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Background: Patients who sustain a hip fracture whilst taking direct oral anticoagulants (DOACs) experience delays to surgery, which can increase morbidity and mortality. Achievement of the prompt surgery aspect of the National Hip Fracture Database (NHFD) best practice tariff (BPT) stipulates surgery within 36 h, which these patients often fail to meet. Patients and methods: Our protocol for expedited hip fracture surgery in patients taking DOACs was implemented. We compared surgery within 36 h (primary outcome) and peri-operative blood transfusions, 30-day mortality, wound leakage, return to theatre and length of hospital stay (secondary outcomes) with standard care of 80 matched non-anticoagulated controls. Results: Median times to theatre were 26.0 h (IQR 16.2 h) in DOAC patients and 22.4 h (IQR 16.9 h) in controls: bootstrapped 95% CI for the difference (−0.935, 7.52). Bias-corrected related samples bootstrapped t -test revealed no evidence for a group difference on the primary outcome (p = 0.133) or any secondary outcome, including post-operative transfusions (χ2(1) = 0.533; p = 0.465, 95% CI for the difference −18.3% to 8.37%); death within 30 days (χ2(1) = 0.667; p = 0.414, 95% CI for the difference −3.48% to 8.48%); wound leakage (χ2(1) = 0.571; p = 0.450, 95% CI −1.79% to 0.792%); return to theatre (χ2(1) = 0.00; p = 1.00); and median length of hospital stay (p = 0.678, bias-corrected bootstrapped 95% CI for the difference −4.47 to 6.68). Discussion: Our protocol is simple, does not require plasma DOAC level testing and can be used to achieve the NHFD recommendation of surgery within 36 h without increasing peri-operative transfusions, wound leakage, return to theatre, length of stay or mortality. [ABSTRACT FROM AUTHOR]

Recently, anticoagulant reversal has become a treatment option for life-threatening bleeding, especially in intracranial hemorrhage. Although evidence of the beneficial efficacy of andexanet alfa accumulates in cases of intracranial hemorrhage, little is known about its effectiveness in head injuries without intracranial hemorrhage. We present the case of an 87-year-old man who suffered a stroke 1 year previously and had been taking apixaban since then, who was brought to the emergency department with facial trauma due to a fall. Upon arrival at the hospital, the patient was conscious, and his vital signs were normal; however, physical examination revealed epistaxis, and plain head computed tomography (CT) showed multiple facial fractures without intracranial hemorrhage. As epistaxis was challenging to control, upper airway obstruction developed. His percutaneous oxygen saturation (SpO2) decreased rapidly, and he underwent tracheal intubation. Contrast-enhanced head CT revealed at least two extravasations, near the anterior wall of the right maxillary sinus and from the nasal canal to the nasopharynx area. However, embolization using interventional radiology was deemed difficult. Because the bleeding did not stop, we determined the bleeding was life-threatening and uncontrollable. Therefore, we infused andexanet alfa to stop the bleeding. After infusion, hemostasis was confirmed. This case suggests the effectiveness of andexanet alfa in cases of facial trauma and extracranial bleeding difficult to stop, resulting in favorable outcomes and hemostatic effects.

Previous meta‐analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)‐associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta‐analysis on the effectiveness of AA versus PCC products for FXaI‐associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn‐Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random‐effects meta‐analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in‐hospital mortality, 30‐day mortality, and thrombotic events. Low–moderate risk of bias studies were meta‐analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty‐eight percent of the studies (n = 5) had low–moderate risk and 72% (n = 13) had a high risk of bias. Studies with low–moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15–6.44); one study], lower in‐hospital mortality [OR 0.48 (95% CI: 0.38–0.61); three studies], and reduced 30‐day mortality [OR 0.49 (95% CI: 0.30–0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01–1.84); 12 studies] and reductions in 30‐day mortality [OR 0.53 (95% CI: 0.37–0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low–moderate, high, or combined risk of bias groups. The evidence from low–moderate quality real‐world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in‐hospital and 30‐day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30‐day mortality risk remain significantly better with AA versus PCC. [ABSTRACT FROM AUTHOR]

Rivaroxaban, a specific factor Xa inhibitor and commonly utilized anticoagulant, has been known to cause hepatotoxicity and liver failure in humans. Although rivaroxaban is frequently used in veterinary medicine, hepatotoxicity has not been previously reported in dogs. The current case report describes a dog that developed severe hepatopathy following rivaroxaban administration for a large right pulmonary artery thrombus. An estimated 6-year-old spayed female mixed-breed dog developed anorexia and lethargy 9 days after rivaroxaban administration began. Subsequent labwork revealed severe hepatocellular hepatopathy, and rivaroxaban was discontinued. Additional diagnostics did not reveal an underlying etiology, although hepatic cytology could be consistent with a toxic injury. The hepatopathy and clinical signs improved after rivaroxaban was discontinued. The time to onset, type of hepatopathy, and time to resolution were all similar to those reported for human cases. This case provides precedence to advocate for improved and closer monitoring of dogs receiving factor Xa inhibitors. In cases of suspected hepatotoxicity with no other identifiable cause, a risk-benefit analysis should be performed, and discontinuation of rivaroxaban administration or alternative anticoagulant medications should be considered. [ABSTRACT FROM AUTHOR]

