rivaroxaban and Drug-Related-Side-Effects-and-Adverse-Reactions

Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify genetic variants correlated with rivaroxaban exposure and evaluate their importance.. We systematically searched PubMed, Web of Science, and Scopus databases for all observational and interventional studies. The fixed effect method was used to pool the data when the Q-test's. Data from ten studies (4721 participants) were analyzed in the current review. Qualitative synthesis from included studies found that two variants of ABCB1 (rs1045642 and rs2032582) and one variant of APOB (rs13306198) are potential contributors to rivaroxaban concentrations. Both wild homozygotes (AA) and heterozygotes (AC) of rs1045642 have significantly lower rivaroxaban concentrations compared to mutated homozygotes (CC) (SMD = 0.516, 95% CI: 0.115 to 0.917; SMD = 0.772, 95% CI: 0.088 to 1.455, respectively). Nevertheless, pooling unadjusted odds ratios did not yield a statistically significant correlation between rivaroxaban ADRs and genetic mutations.. This study revealed that being an AC or CC for rs1045642 is attributed to a considerably higher rivaroxaban level in participants using rivaroxaban. That is to say, rs1045642 is a remarkable predictor of rivaroxaban metabolism. We concluded that identifying rs1045642 before drug administration might decrease ADRs although further studies adjusted for potential confounders are strongly suggested.

Topics: Drug-Related Side Effects and Adverse Reactions; Heterozygote; Homozygote; Humans; Pharmacogenetics; Rivaroxaban

The availability of direct oral anticoagulants (DOAC) in clinical practice has transformed the health care provided to patients for the prevention and treatment of thromboembolism. Safety and efficacy data guide clinicians in the choice of the drug used. To date, no evidence is available from head-to-head trials comparing different DOAC with regard to safety and efficacy; information is mainly derived from several meta-analyses and real-life studies. Conclusions from these studies are inconsistent and unsatisfactory. The evaluation of self-reported adverse drug reactions (ADR) available from databases of drug-regulatory agencies such as the Italian Medicines Agency (AIFA) pharmacovigilance database represents a novel aid to guide decision-making.. To analyze potential suspected ADR of DOAC using a previously described risk index (RI) in daily clinical practice in Italy.. The National Pharmacovigilance Network database (from the AIFA website) was searched in order to retrieve information on all ADR related to oral anticoagulants occurring from 2013 to 2018. The ADR RI for each drug was calculated, where an RI = 1 indicates a balance between the percentage of ADR share and the percentage of market share for each DOAC; and an RI <1 indicates a rate of ADR lower than the rate of market share (safer DOAC). The following DOAC molecules were considered: dabigatran, rivaroxaban, apixaban, and edoxaban.. The results showed that rivaroxaban is the DOAC with the lowest RI among the 4 molecules available today in Italy.. Based on the RI, we identified rivaroxaban as the DOAC having the best safety profile.

Topics: Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Humans; Italy; Pharmacovigilance; Rivaroxaban

Many patients with venous thromboembolism (VTE) are at risk of recurrence if anticoagulant therapy is stopped. Whereas 3 months of anticoagulation treatment is sufficient for patients with VTE provoked by major surgery or trauma, in many cases a longer course is needed. Extended therapy with vitamin K antagonists (VKAs) requires frequent coagulation monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range; furthermore, there is a risk of major bleeding even if a therapeutic INR is maintained. Therefore, more convenient and safer anticoagulants are needed.The non-VKA oral anticoagulants (NOACs)-apixaban, dabigatran, edoxaban and rivaroxaban-simplify extended therapy because they can be given in fixed doses without routine coagulation monitoring. Randomized clinical trials have demonstrated the efficacy and safety of NOACs for extended VTE treatment, but bleeding remains a concern. Patients and physicians may, therefore, be reluctant to continue anticoagulation beyond 3 to 6 months except in patients at high risk of recurrence. Acetylsalicylic acid (ASA) is often prescribed instead of an anticoagulant because of its perceived lower risk of bleeding; however, the recent EINSTEIN CHOICE trial demonstrated that once-daily rivaroxaban at a dose of either 20 or 10 mg reduced the risk of recurrent VTE by 70% compared with ASA without significantly increasing the risk of bleeding. In this review, we discuss the EINSTEIN CHOICE trial in the context of previous trials for extended VTE treatment and examine some of the lessons that can be applied to clinical practice.

