Direct Oral Anticoagulants Rivaroxaban Research Articles

Effect of direct oral anticoagulants on bleeding during and after cataract surgery

PurposeTo assess the risk for intraoperative and postoperative ocular bleeding associated with direct oral anticoagulant treatment in patients undergoing phacoemulsification surgery.MethodsConsecutive patients had phacoemulsification and intraocular lens implantation while taking uninterrupted direct oral anticoagulants (dabigatran, rivaroxaban, or apixaban). Gender and age-matched patients without antithrombotic therapy were used as the control group. Patients were examined one week postoperatively. Intraoperative and postoperative hemorrhagic and non-hemorrhagic complications were assessed.ResultsForty patients (56 eyes) on direct oral anticoagulants and 120 patients (172 eyes) without anticoagulation, at a mean age of 77 years, had phacoemulsification. There was no significant difference between the groups in the rate of intraoperative and postoperative bleeding. One eye (1.8%) in the treatment group and 3 eyes (1.7%) in the control group had hyphema (p = 0.72). No patient had thromboembolic event during or after surgery.ConclusionsCataract surgery was safely performed while continuing direct oral anticoagulation.

The AZALEA-TIMI 71 Study and the Future of Factor XI Inhibition: Reflections from the American Heart Association Scientific Congress 2023

Since its earliest days, the effective use of anticoagulation for prevention of stroke and other thromboembolic events has been limited by the risk and fear of bleeding, which was long believed to be inevitable. However, new understanding of the coagulation cascade suggests that, by targeting factor XI, it may be possible to protect patients from pathological thrombosis without significantly affecting physiological haemostasis, and thus greatly reduce the risk of bleeding. The AZALEA-TIMI 71 trial is the first study to provide definitive evidence that factor XI inhibition substantially reduces bleeding compared to a standard-of-care direct oral anticoagulant (DOAC). Based on an interview with Principal Investigator Christian T. Ruff, Thrombolysis in Myocardial Infarction (TIMI) Study Group, Boston, Massachusetts, USA, this article explains the significance of the AZALEA-TIMI 71 trial results, which showed an unprecedented reduction in the rate of bleeding with abelacimab, an investigational dual-acting factor XI/XIa inhibitor, compared with the DOAC rivaroxaban in patients with atrial fibrillation (AF) at moderate-to-high risk of stroke.

Pharmacogenomic Considerations for Anticoagulant Prescription in Patients with Hereditary Haemorrhagic Telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia that commonly results in bleeding but with frequent indications for therapeutic anticoagulation. Our aims were to advance the understanding of drug-specific intolerance and evaluate if there was an indication for pharmacogenomic testing. Genes encoding proteins involved in the absorption, distribution, metabolism, and excretion of warfarin, heparin, and direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran were identified and examined. Linkage disequilibrium with HHT genes was excluded, before variants within these genes were examined following whole genome sequencing of general and HHT populations. The 44 genes identified included 5/17 actionable pharmacogenes with guidelines. The 76,156 participants in the Genome Aggregation Database v3.1.2 had 28,446 variants, including 9668 missense substitutions and 1076 predicted loss-of-function (frameshift, nonsense, and consensus splice site) variants, i.e., approximately 1 in 7.9 individuals had a missense substitution, and 1 in 71 had a loss-of-function variant. Focusing on the 17 genes relevant to usually preferred DOACs, similar variant profiles were identified in HHT patients. With HHT patients at particular risk of haemorrhage when undergoing anticoagulant treatment, we explore how pre-emptive pharmacogenomic testing, alongside HHT gene testing, may prove beneficial in reducing the risk of bleeding and conclude that HHT patients are well placed to be at the vanguard of personalised prescribing.

Laboratory Predictors of Hemorrhagic Complications in Patients With Total Hip Arthroplasty and Treatment With Direct Oral Anticoagulants

Introduction. Direct oral anticoagulants (DOAC) rivaroxaban and apixaban have significantly reduced the risk of developing venous thromboembolic complications (VTEC). However, the use of DOAC may be associated with a higher risk of bleeding, especially actual in patients after total hip arthroplasty (THA).Material and methods. We enrolled 38 patients with moderate osteoarthritis of the hip joints undergoing THA. The mean age of patients was 58 (33; 85) years. All the patients received rivaroxaban or apixaban in the doses specified by Russian clinical guidelines for the diagnosis, treatment and prevention of venous thromboembolic complications (VTEC). Retrospectively, in the postoperative period, the patients were divided into two groups: Group 1 — 31 patients (20 women and 11 men), who had no hemorrhagic complications after hip replacement; and Group 2 — 7 patients (4 women and 3 men) who experienced hemorrhagic events in the form of hematomas in the wound area. Laboratory tests were performed for all patient baseline (1st day of hospitalization), after surgery (1st day after THA), and on the 7th day after THA. Analyses included the determination of hemostasis parameters (INR, aPPT, fibrinogen, D-dimer), hematological (HGB, PLT, RBC) and biochemical parameters (calcium, ionized calcium, serum iron, hs-CRP).Results. The analysis of biochemical parameters in patients with hemorrhagic complications revealed a significant increase of fibrinogen (p=0,023) compared with uncomplicated cases. Serum iron concentration in men with hemorrhagic complications in the postoperative period was significantly lower than in patients without complications. In patients with hemorrhagic complications, the ionized calcium was lower (p=0,032) than in patients without complications, but within the reference values. The hs-CRP concentration in the group with hemorrhagic complications was twice higher than in the group without complication and eight times above the reference values.Conclusion. The concentration of iron in the blood serum in men below 11 mmol/l and a slight hyperfibrinogenemia of 4.65 g/l in all the patients are the risks of developing hematomas in the area of surgery. These parameters should be used to predict the risk of hemorrhagic complications in patients before THA and recommended for control before the surgery and on the 1st day after THA (hs-CRP).

An extension of biorelevant fed-state dissolution tests to clinical pharmacokinetics – A study on gastrointestinal factors influencing rivaroxaban exposure and efficacy in atrial fibrillation patients

A direct oral anticoagulant rivaroxaban fails to prevent stroke and systemic embolism in one-to-several percent of patients with nonvalvular atrial fibrillation (NVAF), but the reasons are unknown. The study used semi-mechanistic in vitro-in vivo prediction (IVIVP) modeling to explore the reasons for ineffective thrombosis prevention in NVAF patients. Steady-state drug concentrations in plasma were measured at 0 h (Ctrough), 3 h (C3h), and 12 h post-dosing in thirty-four patients treated with 20 mg rivaroxaban daily. The clinical data were compared against “virtual twins” generated with a novel IVIVP model that combined drug dissolution modeling, mechanistic description of gastric drug transit, and population pharmacokinetics defining the variability of drug disposition. The nonresponders had significantly lower C3h and Ctrough than the responders (p < 0.001) and the covariates included in the population pharmacokinetic submodel did not fully explain this difference. Simulations involving varied gastrointestinal parameters in the “virtual twins” revealed that lower small intestinal effective permeability (Peff), rather than a slower stomach emptying rate, could explain low rivaroxaban exposure in the nonresponders. IVIVP modeling was effectively used for exploring pharmacotherapy failure. Low Peff, found as a major determinant of ineffective rivaroxaban treatment, encourages further research to find (pato)physiological factors influencing suboptimal absorption.

Trends in use of Direct Oral Anticoagulants and Warfarin in Atrial Fibrillation Patients

Treatments used in atrial fibrillation therapy, such as those of anticoagulants, consist of vitamin K antagonists (warfarin) and direct oral anticoagulants (dabigatran, apixaban, rivaroxaban, and edoxaban). The use of warfarin requires regular monitoring of prothrombin time (PT) and international normalised ratio (INR). The therapeutic dose range is narrow, but the price is cheaper. Oral anticoagulants are directed, the incidence of major bleeding is lower, ease of use, food and drug interactions are minor, the half-life is shorter, and there is a lack of laboratory monitoring needs. Based on this problem, researchers conducted a study to determine the trend of using warfarin and oral anticoagulants in patients with atrial fibrillation at a public hospital in Jakarta. This study uses a qualitative approach, with longitudinal methods and retrospective data using outpatient medical records for the period 2014 to 2018. The trend of using warfarin anticoagulants decreased from 82.3% in 2014 to 62% in 2016, while oral anticoagulants were reduced. Direct oral anticoagulants are rivaroxaban and dabigatran, which are more widely used than apixaban, and edoxaban; no data on their use has been obtained. The opposite was true from 2017 to 2018, when the use of warfarin increased and caused a decrease in the use of direct oral anticoagulants. This research is expected to contribute to various parties, both health practitioners and academics, in terms of selecting therapies for atrial fibrillation.

ANTICOAGULANTS AND EPISTAXIS: A COMPARATIVE ANALYSIS OF EPISTAXIS WITH WARFARIN AND DIRECT ORAL ANTICOAGULANTS

Anticoagulant therapy prevents and treats thromboembolic occasions like profound vein thrombosis, pneumonic embolism, and stroke. Warfarin, a vitamin K bad guy, has been the standard oral anticoagulant for quite some time. The study's main objective is to find that warfarin is associated with higher rates of epistaxis compared to direct oral anticoagulants. This cross-sectional study was conducted at Islamabad Medical and Dental College, Islamabad, from January 2023 till July 2023. Data was collected from 123 patients of both genders. The study population consists of adult patients prescribed anticoagulant therapy for various indications, including atrial fibrillation, venous thromboembolism, and mechanical heart valve replacement. Patients were identified from electronic medical records at the study site. In this study, a total of 123 adult patients receiving anticoagulant therapy were included. Among them, 62 patients were prescribed warfarin, and 61 were on direct oral anticoagulants (DOACs) (rivaroxaban, dabigatran, apixaban, or edoxaban). Warfarin and DOACs demonstrated similar safety profiles regarding other bleeding events and major adverse events. It is concluded that the study found no statistically significant difference in the incidence of epistaxis between the two treatment groups. Both Warfarin and DOACs showed similar safety profiles regarding other bleeding events and major adverse events, indicating that they are generally well-tolerated options for anticoagulation therapy in this patient population.

Venous Thromboembolism Prophylaxis in Major Orthopedic Surgeries and Factor XIa Inhibitors.

Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), poses a significant risk during and after hospitalization, particularly for surgical patients. Among various patient groups, those undergoing major orthopedic surgeries are considered to have a higher susceptibility to PE and DVT. Major lower-extremity orthopedic procedures carry a higher risk of symptomatic VTE compared to most other surgeries, with an estimated incidence of ~4%. The greatest risk period occurs within the first 7-14 days following surgery. Major bleeding is also more prevalent in these surgeries compared to others, with rates estimated between 2% and 4%. For patients undergoing major lower-extremity orthopedic surgery who have a low bleeding risk, it is recommended to use pharmacological thromboprophylaxis with or without mechanical devices. The choice of the initial agent depends on the specific surgery and patient comorbidities. First-line options include low-molecular-weight heparins (LMWHs), direct oral anticoagulants, and aspirin. Second-line options consist of unfractionated heparin (UFH), fondaparinux, and warfarin. For most patients undergoing knee or hip arthroplasty, the initial agents recommended for the early perioperative period are LMWHs (enoxaparin or dalteparin) or direct oral anticoagulants (rivaroxaban or apixaban). In the case of hip fracture surgery, LMWH is recommended as the preferred agent for the entire duration of prophylaxis. However, emerging factor XI(a) inhibitors, as revealed by a recent meta-analysis, have shown a substantial decrease in the occurrence of VTE and bleeding events among patients undergoing major orthopedic surgery. This discovery poses a challenge to the existing paradigm of anticoagulant therapy in this specific patient population and indicates that factor XI(a) inhibitors hold great promise as a potential strategy to be taken into serious consideration.

Thromboembolic Events, Anticoagulation, and COVID-19: Preemptive Treatments and Risks After Vaccination

Thromboembolic Events, Anticoagulation, and COVID-19: Preemptive Treatments and Risks After Vaccination

DOACs and rheumatic valvulopathy: always a red light?

Despite the sharp decline in most high-income industrialized countries, rheumatic heart disease (RHD) continues to be highly prevalent in many rural, low- and middle-income countries. RHD most frequently involves the mitral valve, both in the form of isolated regurgitation and in the form of regurgitation associated with mitral stenosis (mitral stenosis, MS). Atrial fibrillation (AF) is a common complication of RHD that is independently associated with an increased risk of death, heart failure, and systemic thromboembolism. Few studies have focused on the issue of the best oral anticoagulation strategy for patients with RHD and AF. Randomized trials establishing the non-inferiority of new direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) in the prevention of stroke and systemic embolism excluded AF patients with mechanical valves or with moderate-to-severe MS. Nevertheless, variable proportions of patients with other VHD types were included. Recently, the INVICTUS trial demonstrated that in patients with RHD-related AF, direct oral anticoagulant rivaroxaban is inferior to VKAs in preventing stroke, systemic embolism, myocardial infarction, or death and is similar in bleeding risk. These results confirm and reinforce the recommendations of current international guidelines supporting the use of VKAs in patients with RHD-related AF.

502 The effects of removing the requirement for prior reimbursement approval on anticoagulant use in Ireland: A cross sectional study

Abstract Introduction Prior approval for reimbursement is a cost containment policy, aimed at reducing demand (1). It has been used temporarily in the Irish Healthcare system to deal with the initial financial challenges posed by the shift in use towards the Direct Oral Anticoagulants (DOACs) (apixaban, rivaroxaban, edoxaban and dabigatran) from warfarin. Improved safety of DOACs use was a secondary aim of this policy. The use of prior approval policies is increasing in Ireland but studies assessing their effectiveness are limited. Aim To examine the effect of removing the cost containment policy of prior approval for reimbursement of apixaban and rivaroxaban using a national pharmacy claims database. Methods The Health Service Executive-Primary Care Reimbursement Service database in Ireland was used in this cross-sectional study. The prescribing frequencies and associated costs of the oral anticoagulants; ((OACs) apixaban, rivaroxaban, and warfarin) listed in the top 100 most frequently prescribed drugs on the Community Drug Schemes (CDS), between 2018 and 2021 were examined. Levothyroxine was used as a negative control to detect any external deviances in the prescribing data records. Interrupted time series Poisson regression was used to assess the impact of removing the approval requirement of apixaban in September 2019 followed by the other DOACs in November 2020. Results The prescribing frequency of OACs increased by almost 20% during the study period. Figure1 shows the prescribing frequencies of apixaban , rivaroxaban , warfarin and levothyroxine on each of the three community drug schemes – General medical scheme (GMS), Drug payments scheme (DPS) and Long term illness scheme (LTI) during the study period.Timelines at September 2019 and November 2020 show the removal of prior approval for apixaban and all DOACs respectively. This study showed there were significant differences in the proportion of OACs prescribed among the CDS. A statistically significant decreased use of apixaban (&amp;lt;1%, p&amp;lt;0.05) occurred when prior approval was removed for all DOACs. Conclusion The removal of prior approval for reimbursement of DOACs in Ireland had a minimal impact on the prescribing frequency trends of the OACs. Future use of these potentially useful policies by healthcare systems requires careful consideration of drug type, approval criteria and length of time the policy remains in place.

Trends in the Use of Oral Anticoagulants for Adults With Venous Thromboembolism in the US, 2010-2020

The introduction of direct oral anticoagulants (DOACs) has transformed the treatment of venous thromboembolism (VTE). Large health care databases offer valuable insight into how oral anticoagulants (OACs) are used in clinical practice and may aid in understanding reasons for changes in therapy. To evaluate prescribing patterns of OACs for patients with VTE and identify clinical events that precede treatment changes. This retrospective cohort study used data from a public (Medicare fee-for-service) and a commercial (IBM MarketScan) health insurance database on 298 609 patients initiating OACs within 90 days of index VTE hospitalization from January 1, 2009, to December 31, 2020. Statistical analysis was conducted from April to August 2022. Warfarin and the DOACs rivaroxaban, apixaban, dabigatran, and edoxaban. Characteristics of patients initiating different OACs, along with trends over time of patients initiating OACs, were compared. Time receiving continuous anticoagulant therapy, patterns of anticoagulant discontinuation (treatment gap of ≥30 days), and treatment switches were assessed. Clinical events in the 30 days preceding treatment modifications were identified. A total of 203 378 individuals with Medicare (mean [SD] age, 76.9 [7.6] years; 122 554 women [60.3%]) and 95 231 with commercial insurance (mean [SD] age, 57.6 [15.8] years; 47 139 women [49.5%]) were included (N = 298 609). Warfarin was the most frequent OAC prescribed (163 044 [54.6%]), followed by rivaroxaban (66 882 [22.3%]) and apixaban (65 997 [22.1%]). The proportion of patients initiating DOACs increased from 0% in 2010 to 86.8% (22 420 of 25 817) in 2019 for patients with Medicare and 92.1% (4012 of 4357) in 2020 for commercially insured patients. Patients with chronic kidney disease were more likely to initiate warfarin (35 561 [11.9%]) or apixaban (16 294 [5.5%]) than rivaroxaban (10 136 [3.4%]), and those with a history of bleeding were more likely to initiate apixaban (5424 [1.8%]) than rivaroxaban (3007 [1.0%]). Overall, patients received persistent OAC treatment for approximately 6 months (Medicare: median, 175 days [IQR, 76-327 days]; commercial insurance: median, 168 days [IQR, 83-279 days]). A total of 33 011 patients (11.1%) switched anticoagulant therapy within a year. Switching to another anticoagulant was preceded most frequently by codes for a VTE diagnostic procedure (27.2% of all switchers [8983 of 33 011]). This cohort study using data from 2 US health insurance databases suggests that most patients with VTE continued oral anticoagulant treatment for approximately 6 months. Clinical reasons for modifying anticoagulant therapy were identified in one-third of patients. Identifying reasons for treatment modification is crucial for generating valid evidence on drug safety and effectiveness.

Time Trends in Patient Characteristics of New Rivaroxaban Users with Atrial Fibrillation in Germany and the Netherlands.

Use of the direct oral anticoagulant rivaroxaban has strongly increased in Europe since its market approval for non-valvular atrial fibrillation in 2011. Patients characteristics of rivaroxaban initiators may have changed over time but this has not been investigated so far. We aimed to describe time trends of patient baseline characteristics among new rivaroxaban users with non-valvular atrial fibrillation from 2011 to 2016/17 in two European countries. We used data from Germany (German Pharmacoepidemiological Research Database) and the Netherlands (PHARMO Database Network). We included new rivaroxaban users with (i) a first dispensing between 2011 and 2016/17, (ii) ≥2 years of age, and (iii) a diagnosis of non-valvular atrial fibrillation and described their baseline medication and comorbidity prior to starting rivaroxaban stratified by year of inclusion. Overall, 130,652 new rivaroxaban users were included during the study period (Germany: N=127,743, the Netherlands: N=2909). The sex ratio and median age remained relatively stable over time. The proportion of patients without prior use of oral anticoagulants before initiation of rivaroxaban increased in both countries between 2011 and 2016/17 (Germany: from 51 to 76%, the Netherlands: from 57 to 85%). In Germany, we observed a relative decrease by 27% in the proportion of new rivaroxaban users with a history of ischemic stroke and by 18% in the proportion with a transient ischemic attack at baseline. No such a pattern was observed in the Netherlands. The proportion of patients with heart failure at baseline showed a three-fold increase in the Netherlands, while there was a relative decrease by 12% in Germany. Patient characteristics of new rivaroxaban users with non-valvular atrial fibrillation changed between 2011 and 2016/17, but changes differed between countries. These patterns have methodological implications. They have to be considered in the interpretation of observational studies comparing effectiveness and safety of oral anticoagulants, especially regarding potential bias due to unmeasured confounding.

Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti-VEGF agents: a retrospective study.

Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). Of 92 patients (median age 66years (IQR: 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colon/rectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%); 2% had brain metastases. Apixaban 5mg bid (n = 41) or rivaroxaban 20mg daily (n = 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8months (95%CI: 0.7-50.0) with bevacizumab and 11.7months (95%CI: 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%): 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%): 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI: 76.9-NR) for KI and 86.9months (95%CI: 42.9-148.0) for bevacizumab. CONCLUSIONSAND RELEVANCE: In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.

Novel Snake Venom Derived Hemocoagulase Reverses Anticoagulant Effect of Factor Xa Inhibitors, Restores Hemostatic Clot Formation, and Limits Bleeding in Vitro and In Vivo

Background: Direct oral anticoagulants (DOACs) such as rivaroxaban and apixaban are factor Xa (FXa) inhibitors widely used to treat thromboembolism and prevent stroke. Despite improvements in patient outcomes compared to vitamin K antagonists, major bleeding still occurs and there is an urgent unmet need for reversal agents in the event of major bleeding or when emergency surgery is needed. Slounase is a snake venom derived batroxobin (a thrombin-like enzyme) containing FXa that converts fibrinogen to fibrin in a manner distinctly different from thrombin. We recently reported slounase enhances platelet-fibrin clot formation in vivo in heparin-anticoagulated mice suggesting slounase may bypass coagulation to restore hemostasis and prevent bleeding. Here, we investigate if slounase reverses the anticoagulant effect of FXa inhibitors and restores hemostatic clot formation as a novel bypassing agent. Methods: In this study we used in vitro thromboelastography (TEG) to test the effect of slounase on whole blood from healthy human donors spiked with a range of apixaban or rivaroxaban doses. Clot formation kinetics were recorded for 60 minutes and the parameters reaction time and maximum amplitude (MA) were analyzed. The effect of rivaroxaban and apixaban on hemostasis in vivo was determined in wild type (WT) mice pretreated with apixaban (30mg/kg) or rivaroxaban (10mg/kg) via oral gavage using intravital microscopy laser-induced cremaster arteriole thrombosis model. WT mice pretreated with apixaban or rivaroxaban were further treated with slounase (1U/kg) and reversal of anticoagulant effect of FXa inhibition was determined in vivo under intravital microscopy. The dynamics of platelet recruitment and fibrin formation within the growing clot were analyzed for change in fluorescent intensity over the course of thrombus formation in response to vascular injury. Additionally, mice were pretreated with FXa inhibitors via oral gavage and then intravenously dosed slounase (1U/kg) 10 minutes prior to tail bleeding assay to test the effect on bleeding time and blood loss. Results: A high dose of apixaban and rivaroxaban spiked in human whole blood caused full inhibition of the TEG parameters and an inability to form a stable thrombus in vitro. However, slounase treatment dose dependently restored the parameters of clot formation into the range of control. The in vivo laser-induced cremaster arteriole model was used to test slounase as an intervention to apixaban and rivaroxaban pretreatment. The severe hemostatic defect was determined by limited platelet accumulation and fibrin formation at the site of vascular injury in both groups. Additionally, platelet adherence was transient and fibrin formation was unstable in mice treated with rivaroxaban and apixaban. Intravenous intervention with slounase (1U/kg) increased platelet accumulation and fibrin formation at the site of vascular injury. Slounase treatment reversed the anticoagulant effect of FXa inhibitors in vivo and restored the hemostatic clot formation in response to vascular injury in mice treated with FXa inhibitors. In the in vivo tail bleeding assay WT mice pretreated with FXa inhibitors bled continually until intervention via cauterization. Slounase pretreatment significantly decreased blood loss and bleeding time into the range of WT controls. Conclusions: Slounase is a potential bypassing agent for reversal of anticoagulation by DOACs rivaroxaban and apixaban. Using TEG, our data demonstrated the anticoagulant effect of FXa inhibitors in vitro and the reversal of anticoagulation by slounase. Slounase dose dependently restored clot formation in human whole blood pretreated with an inhibitory dose of FXa inhibitors. Slounase intervention improved hemostasis in vivo by increasing platelet accumulation and fibrin formation at the site of vascular injury. Additionally, slounase treatment decreased bleeding and blood loss in an in vivo bleeding assay demonstrating its potential to quickly reverse effects of DOACs and prevent bleeding episodes. This study further demonstrates slounase is a novel bypassing agent that promotes platelet procoagulant activity and converts fibrinogen to fibrin independent of thrombin activity.

Prevalence and treatment of venous thromboembolism in patients with solid tumors.

Cancer-associated venous thromboembolism (VTE) has exhibited a rising incidence rate. Research focusing on cancer-associated VTE and current anticoagulation therapy strategies is limited. The present study aimed to investigate the prevalence, characteristics and anticoagulation therapy strategies of cancer-associated VTE. The study was performed on patients with major solid tumors who were admitted to The First Affiliated Hospital of Guangxi Medical University (Nanning, China) between January 2020 and December 2020. The medical records of the patients' demographic characteristics, disease and treatment were extracted from the medical record data system and reviewed. The prevalence of cancer-associated VTE was calculated, followed by statistical analysis. Patients who received anticoagulation therapy for cancer-associated VTE were followed up for 1 year. The characteristics and efficacy of anticoagulation therapy strategies were compared and analyzed. A total of 4,926 patients with major solid tumors (mean age, 55.86±11.97 years) were included in the analysis, of which 117 (2.4%; 117/4,926) were diagnosed with cancer-associated VTE. Patients with pancreatic cancer exhibited the highest prevalence of VTE (10.2%; 5/49), followed by patients with ovarian cancer (5.8%; 9/156) and lung cancer (3.3; 73/2,237). Multivariate analysis identified hypertension comorbidity [odds ratio (OR), 1.661; 95% CI, 1.031-2.674; P=0.037)] and cancer stage (OR, 1.266; 95% CI, 1.079-1.486; P=0.004) as independent risk factors for cancer-associated VTE. Deep vein thrombosis (DVT) of the lower extremity accounted for 62.0%; 62/100) of all DVTs. Moreover, pulmonary embolism (PE) with lower extremity DVT accounted for 53.5% (23/43) of all PE cases. The majority of cancer-associated VTE cases (63.2%; 74/117) developed 30 days before or after a cancer diagnosis. In addition, cancer-associated VTE was dominated by symptomatic VTE (59.8%; 70/117). Only 74.4% (87/117) of patients with VTE received anticoagulant treatment, with a median duration of 79 days. The most common anticoagulant treatment strategies were heparin during hospitalization and direct oral anticoagulants (rivaroxaban) after discharge. The anticoagulants associated with bleeding events were rivaroxaban (4.2%; 3/72) and enoxaparin (1.9%; 1/54). In total, 62.1% (36/58) of the patients received anticoagulant treatment for <90 days. In conclusion, the results indicated that the prevalence of cancer-associated VTE is common and exhibits numerous characteristics. Rivaroxaban has been widely used in cancer-associated VTE treatment. However, compliance with long-term anticoagulant treatment is not adequate at present, while the efficacy and safety of rivaroxaban must be evaluated to improve long-term medication monitoring and follow-up among patients with cancer-associated VTE.

Identification of Infigratinib as a Potent Reversible Inhibitor and Mechanism-Based Inactivator of CYP2J2: Nascent Evidence for a Potential In Vivo Metabolic Drug-Drug Interaction with Rivaroxaban.

Infigratinib (INF) is a fibroblast growth factor receptor inhibitor that was recently United States Food and Drug Administration-approved for the treatment of advanced or metastatic cholangiocarcinoma. We previously established that INF inhibited and inactivated cytochrome P450 3A4 (CYP3A4). Here, in a follow up to our previous study, we identified for the first time that INF also elicited potent competitive inhibition and mechanism-based inactivation of CYP2J2 with kinetic parameters K i, K I, k inact, and a partition ratio of 1.94 µM, 0.10 µM, 0.026 minute-1, and ∼3, respectively, when rivaroxaban was harnessed as the probe substrate. Inactivation was revealed to exhibit cofactor-dependency and was attenuated by an alternative substrate (astemizole) and direct inhibitor (nilotinib) of CYP2J2. Additionally, the nature of inactivation was unlikely to be pseudo-irreversible and instead arose from covalent modification due to the lack of substantial enzyme activity recovery after dialysis and chemical oxidation, as well as the lack of a resolvable Soret band in spectral scans. Glutathione trapping confirmed that the identity of the putative reactive intermediate implicated in the covalent inactivation of both CYP2J2 and CYP3A4 was identical and likely attributable to an electrophilic p-benzoquinonediimine intermediate of INF. Finally, mechanistic static modeling revealed that by integrating the previously arcane inhibition and inactivation kinetic parameters of CYP2J2-mediated rivaroxaban hydroxylation by INF illuminated in this work, together with those previously documented for CYP3A4, a 49% increase in the systemic exposure of rivaroxaban was projected. Our modeling results predicted a potential risk of metabolic drug-drug interactions between the clinically relevant combination of rivaroxaban and INF in the setting of cancer. SIGNIFICANCE STATEMENT: This study reported that INF elicits potent reversible inhibition and mechanism-based inactivation of CYP2J2. Furthermore, static modelling predicted that its coadministration with the direct oral anticoagulant rivaroxaban may potentially culminate in a metabolic drug-drug interaction (DDI) leading to an increased risk of major bleeding. As rivaroxaban is steadily gaining prominence as the anticoagulant of choice in the treatment of cancer-associated venous thromboembolism, the DDI projections reported here are clinically relevant and warrant further investigation via physiologically based pharmacokinetic modelling and simulation.

Thromboprophylaxis of Patients Submitted to Total Hip and Knee Arthroplasty: A Cost-Effectiveness Assessment From the Perspective of the Brazilian National Health System

ObjectivesVenous thromboembolism (VTE) is a serious national and international public health issue. Major orthopedic surgeries, such as a total hip (THA) and knee (TKA) arthroplasties, are associated with an increased risk of VTE, long-term complications, functional disability, and death resulting from hypercoagulability by surgical trauma. This pharmacoeconomic analysis aimed to identify the most cost-effective anticoagulant alternative in preventing VTE in patients undergoing THA and TKA. MethodsA decision tree model was developed, comparing direct oral anticoagulants (rivaroxaban, apixaban, and dabigatran) with enoxaparin, with separate THA and TKA models a 3-month time horizon from the perspective of the Brazilian National Health System. The results were presented as incremental cost-effectiveness ratio (ICER), and the outcomes analyzed were avoided complications (ACs) after thromboprophylaxis. Comparative effectiveness was obtained from a published meta-analysis. A willingness to pay value of approximately R$ 15 000.00 was used per AC, and a probabilistic sensitivity analysis with the Monte Carlo simulation was conducted. ResultsApixaban was the anticoagulant that presented the best ICER for patients undergoing THA (R$ 207.52/AC) and TKA (R$ 133.59/AC), followed by rivaroxaban (R$ 347.21/AC), dabigatran (R$ 372.56/AC), and enoxaparin (R$ 711.44/AC) for THA and by dabigatran (R$ 194.07/AC), rivaroxaban (R$ 221.12/AC), and enoxaparin (R$ 747.25/AC) for TKA. After ICER analysis, apixaban prevails over the other technologies analyzed for both surgical procedures, confirmed after sensitivity analysis. ConclusionOur model suggests that, in the Brazilian National Health System, apixaban is the most cost-effective alternative in preventing VTE after THA and TKA.

Variation in Plasma Levels of Apixaban and Rivaroxaban in Clinical Routine Treatment of Venous Thromboembolism.

Direct oral anticoagulants (DOACs) apixaban and rivaroxaban are broadly used in the management of venous thromboembolism (VTE). Although not routinely required, measurement of their plasma concentration is advised for an increasing number of indications. Due to the lack of therapeutic ranges, current guidelines recommend reporting DOAC plasma levels together with expected levels from previous pivotal studies. The aim of this study was to assess DOAC level variation in a large VTE patient population. Drug concentrations determined by measurement of the anti-Xa-activity using drug-specific calibrators in citrated plasma samples from patients on rivaroxaban (n = 1471) or apixaban (n = 725) were analyzed. Observed 5th–95th percentile ranges of apixaban peak/trough levels (63–299/13–114 ng/mL for 5 mg, 37–161/7–68 ng/mL for 2.5 mg twice daily) were similar to previously reported mass-spectrometry-based reference data, and 10th–90th percentile ranges of rivaroxaban peak/trough levels (98–367/8–55 ng/mL for 20 mg, 51–211/5–27 ng/mL for 10 mg once daily) were even narrower. Age and drug levels correlated weakly (r ≤ 0.330). Drug levels measured repeatedly in subgroups of patients showed a strong correlation (r ≥ 0.773). In conclusion, anti-Xa-activity-based measurement of apixaban and rivaroxaban yields reliable results. However, the paucity of levels off-range underlines the need for evidence-based thresholds to better assist clinical decision making.

Stroke and Thromboembolism in Patients with Heart Failure and Sinus Rhythm: A Matter of Risk Stratification?

Patients with heart failure (HF) in sinus rhythm (SR) experience an increased incidence of thromboembolic events including stroke. Among patients with HF, high-quality evidence supports the use of oral anticoagulation when atrial fibrillation is present, but the benefit of anticoagulation in SR in the absence of other known indications for anticoagulation is unclear. In four randomized controlled trials (RCTs), warfarin did not improve a composite of clinical outcomes compared with aspirin or placebo in patients with HF with reduced ejection fraction (HFrEF) and SR. A recent RCT assessed the efficacy of the direct oral anticoagulant rivaroxaban versus placebo in patients with HFrEF (including mildly reduced ejection fraction), SR, and coronary artery disease. While rivaroxaban had a neutral effect on the primary composite outcome of myocardial infarction, stroke, or all-cause mortality, exploratory analyses revealed a significant reduction in strokes. It is thus possible that a subgroup of patients with HFrEF who are at high risk of stroke may benefit from anticoagulation. The challenge is to adequately identify this subgroup and to balance the potential benefit of anticoagulation with the risk of major bleeding. There is also an unmet need for evidence around anticoagulation in HF with preserved ejection fraction and SR. This review explores the current evidence around anticoagulation in patients with HF and SR, identifies challenges regarding outcome definitions and patient selection, and offers suggestions for future research.