Abstract Background Thrombosis is a common critical complication relating to radiofrequency catheter ablation and cryoablation. There is a possibility that high‐temperature stimulation during radiofrequency ablation or low‐temperature stimulation during cryoablation may affect the coagulability of blood. In this study, we aimed to determine the impacts of transient temperature stimulations on the coagulability of whole blood and to clarify if edoxaban suppressed the hypercoagulability. Methods Citrated blood samples were drawn from 41 healthy subjects. Some blood samples were mixed with tissue factor (TF) and several concentrations of edoxaban (50, 100, and 200 ng/mL). Blood samples were exposed to several temperature stimulations for 1 min: heat stimulation (50°C) or cryostimulation (−20°C), and compared with control (37°C). Repeated cryostimulations or sequential cryo‐ and heat stimulation were also applied. Coagulability of whole blood was measured using a dielectric blood coagulometry. As an index of coagulability, the end of acceleration time (EAT) was used. Results Both heat‐ and cryostimulations significantly shortened the EAT compared to the control, indicating that hypercoagulability was induced by temperature stimulations. Application of TF enhanced and extended the hypercoagulability after the temperature stimulations. Sequential application of cryo‐ followed by heat stimulation further enhanced the hypercoagulability of blood. Application of edoxaban increased the EAT in a concentration‐dependent manner in control condition. Edoxaban at 100 or 200 ng/mL completely suppressed the shortening of EAT evoked by these temperature stimulations. Conclusion Transient temperature stimulations evoked hypercoagulability regardless of cryo‐ or heat stimulation. Edoxaban with 100 ng/mL or more eliminated this temperature‐stimulated hypercoagulability.

Study Objective: The purpose of this study is to provide evidence for the safety and efficacy of factor Xa inhibitors in patients with a weight ≤60 kg or BMI < 18.5 kg/m2. Design: Multicenter, retrospective, cohort study. Setting: Twenty‐two Ascension Health hospitals. Patients: Low‐body‐weight adult patients (weight ≤ 60 kg or BMI < 18.5 kg/m2) receiving treatment for atrial fibrillation or venous thromboembolism. Intervention: Factor Xa inhibitors (apixaban or rivaroxaban) or warfarin. Measurements and Main Results: This study included 2538 patients between the factor Xa inhibitors (n = 1695) and warfarin (n = 843) groups with a mean weight of 53.5 ± 5.5 kg and BMI of 20.7 ± 3.1 kg/m2. No significant difference in time to major bleeding was noted after controlling for potential confounders (HR 1.03, 95% CI 0.70–1.53, p = 0.87); similar results were seen following propensity score matching. Thromboembolism (5.3% vs. 6.2%, p = 0.38), composite major + clinically relevant nonmajor bleeding (9.8% vs. 11.5%, p = 0.18), and all‐cause mortality (10.7% vs. 12.8%, p = 0.12) were similar between patients receiving factor Xa inhibitors versus warfarin. Conclusion: No differences in safety or effectiveness were noted between factor Xa inhibitors versus warfarin. These findings provide encouraging evidence to support the use of factor Xa inhibitors in low‐body‐weight patients. [ABSTRACT FROM AUTHOR]

We evaluated the effectiveness of early direct oral anticoagulant (DOAC) monotherapy within one year after percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) using Korean National Health Insurance Service data. AF patients who underwent PCI were included and divided into the DOAC monotherapy group and the combination therapy group (DOAC with an antiplatelet agent) based on the medications used at 6 months after PCI. A major adverse cardiovascular event (MACE) was defined as a composite of cardiovascular death, acute myocardial infarction (AMI), stroke, or systemic thromboembolic event between 6 and 12 months after PCI. In the overall study population, the DOAC dose reduction rate was high in both the monotherapy group (70.8%) and the combination therapy group (79.1%). After propensity score matching, the MACE incidence was not significantly different between the two groups (hazard ratio [HR] 1.42 [0.90–2.24]). The numerical trend for higher MACE in the monotherapy group was mainly driven by the difference in stroke incidence (HR 1.84 [0.97–3.46]). All-cause death (HR 1.29 [0.61–2.74] or the incidence of major bleeding (HR 1.07 [0.49–2.35]) results were similar in the two groups. In conclusion, early DOAC monotherapy was not significantly associated with MACE risk between 6 and 12 months after PCI. [ABSTRACT FROM AUTHOR]

Background: Thrombosis is a common critical complication relating to radiofrequency catheter ablation and cryoablation. There is a possibility that high‐temperature stimulation during radiofrequency ablation or low‐temperature stimulation during cryoablation may affect the coagulability of blood. In this study, we aimed to determine the impacts of transient temperature stimulations on the coagulability of whole blood and to clarify if edoxaban suppressed the hypercoagulability. Methods: Citrated blood samples were drawn from 41 healthy subjects. Some blood samples were mixed with tissue factor (TF) and several concentrations of edoxaban (50, 100, and 200 ng/mL). Blood samples were exposed to several temperature stimulations for 1 min: heat stimulation (50°C) or cryostimulation (−20°C), and compared with control (37°C). Repeated cryostimulations or sequential cryo‐ and heat stimulation were also applied. Coagulability of whole blood was measured using a dielectric blood coagulometry. As an index of coagulability, the end of acceleration time (EAT) was used. Results: Both heat‐ and cryostimulations significantly shortened the EAT compared to the control, indicating that hypercoagulability was induced by temperature stimulations. Application of TF enhanced and extended the hypercoagulability after the temperature stimulations. Sequential application of cryo‐ followed by heat stimulation further enhanced the hypercoagulability of blood. Application of edoxaban increased the EAT in a concentration‐dependent manner in control condition. Edoxaban at 100 or 200 ng/mL completely suppressed the shortening of EAT evoked by these temperature stimulations. Conclusion: Transient temperature stimulations evoked hypercoagulability regardless of cryo‐ or heat stimulation. Edoxaban with 100 ng/mL or more eliminated this temperature‐stimulated hypercoagulability. [ABSTRACT FROM AUTHOR]