Topics: Anticoagulants; Aspirin; Canada; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Recurrence; Risk; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Rivaroxaban is a small-molecule, direct factor Xa inhibitor that is under investigation for the prevention and treatment of venous and arterial thrombosis. To date, oral anticoagulants have been limited largely to vitamin K antagonists. Despite their remarkable benefits, vitamin K antagonists are limited by their narrow therapeutic window, the existence of multiple food and drug interactions, and the need for frequent monitoring and dose-adjustment. Rivaroxaban represents a potentially attractive alternative to warfarin, as it could enable simplified once-daily dosing, requires no therapeutic monitoring, and has a lower potential for drug interactions. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in phase-II and phase-III trials involving over 24,000 patients. Rivaroxaban is also being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes, and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation. The need for new oral anticoagulants, the development and pharmacology of rivaroxaban, results of completed studies of rivaroxaban, and details of ongoing phase-II and phase-III trials with rivaroxaban are the subjects of this chapter.

Topics: Administration, Oral; Animals; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Humans; Morpholines; Rivaroxaban; Thiophenes; Venous Thrombosis

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

Topics: Anticoagulants; Biomarkers, Pharmacological; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Models, Statistical; Prognosis; Prothrombin Time; Risk Adjustment; Risk Assessment; Rivaroxaban; Therapeutic Index; Treatment Outcome; Venous Thromboembolism

We performed a randomized dose-ranging study, double-blind for rivaroxaban doses and open-label for the comparator (low-molecular-weight heparin followed by vitamin K antagonists) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombosis. A total of 543 patients with acute deep-venous thrombosis received rivaroxaban 20, 30, or 40 mg once daily or comparator. Treatment lasted for 84 days. The primary efficacy outcome was the 3-month incidence of the composite of symptomatic venous thromboembolic complications and asymptomatic deterioration in thrombotic burden as assessed by comparison of ultrasound and perfusion lung scanning at day 84 with baseline. The main safety outcome was the composite of major bleeding and clinically relevant nonmajor bleeding. A total of 449 (83%) of the 543 patients could be included in the per-protocol population. The primary efficacy outcome occurred in 6.1%, 5.4%, and 6.6% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 9.9% of those receiving standard therapy. The main safety outcome occurred in 5.9%, 6.0%, and 2.2% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 8.8% of those receiving standard therapy. These results with simple fixed-dose oral regimens justify phase 3 evaluations (www.ClinicalTrials.gov no.NCT00395772).

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antithrombin III; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Male; Middle Aged; Morpholines; Rivaroxaban; Thiophenes; Treatment Outcome; Ultrasonography; Venous Thrombosis

Topics: Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Ethanol; Humans; Rivaroxaban

We report 2 pediatric patients who had acute overdoses of the direct oral anticoagulants medications. Both patients were managed conservatively; neither required reversal agents or blood products nor had any major or minor bleeding events. With therapeutic usage of direct oral anticoagulants, routine coagulation studies typically are considered insufficient measures of anticoagulation and the preferred chromogenic anti-Factor Xa assay is recommended but not widely available. Using a routine hybrid heparin anti-Factor Xa assay, 1 patient demonstrated a strong linear correlation up to a serum rivaroxaban concentration of 940 ng/mL.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Child; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Humans; Rivaroxaban

In Denmark, physicians are legally obliged to report serious adverse drug reactions (ADRs), such as intracranial hemorrhage (ICH) following anticoagulant (AC) treatment, to the Danish Medicines Agency. We were therefore puzzled to discover a high number of reports concerning ICHs following treatment with the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin. This was surprising, as all DOACs have been found to be associated with a lower risk of ICH compared with warfarin in phase III randomized controlled trials.. The primary aim of the study was to estimate the level of underreporting of ICH as an ADR following treatment with warfarin, dabigatran, rivaroxaban, and apixaban.. This observational study covered a 5-year period (2014-2018). Using nationwide registries held by the Danish Health Data Authority, the number of users, exposure time in person-years, and related ICH events for each of the study drugs were estimated. Data on ADR-ICH reports were extracted from the interactive ADR overviews held by the Danish Medicines Agency.. From 2014 to 2018, 97.0% of the identified warfarin-related ICH events were not reported as ADRs. For the DOACs, the level of underreporting ranged from 88.8 to 90.8%.. We found a heavy and differentiated level of underreporting of ICH as an ADR following treatment with the four study drugs.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Denmark; Drug-Related Side Effects and Adverse Reactions; Humans; Intracranial Hemorrhages; Pyridones; Rivaroxaban; Warfarin

