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Item Comparison of Four Bleeding Risk Scores to Identify Rivaroxaban-treated Patients With Venous Thromboembolism at Low Risk for Major Bleeding(Wiley, 2016-02) Kline, Jeffrey A.; Jimenez, David; Courtney, Mark; Ianus, Juliana; Cao, Lynn; Lensing, Anthonie W. A.; Prins, Martin H.; Wells, Philip S.; Department of Chemistry & Chemical Biology, School of ScienceObjectives Outpatient treatment of acute venous thromboembolism (VTE) requires the selection of patients with a low risk of bleeding during the first few weeks of anticoagulation. The accuracy of four systems, originally derived for predicting bleeding in VTE treated with vitamin K antagonists (VKAs), was assessed in VTE patients treated with rivaroxaban. Methods All patients treated with rivaroxaban in the multinational EINSTEIN deep vein thrombosis (DVT) and pulmonary embolism (PE) trials were included. Major bleeding was defined as ≥2 g/dL drop in hemoglobin or ≥2-unit blood transfusion, bleeding in critical area, or bleeding contributing to death. The authors examined the incidence of major bleeding in patients with low-risk assignment by the systems of Ruiz-Gimenez et al. (score = 0 to 1), Beyth et al. (score = 0), Kuijer et al. (score = 0), and Landefeld and Goldman. (score = 0). For clinical relevance, the definition of low risk for all scores except Kuijer includes all patients < 65 years with no prior bleeding history and no comorbid conditions (current cancer, renal insufficiency, diabetes mellitus, anemia, prior stroke, or myocardial infarction). Results A total of 4,130 patients (1,731 with DVT only, 2,399 with PE with or without DVT) were treated with rivaroxaban for a mean (±SD) duration of 207.6 (±95.9) days. Major bleeding occurred in 1.0% (40 of 4,130; 95% confidence interval [CI] = 0.7% to 1.3%) overall. Rates of major bleeding for low-risk patients during the entire treatment period were similar: Ruiz-Gimenez et al., 12 of 2,622 (0.5%; 95% CI = 0.2% to 0.8%); Beyth et al., nine of 2,249 (0.4%; 95% CI = 0.2% to 0.8%); Kuijer et al., four of 1,186 (0.3%; 95% CI = 0.1% to 0.9%); and Landefeld and Goldman, 11 of 2,407 (0.5%; 95% CI = 0.2% to 0.8%). At 30 days, major bleed rates for low-risk patients were as follows: Ruiz-Gimenez et al., five of 2,622 (0.2%; 95% CI = 0.1% to 0.4%); Beyth et al., five of 2,249 (0.2%; 95% CI = 0.1% to 0.5%); Kuijer et al., three of 1,186 (0.3%; 95% CI = 0.1% to 0.7%); and Landefeld and Goldman, seven of 2,407 (0.3%; 95% CI = 0.1% to 0.6%). No low-risk patient had a fatal bleed. Conclusions Four scoring systems that use criteria obtained in routine clinical practice, derived to predict low bleeding risk with VKA treatment for VTE, identified patients with less than a 1% risk of major bleeding during full-course treatment with rivaroxaban.Item Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants(MDPI, 2019-01-17) Kanuri, Sri H.; Kreutz, Rolf P.; Pharmacology and Toxicology, School of MedicineDirect oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.Item Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial(Elsevier, 2020-01) Male, Christoph; Lensing, Anthonie W. A.; Palumbo, Joseph S.; Kumar, Riten; Nurmeev, Ildar; Hege, Kerry; Bonnet, Damien; Connor, Philip; Hooimeijer, Hélène L.; Torres, Marcela; Chan, Anthony K. C.; Kenet, Gili; Holzhauer, Susanne; Santamaría, Amparo; Amedro, Pascal; Chalmers, Elizabeth; Simioni, Paolo; Bhat, Rukhmi V.; Yee, Donald L.; Lvova, Olga; Beyer-Westendorf, Jan; Biss, Tina T.; Martinelli, Ida; Saracco, Paola; Peters, Marjolein; Kállay, Krisztián; Gauger, Cynthia A.; Massicotte, M. Patricia; Young, Guy; Pap, Akos F.; Majumder, Madhurima; Smith, William T.; Heubach, Jürgen F.; Berkowitz, Scott D.; Thelen, Kirstin; Kubitza, Dagmar; Crowther, Mark; Prins, Martin H.; Monagle, Paul; EINSTEIN-Jr Phase 3 Investigators; Pediatrics, School of MedicineBackground Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. Methods In a multicentre, parallel-group, open-label, randomised study, children (aged 0–17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. Findings From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87–95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29–35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11–1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51–6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. Interpretation In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants.Item An Unusual Case of Acute Carpal Tunnel Syndrome(Cureus, 2021-12-31) Singh, Simranjit; Sanna, Fnu; Singh, Natasha; Adhikari, Ramesh; Kumar, Vinod; Medicine, School of MedicineAcute atraumatic carpal tunnel syndrome (CTS) that results from a hematoma as a complication of oral anticoagulation use is a highly uncommon presentation. CTS is a common type of peripheral compression neuropathy, with CTS's acute presentation being less common than chronic. The acute type is commonly caused either by recent trauma, including fractures of the distal radius and carpal dislocations, atraumatic etiologies like infections, or inflammatory conditions that increase the pressure in the carpal tunnel. Timely diagnosis of acute CTS is essential, as often surgical decompression is required if symptoms do not improve within hours. A 79-year-old female presented to the ED with a past medical history significant for stroke, paroxysmal atrial fibrillation on rivaroxaban, and hypertension. She complained of a one-day history of left wrist pain, swelling, and restricted range of motion, associated with numbness in the median nerve distribution and weakening of the handgrip. The patient denied any trauma or unusual physical activity. CCT imaging of the left upper extremity showed soft tissue expansion around the flexor pollicis longus proximal to and just distal to the carpal tunnel consistent with dissecting hematoma within the flexor compartment. The orthopedics hand team evaluated the patient. Her rivaroxaban was held, and she was monitored for 24 hours in the hospital. The next day, she almost had a complete resolution of her symptoms. She was discharged home with a close follow-up. There are various atraumatic causes of acute CTS. Spontaneous atraumatic hematoma occurring in the forearm's flexor compartment and resulting in acute CTS is extremely uncommon. In contrast to chronic CTS, acute CTS requires urgent carpal tunnel release to prevent irreversible median nerve damage. Anticoagulants in such cases increase the bleeding risk. This case highlights the importance of considering CTS into the differential diagnosis of someone on an anticoagulant and presenting with acute wrist swelling and pain. Despite the absence of any direct trauma, timely diagnosis of this condition is prudent and greatly affects the outcomes.