero of 48).. Vaginal bleeding, particularly heavy menstrual bleeding, is a common complication in women of reproductive age on direct oral factor Xa inhibitor therapy. Most cases can be treated conservatively, but patients with severe or recurrent vaginal bleeding complications should be assessed for underlying anatomical abnormalities, which might require surgical or interventional treatment. Further data are needed to provide guidance on prevention and treatment of vaginal bleeding complications in this patient population.. None.

Topics: Administration, Oral; Adult; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hormone Replacement Therapy; Humans; Menorrhagia; Middle Aged; Progesterone; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Uterine Hemorrhage; Venous Thromboembolism

Anticoagulants increase the risk of heavy menstrual bleeding (HMB). We sought to investigate the incidence, predictors and management of HMB in women on rivaroxaban compared to those on vitamin K antagonists (VKA). We addressed the issue as to whether HMB is associated with VTE recurrences. We performed a single-center prospective study in menstruating women aged 18-55years treated with rivaroxaban or VKA≥3months since the index VTE episode. Seventy six women on rivaroxaban and 45 patients on VKA were included. Patients on rivaroxaban more commonly reported HMB compared with those on VKA (31 [41%] vs. 8 [18%], p=0.009). Women treated with rivaroxaban 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 13months, there were 8 (11%) recurrent VTE on rivaroxaban and 3 (7%) on VKA (p=0.5). Rivaroxaban treatment predisposed to HMB (odds ratio [OR] 3.2, 95% [confidence interval] CI 1.4-8.2, p=0.007) and the interruption of anticoagulant treatment for 2-3days (OR 3.2, 95% CI 1.1-11.6, p=0.033). HMB during the rivaroxaban treatment predisposed to recurrent VTE (OR 5.3, 95% CI 1.1-33.3, p=0.038). In menstruating women following VTE, rivaroxaban is associated with a two-fold higher risk of HMB compared with VKA. HMB predisposes to recurrent VTE episode, most likely due to the short interruptions of anticoagulation.

Topics: Adult; Anticoagulants; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Middle Aged; Prospective Studies; Recurrence; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism; Vitamin K; Young Adult

Rivaroxaban is a convenient oral anticoagulant for patients with venous thromboembolism (VTE). The impact of rivaroxaban and vitamin K antagonists (VKAs) on abnormal uterine bleeding (AUB) in real life has not been previously explored.. We performed a single-center retrospective study on AUB in female VTE patients of reproductive age who were treated with either rivaroxaban or VKAs.. Questionnaire results were available for 52 patients in each treatment group. Approximately two thirds of all women reported AUB after initiation of anticoagulant therapy. Patients using rivaroxaban were more likely to experience prolonged (>8days) menstrual bleeding (27 % vs. 8.3%, P=0.017). Rivaroxaban treatment increased the duration of menstrual bleeding from median 5 (IQR 3.5-6.0) days before start of treatment to 6 (IQR 4.1-8.9) days (P<0.001). VKA treatment did not lead to significant prolongation of the menstrual period. Patients on rivaroxaban more frequently reported an unscheduled contact with a physician for AUB than women using VKAs (41% vs. 25%, P=0.096). They also reported increased need for menorrhagia-related 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).. AUB is frequent after initiation of anticoagulant therapy for acute symptomatic VTE. Compared to VKAs, rivaroxaban was associated with prolonged menstrual bleeding and more medical interventions and adaptation of anticoagulant treatment for AUB. These data can guide proactive discussion with patients starting anticoagulant therapy.

Topics: Adult; Anticoagulants; Female; Humans; Retrospective Studies; Risk Factors; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism; Vitamin K; Young Adult

Guidelines concerning the prevention and treatment of pregnancy-associated venous thromboembolism (VTE) have been elaborated by the American College of Chest Physicians and published in Chest in 2008. In this review, they have been compared with European guidelines and discussed taking into account the papers published since 2008.Most recommendations are of low grade of evidence because randomized studies are lacking during pregnancy and many reflect guidelines proposed by experts. The decisions on the most appropriate prophylaxis, dose to be administered and moment of pregnancy for starting prophylaxis are often decided case by case after careful assessment of the risk of pregnancy-associated VTE, on one hand, and the risk for the mother, on the other.Risk factors (age >or= 35, obesity, history of VTE with or without sequellae, in vitro fertilization)or thrombophilia have to be taken into account. Scores have been proposed to improve standardisation and evaluation of the risk of VTE and they should be validated.

Topics: Abnormalities, Drug-Induced; Adult; Anticoagulants; Benzimidazoles; Blood Loss, Surgical; Cesarean Section; Contraindications; Dabigatran; Europe; Evidence-Based Medicine; Female; Fetus; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Infant, Newborn; Morpholines; Polysaccharides; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Hematologic; Puerperal Disorders; Pyridines; Rivaroxaban; Societies, Medical; Thiophenes; Thrombophilia; United States; Uterine Hemorrhage; Venous Thromboembolism; Warfarin