Crossover between direct oral anticoagulants (DOACs) has been underinvestigated, but happens frequently in clinical practice. The purpose of this study was to evaluate causes, rates and outcomes of a DOAC-to-DOAC switch.. Patients receiving their first DOAC prescription at the Anticoagulation Center, Cardiology Dept, Bologna-Bellaria Hospital in 2017-2018 were consecutively included and prospectively followed up. DOAC-to-DOAC switch was the main outcome; causes of switch (cardiovascular events and noncardiovascular drug-related adverse events) had direct biannual assessment before and after the switch.. Among 300 patients enrolled (mean age = 79.3 years, mean follow-up = 1.5 years), with no difference in cardiovascular risk factors depending on index DOAC, 13% underwent DOAC-to-DOAC switch, minor bleeding and noncardiovascular adverse events being the most frequent causes. Dabigatran carried a three-fold increase in risk of switch compared with other DOACs, but the mean age of patients who switched was 83. Factors leading to switch resolved in 87% of cases afterwards. Annual rates of cardiovascular/noncardiovascular V events did not differ before and after the switch.. DOAC-to-DOAC switch happens in 9% of patients using DOAC each year, and seems not to impact rates of cardiovascular events after switch. Dabigatran, in the elderly, might be associated with a higher risk of DOAC-to-DOAC switch. Further studies are needed to confirm the long-term safety and effectiveness of switching paradigm.

Topics: Age Factors; Aged; Aged, 80 and over; Cardiovascular Diseases; Dabigatran; Drug Monitoring; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Female; Heart Disease Risk Factors; Humans; Italy; Long Term Adverse Effects; Male; Medication Therapy Management; Risk Adjustment; Rivaroxaban

Limited information is available on anticoagulant-related nephropathy (ARN). We therefore reviewed the Japanese Adverse Drug Event Report database to investigate kidney injury (KI) in patients administered warfarin or direct oral anticoagulants (DOACs) and sought to clarify the risk factors for ARN. KI risk in warfarin users was associated with male sex (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.35-2.13; P < .01) and age ≥80 years (OR, 1.35; 95% CI, 1.07-1.72; P = .01). KI risk in DOAC users was associated with body weight ≥80 kg (OR, 1.60; 95% CI, 1.01-2.53; P = .04) and use of dabigatran (OR, 1.61; 95% CI, 1.09-2.37; P < .01). Our findings suggest that risk factors for ARN differ between warfarin and DOACs and that these risk factors may be associated with bleeding risk. Therefore, the risk of ARN may be decreased by better managing bleeding risk in patients taking anticoagulants.

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Humans; Japan; Male; Risk Factors; Rivaroxaban; Stroke; Warfarin

Direct oral anticoagulant (DOAC) starter packs are designed for unique treatment dosing for acute venous thromboembolism (VTE). Inappropriate use of 30-day DOAC starter packs in patients with atrial fibrillation (AF) may increase the risk for bleeding events given higher dosing in the first 1-3 weeks of treatment. A retrospective analysis of medical and outpatient pharmacy claims data from 2015 to 2018 in Optum's De-identified Clinformatics® Data Mart was performed. Patients greater than 18 years of age with AF and a new prescription of apixaban or rivaroxaban were included. Patients with an acute VTE were excluded. The main outcome of interest was adverse events (emergency department [ED] visits, hospitalizations, and deaths within 90 days after prescription fill date) associated with inappropriate DOAC starter pack prescription. A total of 90,950 DOAC-treated patients with AF were identified. The mean age was 74.5 years (SD 10.0) and 42,717 (47.0%) were female. Inappropriate starter packs were used by 117 (0.1%) patients, who were younger than non-starter pack patients (71.3 years vs. 74.5 years). Patients who received an inappropriate DOAC prescription were more likely to identify as Black (12.0% vs. 8.8%). Rates of ED visits, hospitalizations, and deaths overall were numerically lower in patients with starter pack compared to non-starter pack DOAC prescriptions. In contrast, rates of ED visits and hospitalizations related to significant bleeding were numerically higher in patients with starter pack compared to non-starter pack DOAC prescriptions. Among patients with AF but no VTE, those who received an inappropriate DOAC starter pack had numerically higher rates of severe bleeding leading to ED visits and hospitalizations compared to those prescribed an appropriate non-starter pack DOAC anticoagulant.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Prescriptions; Retrospective Studies; Rivaroxaban; Venous Thromboembolism

Our aim was to compare adverse drug reactions (ADRs) associated with direct-acting oral anticoagulants and vitamin K antagonists from the European EudraVigilance (EV) database. The EV database is the system for the analysis of information on suspected ADRs that are authorised, or being evaluated in clinical trials, in the European Economic Area. Registered ADRs (from the groups "Gastrointestinal disorders", "General disorders and administration site conditions", "Injury, poisoning and procedural complications", "Nervous system (NS) disorders" and "Vascular disorders") for apixaban, rivaroxaban, dabigatran and vitamin K antagonists (VKA) were collected by age group (< 65 years; 65-85 years and > 85 years) and by sex. The proportional reporting ratio (PRR) was used to compare ADRs in relation to the anticoagulants tested. A total of 274,693 ADRs were analysed. For gastrointestinal ADRs, patients treated with rivaroxaban and dabigatran (PRR 2.17 and 2.51, respectively) were at significantly higher risks than those treated with apixaban and VKA (PRR 1.27 and 1.47, respectively), while risks for vascular disorders were increased by all anticoagulants that were tested. Lastly, none of the anticoagulants significantly increased the risk of ADRs within the NS group. Rivaroxaban and dabigatran were associated with a significantly higher risk of gastrointestinal ADR than apixaban or VKA. All anticoagulants increased the risk of vascular pathology while none of them demonstrated significant increased risk of ADR to NS.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Pharmacovigilance; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K; Young Adult

Rivaroxaban is a novel, oral direct acting anticoagulant (DOAC) that is used for both treatment and prevention of thromboembolic diseases. Due to mechanism of action; most common side effect may be seen with hemorrhage. Here in we reported that a patient with chronic atrial fibrillation presented with thrombocytopenia while taking rivaroxaban.. A 76-year-old female patient with atrial fibrillation was given rivaroxaban, after lack of dose administration of warfarin and gastrointestinal bleeding. In 12th dayweek of treatment, the patient was admitted to emergency department (ED) with oral mucosal bleeding and petechial spots.The patient diagnosed as Drug-induced Thrombocytopenia (DITP)due to rivaroxaban use, after ruled out most possibilities ofITP (immune thrombocytopenic purpura). After rivaroxaban is discontinued, the patient's bleeding complaints regressed,symptoms were completely resolved, and platelet count rapidly increased towards physiological level in days. The patient is currently in the 6th month of follow-up and is has no bleeding.. To the best of our knowledge there are only two cases about rivaroxaban induced thrombocytopenia (RIT). In addition to the well-known side effects ofrivaroxaban treatment, it should be kept in mind that thrombocytopenia may also develop.Naranjo adverse drug reaction probability scale calculated as 7 points.(probable cause for the patient's thrombocytopenia).

Topics: Aged; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Female; Humans; Rivaroxaban; Thrombocytopenia

The aim of this study is to assess patterns of potential drug-drug interactions (DDIs) with direct oral anticoagulants (DOACs) in an inpatient hospital setting.. A retrospective chart review was conducted at the Brookdale University Hospital and Medical Center (BUHMC) from January 2014 to November 2016. All adult patients admitted to the BUHMC who were treated with a DOAC for at least 3 days were screened. Among them, those who received selected interacting drugs at any time during the course of DOAC therapy were included in this study.. This study included 165 patients with an average of 73 years (standard deviation [SD] = 12.3) and 233 cases. The most commonly used concomitant drug with a DOAC was aspirin (58%), followed by amiodarone (16%) and P2Y. Despite computerized DDI alerts, potentially significant DDIs with DOACs still occur. While the present study provides insight into the current patterns of DDIs, further studies are needed to evaluate clinical outcomes of the potential DDIs with DOACs in practice.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Dabigatran; Drug Combinations; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Hospitals, Urban; Humans; Male; Middle Aged; Pyridones; Retrospective Studies; Rivaroxaban