Rivaroxaban, a specific factor Xa inhibitor and commonly utilized anticoagulant, has been known to cause hepatotoxicity and liver failure in humans. Although rivaroxaban is frequently used in veterinary medicine, hepatotoxicity has not been previously reported in dogs. The current case report describes a dog that developed severe hepatopathy following rivaroxaban administration for a large right pulmonary artery thrombus. An estimated 6-year-old spayed female mixed-breed dog developed anorexia and lethargy 9 days after rivaroxaban administration began. Subsequent labwork revealed severe hepatocellular hepatopathy, and rivaroxaban was discontinued. Additional diagnostics did not reveal an underlying etiology, although hepatic cytology could be consistent with a toxic injury. The hepatopathy and clinical signs improved after rivaroxaban was discontinued. The time to onset, type of hepatopathy, and time to resolution were all similar to those reported for human cases. This case provides precedence to advocate for improved and closer monitoring of dogs receiving factor Xa inhibitors. In cases of suspected hepatotoxicity with no other identifiable cause, a risk–benefit analysis should be performed, and discontinuation of rivaroxaban administration or alternative anticoagulant medications should be considered.

Abstract Background Cervical epidural hematoma (CEH) is defined as a collection of blood in the suprameningeal space. Mechanisms of this rare pathology include spontaneous, postsurgical, and traumatic as the main subtypes. This unique case of traumatic CEH represents an even smaller subset of these cases. Management varies by symptom presentation, mechanism of injury, and other contraindications. Case presentation This case presents a 32 year old African American female on an oral anticoagulant sustaining traumatic cervical hematoma after a motor vehicle collision. Patient complained of neck, abdominal, and back pain. Imaging revealed a cervical spinal hematoma at the level of C3–C6. This case discusses the management of CEH for the general population and in the setting of anticoagulation. Conclusion Management of each case of CEH must be carefully considered and tailored based on their symptom presentation and progression of disease. As the use of anticoagulation including factor Xa inhibitors becomes more prevalent, there is greater need to understand the detailed pathophysiological aspect of the injuries. Targeted reversal agents such as Prothrombin Concentrate can be used for conservative treatment. Adjunct testing such as thromboelastogram can be used to help guide management.

Abstract Background Dual antithrombotic treatment (DAT) with clopidogrel and rivaroxaban sometimes is prescribed to cats with hypertrophic cardiomyopathy at risk of thromboembolism. To date, no studies have evaluated their combined effects on platelet function. Objectives/Hypothesis Evaluate the safety of DAT in healthy cats and compare, ex vivo, platelet‐dependent thrombin generation and agonist‐induced platelet activation and aggregation in cats treated with clopidogrel, rivaroxaban, or DAT. We hypothesized that DAT would safely modulate agonist‐induced platelet activation and aggregation more effectively than single agent treatment. Animals Nine apparently healthy 1‐year‐old cats selected from a research colony. Methods Unblinded, nonrandomized ex vivo cross‐over study. All cats received 7 days of rivaroxaban (0.6 ± 0.1 mg/kg PO), clopidogrel (4.7 ± 0.8 mg/kg PO), or DAT with defined washout periods between treatments. Before and after each treatment, adenosine diphosphate (ADP)‐ and thrombin‐induced platelet P‐selectin expression was evaluated using flow cytometry to assess platelet activation. Platelet‐dependent thrombin generation was measured by fluorescence assay. Platelet aggregation was assessed using whole blood impedance platelet aggregometry. Results No cats exhibited adverse effects. Of the 3 treatments, only DAT significantly decreased the number of activated platelets (P = .002), modulated platelet activation in response to thrombin (P = .01), dampened thrombin generation potential (P = .01), and delayed maximum reaction velocity (P = .004) in thrombin generation. Like clopidogrel, DAT inhibited ADP‐mediated platelet aggregation. However, rivaroxaban alone resulted in increased aggregation and activation in response to ADP. Conclusion and Clinical Importance Treatment combining clopidogrel and rivaroxaban (DAT) safely decreases platelet activation, platelet response to agonists, and thrombin generation in feline platelets more effectively than monotherapy with either clopidogrel or rivaroxaban.

BackgroundStent thrombosis (ST) is an uncommon but serious complication of stent implantation. This study aimed to explore factors associated with early, late, and very late ST to help guide risk assessment and clinical decision-making on ST.MethodsThe analysis included patients who received stent placement for the index acute coronary syndrome (ACS). Cumulative incidence of ST was assessed at 30 days (early ST), 31–360 days (late ST), 361–720 days (very late ST), and up to 720 days. Cox proportional hazards models were used to assess associations between ST and various factors, including patient characteristics [i.e., age, sex, ACS presentation, history of hypertension, smoking, diabetes, prior myocardial infarction (MI), heart failure, prior ischemic stroke, and cancer], laboratory tests [i.e., positive cardiac biomarker, hemoglobin, platelet count, white blood cell (WBC) count], and treatment [i.e., drug-eluting stent (DES) vs. bare-metal stent (BMS) and anticoagulant with rivaroxaban vs. placebo].ResultsAmong the 8,741 stented patients, 155 ST events (2.25%) occurred by Day 720. The cumulative incidences of early, late, and very late ST were 0.80%, 0.81%, and 0.77%, respectively. After multivariable adjustment, age ≥ 75 [hazard ratio (HR) = 2.13 (95% confidence interval, CI: 1.26–3.60)], a history of prior MI [HR = 1.81 (95% CI: 1.22–2.68)], low hemoglobin level [HR = 2.34 (95% CI: 1.59–3.44)], and high WBC count [HR = 1.58 (95% CI: 1.02–2.46)] were associated with a greater risk of overall ST, whereas DES [HR = 0.56 (95% CI: 0.38–0.83)] and rivaroxaban therapy [HR = 0.63 (95% CI: 0.44–0.88)] were associated with a lower risk of overall ST up to 720 days. Low hemoglobin level and high WBC count were associated with early ST (low hemoglobin: HR = 2.35 [95% CI: 1.34–4.12]; high WBC count: HR = 2.11 [95% CI: 1.17–3.81]). Low hemoglobin level and prior MI were associated with a greater risk of late ST (low hemoglobin: HR = 2.32 [95% CI: 1.26–4.27]; prior MI: HR = 2.98 [95% CI: 1.67–5.31]), whereas DES was associated with a lower risk of late ST [HR = 0.33 (95% CI: 0.16–0.67)]. Age ≥75 years was associated with very late ST.ConclusionThe study identified positive and negative associations with early, late, and very late ST. These variables may be useful in constructing risk assessment models for ST.Clinical Trial Registrationhttp://www.clinicaltrials.gov, identifier NCT00809965.

Andexanet alfa is a Gla-domainless FXa (GDXa) analog used as an antidote to FXa inhibitors. Despite its clinical use, laboratory monitoring for anti-Xa reversal and the effect of andexanet on fibrinolysis has not been explored. We used a GDXa with a serine-to-alanine mutation at position 195 (chymotrypsin numbering) to model the interaction between andexanet and apixaban. Six batches of pooled plasma, and whole blood from healthy volunteers were treated with increasing concentrations of apixaban with/without GDXa. Thrombin generation and plasmin generation (TG and PG) were tested in plasma, and whole blood thrombus formation was tested using thromboelastometry or a flow-chamber system. FXa was also tested in isolation for its ability to support plasmin activation with/without apixaban and GDXa. Apixaban (250–800 nM) concentration-dependently decreased the velocity and peak of TG in plasma. Apixaban prolonged the onset of thrombus formation in thromboelastometry and flow-chamber tests. GDXa normalized apixaban-induced delays in TG and whole blood thrombus formation. However, GDXa minimally affected the low PG velocity and peak caused by apixaban at higher concentrations (500–800 nM). FXa promoted plasmin generation independent of fibrin that was inhibited by apixaban at supratherapeutic concentrations. This study demonstrated the feasibility of assessing coagulation lag time recovery in plasma and whole blood following in vitro apixaban reversal using GDXa, a biosimilar to andexanet. In contrast, GDXa-induced changes in plasmin generation and fibrinolysis were limited in PG and tPA-added ROTEM assays, supporting the endogenous profibrinolytic activity of FXa and its inhibition at elevated apixaban concentrations. Schemata of putative mechanisms of factor Xa modulation of plasmin generation. A trace amount of fibrin initiates the formation of plasmin (Pln), which proteolyzes phospholipid-bound factor Xaα into Xaβ. The latter is further proteolyzed by plasmin into a heterodimer of 33 kDa and 13 kDa fragments (Xa33/13). Both Xaβ and Xa33/13 express carboxy-terminal lysine residues (⊕ in yellow) to which plasminogen (Plg) can be bound and subsequently activated by tissue plasminogen activator (tPA), facilitating the initiation of fibrinolysis. After binding of apixaban to factor Xaα, thrombin (IIa) generation is slowed down (|| in red), and Xa33/13 formation is blocked (× in red), resulting in reduced velocities of plasmin generation. [Display omitted] • Gla-domainless factor Xa S195A (GDXa) is useful in modeling a factor Xa inhibitor reversal with andexanet alpha in vitro • Profibrinolytic activity of factor Xa is inhibited by apixaban. • Despite the recovery of thrombin generation, GDXa had minimal effect on the changes in plasmin generation and fibrinolysis at elevated apixaban concentrations. [ABSTRACT FROM AUTHOR]

Aims Limited real-world data show that rivaroxaban following dosage criteria from either ROCKET AF [20 mg/day or 15 mg/day if creatinine clearance (CrCl) < 50 mL/min] or J-ROCKET AF (15 mg/day or 10 mg/day if CrCl < 50 mL/min) is associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We are aimed to study whether these observations differ between Asian and non-Asian subjects. Methods and results A systematic review and meta-analysis with random effects was conducted to estimate the aggregate hazard ratio (HR) and 95% confidence interval (CI) using PubMed and MEDLINE databases from 8 September 2011 to 31 December 2022 searched for adjusted observational studies that reported relevant clinical outcomes of NVAF patients receiving rivaroxaban 10 mg/day if CrCl > 50 mL/min, on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and rivaroxaban 20 mg/day if CrCl < 50 mL/min. Effectiveness and safety endpoints were compared between ROCKET AF and J-ROCKET AF dosing regimen in Asian and non-Asian subjects, separately. Also, risks of events of rivaroxaban 10 mg/day despite of CrCl > 50 mL/min and rivaroxaban 20 mg/day despite of CrCl < 50 mL/min were compared to that of 'ROCKET AF/J-ROCKET AF dosing'. Sensitivity analyses were performed by sequential elimination of each study from the pool. The meta-regression analysis was performed to explore the influence of potential factors on the effectiveness and safety outcomes. Eighteen studies involving 67 571 Asian and 54 882 non-Asian patients were included. Rivaroxaban following J-ROCKET AF criteria was associated with comparable risks of thromboembolism in the Asian subgroup, whereas rivaroxaban following J-ROCKET AF criteria was associated with higher risks of all-cause mortality (HR:1.30; 95% CI:1.05–1.60) compared with that of ROCKET AF criteria in the non-Asian population. There were no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF vs. ROCKET AF criteria either in the Asian or non-Asian population. The use of rivaroxaban 10 mg despite of CrCl > 50 mL/min was associated with a higher risk of thromboembolism (HR:1.64; 95% CI:1.28–2.11) but lower risk of major bleeding (HR:0.72; 95% CI:0.57–0.90) compared with eligible dosage criteria. The use of rivaroxaban 20 mg despite of CrCl < 50 mL/min was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.32; 95% CI:1.09–1.59), mortality (HR:1.33; 95% CI:1.10–1.59), and major bleeding (HR:1.26; 95% CI:1.03–1.53) compared with eligible dosage criteria. The pooled results were generally in line with the primary effectiveness and safety outcomes by removing a single study at one time. Meta-regression analyses failed to detect the bias in most potential patient characteristics associated with the clinical outcomes. Conclusion Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favourable for the non-Asian population. The use of rivaroxaban 10 mg despite of CrCl > 50 mL/min was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while use of rivaroxaban 20 mg despite of CrCl < 50 mL/min was associated with worse outcome in most clinical events. [ABSTRACT FROM AUTHOR]

Abstract Objective To define and contextualize life‐threatening gastrointestinal (GI) bleeding in the setting of factor Xa (FXa) inhibitor therapy and to derive a consensus‐based, clinically oriented approach to the administration of FXa inhibitor reversal therapy. Methods We convened an expert panel of clinicians representing specialties in emergency medicine, gastroenterology, vascular medicine, and trauma surgery. Consensus was reached among the clinician panelists using the Delphi technique, which consisted of 2 survey questionnaires followed by virtual, real‐time consensus‐building exercises. Results Hypovolemia and hemodynamic instability were considered the most important clinical signs of FXa inhibitor–related, life‐threatening GI bleeds. Clinician panelists agreed that potentially life‐threatening GI bleeding should be determined on the basis of hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. Last, the panel agreed that all patients with life‐threatening, FXa inhibitor–associated GI bleeding should be considered for FXa inhibitor reversal therapy; the decision to reverse FXa inhibition should be individualized, weighing the risks and benefits of reversal; and when reversal is elected, therapy should be administered within 1 h after initial emergency department evaluation, when possible. Conclusions Consensus‐based definitions of life‐threatening GI bleeding and approaches to FXa inhibitor reversal centered on hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. The results from this Delphi panel may inform clinical decision‐making for the treatment of patients experiencing GI bleeding associated with FXa inhibitor use in the emergency department setting.

Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte–monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R. [ABSTRACT FROM AUTHOR]

Background: To investigate risks of hospitalization for upper gastrointestinal bleeding (UGIB) in H. pylori‐eradicated patients newly started on warfarin or direct oral anti‐coagulants (DOACs). Methods: We identified all patients who had previously received H. pylori eradication therapy or were found to have no H. pylori on endoscopy and were then newly started on warfarin or DOACs from a population‐based electronic healthcare database. Primary analysis was the risk of UGIB between warfarin and DOACs users in H. pylori‐eradicated patients. Secondary analysis included the UGIB risk between H. pylori‐eradicated and H. pylori‐negative patients who were newly started on warfarin or DOACs. The hazard ratio (HR) of UGIB was approximated by pooled logistic regression model incorporating the inverse propensity of treatment weightings with time‐varying covariables. Results: Among H. pylori‐eradicated patients, DOACs had a significantly lower risk of UGIB (HR: 0.26, 95% CI 0.09–0.71) compared with warfarin. In particular, lower UGIB risks with DOACs were observed among older (≥65 years) patients, female, those without a history of UGIB or peptic ulcer, or ischemic heart disease, and non‐users of acid‐suppressive agents or aspirin. Secondary analysis showed no significant difference in UGIB risk between H. pylori‐eradicated and H. pylori‐negative patients newly started on warfarin (HR: 0.63,95% CI 0.33–1.19) or DOACs (HR: 1.37, 95% CI 0.45–4.22). Conclusions: In H. pylori‐eradicated patients, new users of DOACs had a significantly lower risk of UGIB than new warfarin users. Furthermore, the risk of UGIB in new warfarin or DOACs users was comparable between H. pylori‐eradicated and H. pylori‐negative patients. [ABSTRACT FROM AUTHOR]

Background: Dual antithrombotic treatment (DAT) with clopidogrel and rivaroxaban sometimes is prescribed to cats with hypertrophic cardiomyopathy at risk of thromboembolism. To date, no studies have evaluated their combined effects on platelet function. Objectives/Hypothesis: Evaluate the safety of DAT in healthy cats and compare, ex vivo, platelet‐dependent thrombin generation and agonist‐induced platelet activation and aggregation in cats treated with clopidogrel, rivaroxaban, or DAT. We hypothesized that DAT would safely modulate agonist‐induced platelet activation and aggregation more effectively than single agent treatment. Animals: Nine apparently healthy 1‐year‐old cats selected from a research colony. Methods: Unblinded, nonrandomized ex vivo cross‐over study. All cats received 7 days of rivaroxaban (0.6 ± 0.1 mg/kg PO), clopidogrel (4.7 ± 0.8 mg/kg PO), or DAT with defined washout periods between treatments. Before and after each treatment, adenosine diphosphate (ADP)‐ and thrombin‐induced platelet P‐selectin expression was evaluated using flow cytometry to assess platelet activation. Platelet‐dependent thrombin generation was measured by fluorescence assay. Platelet aggregation was assessed using whole blood impedance platelet aggregometry. Results: No cats exhibited adverse effects. Of the 3 treatments, only DAT significantly decreased the number of activated platelets (P =.002), modulated platelet activation in response to thrombin (P =.01), dampened thrombin generation potential (P =.01), and delayed maximum reaction velocity (P =.004) in thrombin generation. Like clopidogrel, DAT inhibited ADP‐mediated platelet aggregation. However, rivaroxaban alone resulted in increased aggregation and activation in response to ADP. Conclusion and Clinical Importance: Treatment combining clopidogrel and rivaroxaban (DAT) safely decreases platelet activation, platelet response to agonists, and thrombin generation in feline platelets more effectively than monotherapy with either clopidogrel or rivaroxaban. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate and compare clinical outcomes in patients who experienced intracranial hemorrhage (ICH) while taking apixaban or rivaroxaban and were reversed with four-factor prothrombin complex concentrates (4F-PCC) or andexanet alfa (AA). This retrospective cohort included adult patients that received 4F-PCC or AA for the initial management of an apixaban- or rivaroxaban-associated ICH. A primary outcome of excellent or good hemostatic efficacy at 12 h post-reversal was assessed. Secondary outcomes evaluated were change in hematoma volume size at 12 h, functional status at discharge, need for surgical intervention or additional hemostatic agents post-reversal, new thrombotic event within 28 days, 28-day all-cause mortality, discharge disposition, and hospital and intensive care unit lengths of stay. A total of 70 patients were included (4F-PCC, n = 47; AA, n = 23). For the primary outcome analysis, 21 patients were included in the 4F-PCC group and 12 in the AA group. The rate of effective hemostasis was similar between the 4F-PCC and AA groups (66.7% vs 75%, p = 0.62). There were no statistically significant differences between the groups for secondary outcomes, including 28-day mortality (40.4% vs 39.1%, p = 0.92) and thrombotic complications within 28 days of reversal (17.0% vs 21.7%, p = 0.63). In patients who experienced an ICH while taking apixaban or rivaroxaban, 4F-PCC and AA were found to have similar rates of excellent or good hemostatic efficacy. [ABSTRACT FROM AUTHOR]

The regimens for factor Xa (FXa) inhibitors (apixaban, edoxaban, and rivaroxaban) vary with venous thromboembolism (VTE) or non-valvular atrial fibrillation (NVAF). The dosage and duration of FXa inhibitor therapy also differ. However, the distribution of anti-factor Xa activity (AXA) values, prothrombin time (PT), and activated partial thromboplastin time (APTT) in patients administered each FXa inhibitor has not fully been assessed. Trough and peak AXA values, PT, and APTT were measured in 85 patients taking apixaban, 105 patients taking edoxaban, and 27 patients taking rivaroxaban. The patients were further divided into three groups based on the dosage. Each FXa inhibitor showed various ranges of AXA values, and twice-daily use resulted in higher absolute AXA values than once-daily use. AXA values and PT for 20 mg apixaban at both trough and peak times were significantly higher than those for 5 mg or 10 mg. AXA values for 60 mg edoxaban at peak time were significantly higher than those for 15 mg or 30 mg. AXA values for 30 mg of rivaroxaban at both trough and peak times were significantly higher than those for 10 mg or 15 mg. In a nonlinear regression model of the relationship between AXA and PT or APTT, PT was positively correlated with AXA values for each FXa inhibitor. This study obtained trough and peak levels of AXA, PT, and APTT in patients with VTE or NVAF who were administered apixaban, edoxaban, and rivaroxaban. [ABSTRACT FROM AUTHOR]

Background: Although not routinely recommended, anti-Xa level monitoring for apixaban or rivaroxaban may be useful in certain clinical scenarios. There are currently no laboratory standards, therapeutic ranges, or proven correlation between anti-Xa levels and clinical outcomes. Objective: This study describes the utilization, application, and association of anti-Xa levels with clinical outcomes in patients receiving apixaban or rivaroxaban. Methods: This retrospective, descriptive study included adult inpatients within the Houston Methodist System on apixaban or rivaroxaban with at least one anti-Xa level ordered subsequent to administered doses. The primary endpoint was major bleeding according to International Society on Thrombosis and Haemostasis criteria. Secondary endpoints included reasons for anti-Xa level ordering, anti-Xa levels at different time intervals post-dose, and thrombotic events. Pre-specified subgroup analyses were performed to further evaluate the primary endpoint. Results: The study population consisted of 169 patients and 234 anti-Xa levels. Twenty-nine levels were obtained in context of major bleeding. The majority of levels were not drawn as peak levels 2-4 hours post-dose, however remained quantifiable above typical observed levels within this timeframe and well beyond 24 hours post-dose. Patient characteristics with major bleeding included elderly age, acute renal impairment, and low body weight. At least 14 unique reasons for anti-Xa level ordering were identified. Twenty-nine levels were associated with thrombotic events. Conclusion: Anti-Xa levels may be useful for assessment of current drug concentrations, immediate safety of therapy, and guidance for possible clinical interventions. Dose titration and reversal therapies based on anti-Xa level results in major bleeding warrant further research. [ABSTRACT FROM AUTHOR]

Background: There are inadequate data on the optimal strategy for transitioning factor Xa inhibitors (FXai; apixaban, rivaroxaban) to unfractionated heparin (UFH) infusions. Objective: In patients transitioning from an FXai to an UFH infusion, this study compared the safety and efficacy of monitoring UFH infusions using an activated partial thromboplastin time (aPTT) titration scale versus utilizing an UFH-calibrated anti-Xa titration scale aided by a novel institutional guideline. Methods: A retrospective cohort analysis was conducted on adult patients transitioning from an FXai to an UFH infusion at 2 medical centers from June 1, 2018, to November 1, 2020. One institution utilized aPTT while the other institution primarily used UFH-calibrated anti-Xa. The primary endpoint was a composite of death, major bleeding, or new thrombosis during the hospitalization with a planned noninferiority analysis. Secondary outcomes were also collected including the amount and duration of UFH administered between cohorts. Results: The incidence rate of the primary composite endpoint was 6.3% in the anti-Xa group and 11% in the aPTT group (P < 0.001 for noninferiority, P = 0.138 for superiority) meeting noninferiority criteria. No statistical differences were seen in new thrombosis, major bleeding, or any bleeding. Conclusion and Relevance: This represents the first report of a comparison between aPTT versus anti-Xa monitoring in relation to clinical outcomes for patients transitioning from an FXai to an UFH infusion. A transition guideline primarily utilizing an UFH-calibrated anti-Xa assay appears to be a safe alternative to aPTT monitoring and can aid facilities in the management of patients during these complex transitions. [ABSTRACT FROM AUTHOR]

Aim: Intimal hyperplasia causes vascular occlusion and its optimal treatment is unknown. In this study, we evaluated the effectiveness of Apixaban and Rivaroxaban treatment for preventing intimal hyperplasia in rabbits. Material and Methods: The rabbits (n = 15) were randomly divided into three groups. Reanastomoses are applied to the carotid artery. All groups received 100 U/kg heparin sodium during the operation period. Group A (n = 5) as a control group had no medication. Group B (n = 5) was given Rivaroxaban 3 mg/kg/day. In-group C (n = 5) Apixaban was administered per orally 10 mg/kg. At the end of the treatment on the 28th day, carotid artery specimens were excised and evaluated histologically. Results: Increased intima thickness was observed in the control group than the drug groups (P=0.019, P=0.007). It was found that there was no difference between groups in terms of lumen diameter, lumen area, tunica media area and tunica media thickness. There was difference between groups in terms of caspase 3 or TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining (p [Turk J Vasc Surg 2022; 31(3.000): 148-56]

[Display omitted] The goal of the current study was to formulate and examine the potential of poly (lactic-co-glycolic acid) (PLGA) as carriers to facilitate the targeted administration of edoxaban tosylate monohydrate (ETM). ETM-PLGA-NPs were effectively formulated using the nanoprecipitation technique. Particle size, drug entrapment percentage, zeta potential, assessment of intestinal absorption, FT-IR, SEM, drug dissolution behavior, and histopathology investigations were used to describe ETM-PLGA-NPs. The produced NPs had a roughly spherical shape with a particle size of 99.85 d.nm, a PDI of 0.478, and a zeta potential of 38.5 mV with a maximum drug entrapment of 82.1 %. FTIR measurements showed that the drug's chemical stability remained intact after preapred into nanoparticles. In vitro drug release behavior followed the Higuchi model and revealed an early burst release of 30 % and persistent drug release of 78 % from optimized NPs for up to 120 hrs. According to in vitro data, a 1:10 ratio of ETM to PLGA provided longer-lasting ETM release and improved encapsulation efficiency. Images captured with an inverted fluorescent microscope exhibited that NPs may both greatly increase the amount of ETM accumulated in the intestinal tract and make it easier for ETM to enter the membrane beneath the cells of the intestines. The study found that using PLGA nanoparticles to encapsulate the ETM resulted in longer circulation duration (aPTT, PT, TT). In vivo investigations found that nanoparticles encapsulated had no negative impact on hematological parameters, lung, liver, or kidney tissues. All things considered, the NPs are a potential delivery method to increase the oral absorption and antithrombotic activity of ETM. [ABSTRACT FROM AUTHOR]

Aim: Intimal hyperplasia causes vascular occlusion and its optimal treatment is unknown. In this study, we evaluated the effectiveness of Apixaban and Rivaroxaban treatment for preventing intimal hyperplasia in rabbits. Material and Methods: The rabbits (n = 15) were randomly divided into three groups. Reanastomoses are applied to the carotid artery. All groups received 100 U/kg heparin sodium during the operation period. Group A (n = 5) as a control group had no medication. Group B (n = 5) was given Rivaroxaban 3 mg/kg/day. In-group C (n = 5) Apixaban was administered per orally 10 mg/kg. At the end of the treatment on the 28th day, carotid artery specimens were excised and evaluated histologically. Results: Increased intima thickness was observed in the control group than the drug groups (P=0.019, P=0.007). It was found that there was no difference between groups in terms of lumen diameter, lumen area, tunica media area and tunica media thickness. There was difference between groups in terms of caspase 3 or TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining (p<0.05). Conclusion: Apixaban and Rivaroxaban may have protective efficacy against intimal hyperplasia after vascular surgical intervention. [ABSTRACT FROM AUTHOR]

Background: Anticoagulant use prior to trauma has been associated with increased incidence of traumatic brain injury (TBI), intracranial hemorrhage (ICH) progression, and mortality. Prothrombin complex concentrates (PCCs) are commonly used as off-label treatments for factor Xa inhibitor-associated life-threatening hemorrhage. At this time, there is no consensus regarding appropriate indication, target dose, or outcomes of PCC administration in patients presenting with traumatic ICH. This study seeks to evaluate the impact of reversal with PCC on hemorrhage progression and outcomes in patients with TBI on preinjury factor Xa inhibitors. Methods: This single-center retrospective cohort study included patients ≥ 18 years presenting with an acute TBI of any severity on apixaban or rivaroxaban from September 1, 2016, to September 1, 2019. Patients were grouped on the basis of receipt of PCCs for reversal (i.e., reversal or no reversal). Exclusion criteria included spontaneous ICH or known coagulopathy. Propensity score matching was conducted with the following variables: age, Abbreviated Injury Scale (head) score, and Charlson Comorbidity Index score. The primary outcome was hemorrhage stability within 48 h. Secondary outcomes included degree of hemorrhage progression, in-hospital mortality, discharge disposition, and incidence of thromboembolic events. Results: Of the 115 patients meeting inclusion criteria, 84 were included in the propensity score matched data set. Baseline characteristics, comorbidities, and TBI severity were similar. The majority of patients in the reversal group (35 [83.3%]) and the no reversal (NR) group (40 [95.2%]) experienced a mild TBI (admission Glasgow Coma Scale score of 14 to 15). In the reversal group, patients received 34.3 units/kg activated PCC, 30.5 units/kg four-factor PCC, or 54.9 units/kg four-factor PCC and activated PCC on average. There was no difference observed in the incidence of hemorrhage progression (10.8% NR vs. 15.0% reversal; p = 0.739) or in median change in ICH volume (0 mL NR vs. 1 mL reversal; p = 0.2199) between groups. Additionally, reversal did not affect in-hospital mortality (3 [7.1%] NR vs. 4 [9.5%] reversal; p > 0.999). One patient in the reversal group developed a deep vein thrombosis (DVT) during the hospitalization; however, this did not result in a statistically significant difference in the occurrence of DVT (p > 0.999). Conclusions: This study demonstrated that PCC used for the treatment of factor Xa inhibitor-associated ICH related to mild TBI did not significantly impact the incidence or degree of hemorrhage progression, and PCC treatment did not result in increased thromboembolic events. [ABSTRACT FROM AUTHOR]

Apixaban is a factor Xa (FXa) inhibitor and standard‐of‐care anticoagulant with FXa Ki and plasma protein binding (free fraction) averages 0.08 nM and 0.13 in humans and 0.16 nM and 0.37 in rabbits, respectively. Apixaban at the approved dose of 5 mg BID achieved maximum and minimum plasma concentration of 373 nM (95% CI: 198 – 699 nM) and 224 nM (95% CI 89–501 nM), respectively, in patients with nonvalvular atrial fibrillation (AF). We calibrated the rabbit model of electrolytic‐mediated arterial thrombosis (ECAT) against apixaban and correlated the potencies derived from the rabbit ECAT to in vivo efficacious exposure levels in AF patients. Vehicle and apixaban at multiple doses were infused IV in ECAT rabbits and their effects on thrombus weight were measured. Apixaban exhibited dose‐related efficacy in preventing thrombosis in ECAT rabbits with EC20, EC50, EC60, EC70 and EC80 of 18, 101, 169, 296, and 585 nM, respectively. After correcting for the human‐to‐rabbit potency based on FXa Ki and plasma protein binding, we estimated a rabbit‐equally‐effective plasma concentration of 157 and 259 nM to the trough and peak plasma concentration in AF patients treated with 5 mg BID of apixaban. These rabbit‐equally‐effective plasma concentrations matched well with the rabbit ECAT EC60 and EC70. This study supports the potential of the rabbit ECAT to predict in vivo therapeutic drug exposure of FXa inhibitors. Achieving human‐equally‐effective plasma concentrations to the rabbit ECAT EC60 and EC70 may produce clinical efficacy in patient populations like AF.The rabbit model of electrolytic‐mediated arterial thrombosis (ECAT) was calibrated against the standard‐of‐care anticoagulant apixaban. Reverse translation from human apixaban data to rabbit suggested achieving human‐equally‐effective plasma concentrations to the rabbit ECAT EC60 and EC70 may produce clinical efficacy in patient populations like nonvalvular atrial fibrillation. [ABSTRACT FROM AUTHOR]

After orthopedic surgeries, such as hip replacement, many patients are prone to developing deep vein thrombosis (DVT), which in severe cases can lead to fatal pulmonary embolism or major bleeding. Clinical intervention with high-dose anticoagulant therapy inevitably carries the risk of bleeding. Therefore, a targeted drug delivery system that adjusts local DVT lesions and potentially reduces drug dosage and toxic side effects important. In this study, we developed a targeted drug delivery platelet-derived nanoplatform (AMSNP@PM-rH/A) for DVT treatment that can simultaneously deliver a direct thrombin inhibitor (DTI) Recombinant Hirudin (rH), and the Factor Xa inhibitor Apixaban (A) by utilizing Aminated mesoporous silica nanoparticles (AMSNP). This formulation exhibits improved biocompatibility and blood half-life and can effectively eliminate deep vein thrombosis lesions and achieve therapeutic effects at half the dosage. Furthermore, we employed various visualization techniques to capture the targeted accumulation and release of a platelet membrane (PM) coating in deep vein thrombosis and explored its potential targeting mechanism. Development of a targeted delivery platelet-derived nanoplatform for treating deep vein thrombosis by delivering direct thrombin inhibitors and factor Xa inhibitors, with the ability to be tracked using digitalization and visualization technologies. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Apixaban is a factor Xa (FXa) inhibitor and standard‐of‐care anticoagulant with FXa Ki and plasma protein binding (free fraction) averages 0.08 nM and 0.13 in humans and 0.16 nM and 0.37 in rabbits, respectively. