Direct Oral Anticoagulants Rivaroxaban Research Articles

Abstract 4135975: Anticoagulation versus Antiplatelets in Coronary Artery Ectasia and Acute Coronary Syndrome: A Systematic Review and Meta-analysis

Introduction: Coronary artery ectasia (CAE) is a rare but well-recognized anatomical abnormality of the coronary arteries with a prevalence of up to 9% in patients presenting with acute coronary syndrome (ACS). While anticoagulants have been suggested to reduce recurrent events, the optimal antithrombotic therapy in CAE and ACS remains unclear. Research Question: What is the comparative effect of anticoagulation therapy versus no anticoagulation in patients with CAE and ACS receiving background antiplatelet therapy? Goals: To perform a systematic review and meta-analysis evaluating the efficacy of anticoagulation in preventing major adverse cardiovascular events (MACE) among patients with CAE and ACS. Methods: We searched PubMed, Embase, and Cochrane to identify studies comparing the use of anticoagulants versus no use of anticoagulants as part of the antithrombotic therapy in patients presenting CAE and ACS, and reported MACE. Statistical analysis was performed using R version 4.2.2 adopting the Mantel-Haenszel random-effects model. Heterogeneity was assessed using Cochrane's Q statistic and Higgins and Thompson’s I2 statistics. Pooled risk ratios were used to evaluate the effectiveness of anticoagulant therapy in CAE and ACS. Results: We included 3 studies, including 1 randomized controlled trial and 2 observational studies, comprising a total of 441 patients, of whom 162 (36.7%) received anticoagulants, including vitamin K antagonists (warfarin and acenocoumarol) or direct oral anticoagulants (rivaroxaban, apixaban, and dabigatran). Time of follow-up ranged from 12 to 52 months, mean age was 57.9 ± 11.4 years, and 388 (87.9%) were male. We found no significant difference in MACE between patients who received anticoagulation and patients who did not (RR 0.64; 95% CI 0.31, 1.32; p=0.22; I2 = 0%). Additionally, there was no difference in the risk of re-infarction (RR 0.71; 95% CI 0.43, 1.18; p=0.19; I2 = 0%). Finally, there was no significant difference in risk of bleeding between both groups (RR 1.41; 95% CI 0.70, 1.85; p=0.19; I2 = 0.59%). Conclusion: Our findings suggest that, among patients with CAE and ACS, anticoagulation does not reduce the risk of MACE or re-infarction as compared with no anticoagulation.

Comparative analysis of the efficacy of direct oral anticoagulant rivaroxaban and low molecular weight heparin in the treatment of tumor patients with venous thromboembolism

Objective: To explore the effectiveness and safety of direct oral anticoagulant rivaroxaban and low molecular weight heparin (LMWH) in the treatment of tumor patients with venous thromboembolism (VTE). Methods: A retrospective analysis was conducted on 296 patients diagnosed with tumor associated VTE in the Shanghai Pulmonary Thromboembolism Database from December 2020 to September 2022. Patients were grouped according to the prescription of anticoagulant drugs. Thirteen baseline variables [age, gender, smoking history, physical state (PS) score, tumor type, tumor stage, tumor treatment method, hemoglobin, platelets, D-dimer, creatinine, alanine aminotransferase, and VTE site] were matched. After matching, 100 cases were assigned to rivaroxaban group, including 64 males and 36 females, aged [M (Q1, Q3)] 70 (62,74) years old; There were 100 cases in the LMWH group, including 69 males and 31 females, aged 68 (60,73) years old. Kaplan-Meier method was used to plot survival curves. The differences between the rivaroxaban group and LMWH group in 6-month cumulative VTE recurrence rate, clinically significant bleeding rate, and all-cause mortality rate were analysed using log-rank test. Results: There were no statistically significant differences between the rivaroxaban group and the LMWH group in the 6-month cumulative VTE recurrence rate [13.5% (95%CI: 6.4%-20.1%) vs 7.5% (95%CI: 2.0%-12.7%), P=0.171], bleeding incidence rate [9.2% (95%CI: 3.3%-14.8%) vs 6.2% (95%CI: 1.3%-10.9%), P=0.438] and all-cause mortality rate [8.0% (95%CI: 2.5%-13.2%) vs 10.0% (95%CI: 3.9%-15.7%), P=0.602]. Conclusion: The anticoagulant efficacy and safety of rivaroxaban and LMWH are comparable in tumor patients with VTE.

Exposure Matching-Based Pediatric Dose Selection for Drugs with Renal Excretion - Lessons Learned from Pediatric Development of Direct Oral Anticoagulants.

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations.

The incidence of death and risk factors for mortality following major bleeding in patients anticoagulated with factor Xa inhibitors: an observational study in the UK clinical setting (AXIOM UK)

Abstract Background Major bleeding (MB) in association with anticoagulant use results in significant mortality. Mortality can be directly attributed to bleeding, or may follow bleeding complications such acute kidney injury, myocardial infarction, stroke and other cardiovascular events. Most real-world data relating to bleeding mortality is derived from cohorts receiving vitamin-K antagonists. We investigated all-cause mortality (ACM) after MB in a large cohort anticoagulated with Factor Xa inhibitors (FXai), e.g. direct oral anticoagulants (DOAC) rivaroxaban, apixaban and low-molecular-weight heparins (LMWH). Purpose To describe incidence rates of and risk factors for ACM following MB in patients receiving FXai. To investigate MB related ACM by bleeding site, treatment indication, treatment subgroups and individual and cumulative time periods. Methods Retrospective cohort analysis of new users of FXai, between 2012-2020, for therapeutic indications including atrial fibrillation (AF), venous thromboembolism, bioprosthetic cardiac valves or adult congenital heart disease was conducted. MB was defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Incidence rates were reported per 100 person-years. Sub-distribution hazard ratios with 95% confidence intervals (95% CI) were estimated from Fine and Gray regression models accounting for competing risks. Results In 240,357 new users of FXai, 88% used an oral FXai. The most common FXai indication was AF (72%). There were 10,163 patients (4.2%) hospitalised for bleeding events during FXai use. Of these, 3,873 MB events (38%) fulfilled the ISTH definition of MB and 1312 died during 3,542 person years of follow-up (Table 1). ACM incidence rates varied by time, indication, bleeding subtype, and drug type. ACM occurred in 926 patients (23.9%) in the first month. Mortality rates were highest in the first month 607 (95% CI 568-647) per 100 person years, the rates then decreased over the year but remained elevated throughout the first year compared with subsequent years. Those receiving LMWH had higher ACM than those receiving a DOAC, but this was not significant in the adjusted risk factor analysis. Risk factors for ACM following bleeding included age ≥80, and a history of current smoking, myocardial infarction, congestive heart failure, peripheral artery disease, Stage 4 or 5 kidney disease, metastatic cancer, and intracranial haemorrhage. Age<60, bleeding following major trauma, and a history of anaemia were associated with lower risk of ACM (Table 2). Conclusions There is a significant incidence of ACM following MB among FXai users. The incidence rate of ACM in patients treated with FXai was highest in the first month after FXai initiation, declined during the first year and then plateaued. Multiple risk factors associated with ACM have been recognised and these could guide urgent therapies such as antidotes.

A discovery and verification approach to pharmacovigilance using electronic healthcare data.

Pharmacovigilance is vital for drug safety. The process typically involves two key steps: initial signal generation from spontaneous reporting systems (SRSs) and subsequent expert review to assess the signals' (potential) causality and decide on the appropriate action. We propose a novel discovery and verification approach to pharmacovigilance based on electronic healthcare data. We enhance the signal detection phase by introducing an ensemble of methods which generated signals are combined using Borda count ranking; a method designed to emphasize consensus. Ensemble methods tend to perform better when data is noisy and leverage the strengths of individual classifiers, while trying to mitigate some of their limitations. Additionally, we offer the committee of medical experts with the option to perform an in-depth investigation of selected signals through tailored pharmacoepidemiological studies to evaluate their plausibility or spuriousness. To illustrate our approach, we utilize data from the German Pharmacoepidemiological Research Database, focusing on drug reactions to the direct oral anticoagulant rivaroxaban. In this example, the ensemble method is built upon the Bayesian confidence propagation neural network, longitudinal Gamma Poisson shrinker, penalized regression and random forests. We also conduct a pharmacoepidemiological verification study in the form of a nested active comparator case-control study, involving patients diagnosed with atrial fibrillation who initiated anticoagulant treatment between 2011 and 2017. The case study reveals our ability to detect known adverse drug reactions and discover new signals. Importantly, the ensemble method is computationally efficient. Hasty false conclusions can be avoided by a verification study, which is, however, time-consuming to carry out. We provide an online tool for easy application: https://borda.bips.eu.

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.