Epistaxis is one of the more common reasons for emergency room visits. The main risk factor for epistaxis is anticoagulant therapy. Until recently, the main culprit was oral intake of a vitamin K antagonist, such as warfarin, which has a number of side effects. Even more recently, several direct oral anticoagulants, rivaroxaban and dabigatran, have been approved for use. We investigated the possible differences between treatment of epistaxis with direct oral anticoagulants and vitamin K antagonists.. We conducted a retrospective cohort study at a tertiary referral center in Germany. All patients who were admitted within a 1-year period were included. Patient files were used to obtain the information.. Overall, 677 patients were included in our study. Of these, 159 had been treated with vitamin K antagonists and 49 with direct oral anticoagulants. There were no significant differences in terms of age (p = 0.592), sex (p = 0.372), vital signs, bloodwork, or location of bleeding (p = 0.372). Management of epistaxis between the groups was also comparable (p = 0.399), with similar hospital admission rates (37.1% vs 24.5%; p = 0.145) and duration of stay (3.5 ± 2.1 days vs 3.8 ± 3.3 days; p = 0.650).. We found no evidence to suggest epistaxis is more severe or requires more invasive therapy in patients given direct oral anticoagulants. A significant proportion of patients on vitamin K antagonists were not within the target range for international normalized ratio, highlighting one of the main issues with oral anticoagulation by vitamin K antagonists.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Epistaxis; Female; Follow-Up Studies; Germany; Hospitalization; Humans; Length of Stay; Male; Retrospective Studies; Risk; Rivaroxaban; Treatment Outcome; Warfarin

Patients with nonvalvular atrial fibrillation (NVAF) often have multiple comorbidities requiring concomitant medications in addition to their oral anticoagulant (OAC). The objective of this study was to evaluate the impact of polypharmacy on the effectiveness and safety of rivaroxaban versus warfarin in patients with NVAF managed in routine clinical practice.. Retrospective claims analysis.. United States Truven MarketScan database (November 2012-March 2017).. Adults who were OAC naïve during the 12 months before the day of the first qualifying rivaroxaban or warfarin dispensing (index date); had at least two International Classification of Diseases, Ninth or Tenth Revision diagnosis codes for atrial fibrillation without codes suggesting valvular heart disease; had at least 12 months of continuous insurance coverage prior to the qualifying OAC dispensing; and were experiencing polypharmacy (concomitant prescription claims for five or more unique chronic medication claims) were included. Patients who had concomitant prescription claims for ≥ 10 unique chronic medication claims constituted the substantial polypharmacy cohort used in the secondary analysis. Patients receiving rivaroxaban were propensity-score matched in a 1:1 ratio to patients receiving warfarin (13,981 patients in each polypharmacy OAC group, and 1765 patients in each substantial polypharmacy OAC group).. Patients were followed until occurrence of an event (stroke or systemic embolism [SSE] combined [primary effectiveness outcome] or major bleeding [primary safety outcome]), OAC discontinuation or switch (30-day permissible gap), insurance disenrollment, or end of follow-up period. Rates of SSE, ischemic stroke, and major bleeding were compared by using Cox regression, reported as hazard ratios (HRs) and 95% confidence intervals (CIs). In patients with NVAF taking five or more chronic medications, rivaroxaban was associated with a 34% (95% CI 12-50) and 40% (95% CI 16-57) hazard reduction of SSE and ischemic stroke, respectively. Occurrence of major bleeding was similar between OAC cohorts (HR 1.08, 95% CI 0.92-1.28). A secondary analysis in patients with NVAF with substantial polypharmacy (taking ≥ 10 chronic medications) was also performed. Similar trends in SSE (HR 0.44), ischemic stroke alone (HR 0.62), and major bleeding (HR 1.07) were observed in patients with NVAF who had substantial polypharmacy, although 95% CIs crossed 1.0 for each outcome in this smaller study cohort.. This real-world study suggests that in the setting of polypharmacy and NVAF, rivaroxaban is an effective and safe alternative to warfarin.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Databases, Factual; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Health Services for the Aged; Humans; Insurance Claim Review; Male; Polypharmacy; Retrospective Studies; Rivaroxaban; United States; Warfarin

To assess the outcome of direct oral anticoagulants (DOACs), specifically Xa inhibitors: rivaroxaban and apixaban, for the treatment of venous thromboembolism (VTE) of atypical location (VTE-AL), portal, mesenteric, hepatic, splenic, gonadal, renal, and cerebral veins, prospectively collected data of Mayo Thrombophilia Clinic Registry were used.. Patients with acute VTE-AL treated with DOACs, enrolled between March 1, 2013, and February 1, 2017, were compared with patients with VTE of typical location (VTE-TL: deep vein thrombosis of extremities and/or pulmonary embolism) receiving DOACs and with patients with VTE-AL treated with enoxaparin.. Out of 623 patients with acute VTE receiving the study drug within 14 days of diagnosis, there were 63 with VTE-AL: 36 on DOAC, 23 on enoxaparin, and 4 on warfarin; 352 received DOAC for VTE-TL. The VTE-AL treated with DOAC/enoxaparin included the following: splanchnic (26/22), ovarian (8/2), renal (3/5), and cerebral veins (1/1), respectively. Recurrence rate (per 100 person-years) for the VTE-AL group receiving DOAC was 7.3, which was not different when compared with those for VTE-TL (2.4; P=.13) and VTE-AL groups receiving enoxaparin (23.7; P=.37). Major bleeding rate in the VTE-AL group receiving DOAC was not different compared with those for VTE-TL (7.2 vs 3.0; P=.26) and VTE-AL groups on enoxaparin (22.4; P=.31). Mortality was higher in the VTE-AL group on DOAC compared with the VTE-TL group (21.45 [95% CI, 7.87-46.69] vs 8.26 [95% CI, 5.35, 12.20]; P=.03). All patients with VTE-AL with events had cancer.. The VTE recurrence and bleeding rates for rivaroxaban and apixaban used in VTE-AL are not different from those in patients with VTE-TL and similar to that for enoxaparin.

Topics: Aged; Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Developing an optimal medication strategy poses a challenging task in fragile patients after left atrial appendage closure (LAAC). We report an optimal nonvitamin K antagonist oral anticoagulant (NOAC) therapy in a warfarin-sensitive patient after LAAC.. A 77-year-old nonvalvular atrial fibrillation (NVAF) male carrying 2 warfarin-sensitive alleles experienced 2 gum-bleeding with the international normalized ratio (INR) around 3.. Persistent NVAF with a history of subtotal gastrectomy and moderate renal insufficiency.. Warfarin was discontinued and vitamin K1 was immediately administrated via intravenous infusion. LAAC was regarded as a preferable option, and rivaroxaban 15 mg daily was managed after LACC.. Complete endothelialization on the surface of device was detected via transoesophageal echocardiography (TEE), and no peridevice spillage and adverse event occurred.. A post-LAAC treatment with NOAC may be a viable regimen in patients intolerant to warfarin.

Topics: Aged; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Cardiac Surgical Procedures; Drug-Related Side Effects and Adverse Reactions; Echocardiography, Transesophageal; Humans; Male; Pharmacogenomic Testing; Postoperative Care; Prosthesis Implantation; Risk Adjustment; Rivaroxaban; Septal Occluder Device; Treatment Outcome; Warfarin

The aim of this study was to obtain a better insight into the adverse effects profiles of the new direct-acting oral anticoagulants (DOACs).. A review was undertaken of all reports of adverse effects for warfarin, dabigatran, rivaroxaban and apixaban reported to the regional medicines information and pharmacovigilance centres (RELIS) in the period June 2013-May 2015.. Approximately 65 000 persons used direct-acting oral anticoagulants and 80 000 used warfarin in the period of the study. A total of 409 reports of adverse effects were included. Altogether 55 % of the reports applied to men. In 76 % of the reports for direct-acting oral anticoagulants and 85 % for warfarin, the patients were more than 70 years of age. The most common adverse effects were haemorrhages (48 % for direct-acting oral anticoagulants and 75 % for warfarin), most of which were cerebral haemorrhages (91 for direct-acting oral anticoagulants and 92 for warfarin). Blood clots (therapeutic failure), cognitive effects, headache and hair loss were some of the other adverse effects. The highest comorbidity was among the patients who died. The number of reported deaths was highest for rivaroxaban (1.1 deaths/1000 users) with a declining incidence for apixaban (0.9 ‰), dabigatran (0.7 ‰) and warfarin (0.6 ‰). There were different degrees of reporting for these medications, and the spontaneous reporting system cannot therefore be used to compare the incidence of adverse effects for the drugs.. Adverse effects, including serious effects, may occur when using all anticoagulants. Factors that may increase the risk of adverse effects are advanced age, high comorbidity, reduced renal function, and polypharmacy.

Topics: Age Distribution; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Dabigatran; Databases, Factual; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Sex Distribution; Time Factors; Warfarin

The complex dose regimens of the direct-acting oral anticoagulants (DOAC) make their appropriate prescribing highly challenging. Inappropriate prescribing of the DOAC remains poorly addressed. We studied the patterns of DOAC prescription and estimated the prevalence of drug-related problems (DRPs) associated with their use.. A cross-sectional study was conducted using data from medical records system of the Lyon teaching hospitals. DRPs, identified among patients who received a DOAC, between 1 January 2010 and 31 July 2013, were categorized according to the Pharmaceutical Care Network Europe Classification System. The prevalence of hospital stays with a DRP was estimated, and a subgroup analysis according to DOAC and their indication for use was provided. Clinical outcomes were not assessed.. Of the 4154 hospital stays with at least one DOAC administration [3412 patients; median age (range): 71 years (14-98), 57% female], 70·8% were excluded from the analysis mainly due to missing information for renal function and/or patient weight. Of the 1188 hospital stays that were screened, 100 DRPs were identified (prevalence 8·4%; 95% CI, 6·8-10·0). The highest prevalence was found among patients who received rivaroxaban for atrial fibrillation (14·6%; 95% CI, 10·7-18·5). A too low drug dose was the most frequent DRP (n = 56; 4·7%), followed by a too high drug dose (n = 37; 3·1%), contraindication (n = 5; 0·4%), and pharmacokinetic problem requiring dose adjustment (n = 2; 0·2%).. Drug-related problems associated with the DOACs occur quite commonly among hospitalized patients. Although these DRPs were considered to be of minor severity, prescribing protocols to support better prescribing should be disseminated to reduce the risk to patients. Renal function and body weight data should be mandatory on prescriptions to allow cross-checking.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Drug-Related Side Effects and Adverse Reactions; Female; Hospitalization; Humans; Inappropriate Prescribing; Male; Middle Aged; Prevalence; Rivaroxaban; Young Adult

The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Competence; Consensus; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Food-Drug Interactions; Humans; Internal Medicine; Italy; Liver Diseases; Perioperative Period; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Time Factors; Venous Thromboembolism

Topics: Aged; Biopsy; Drug-Related Side Effects and Adverse Reactions; Exanthema; Humans; Male; Methylprednisolone; Neutrophils; Rivaroxaban; Skin; Vasculitis, Leukocytoclastic, Cutaneous; Venous Thrombosis; Withholding Treatment

Topics: Anticoagulants; Dabigatran; Dose-Response Relationship, Drug; Drug Monitoring; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Pyrazoles; Pyridones; Reference Standards; Risk Factors; Rivaroxaban; Vitamin K

The article discusses various options of anticoagulant therapy for pulmonary thromboembolism and the main criteria of medication choice including the use of unfractionated heparin, low-molecular-weight heparins, and rivaroxaban. The data presented are based on the own experience and results of international clinical trials.

Topics: Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Heparin; Heparin, Low-Molecular-Weight; Humans; Morpholines; Outcome Assessment, Health Care; Patient Selection; Pulmonary Embolism; Risk Adjustment; Rivaroxaban; Thiophenes

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests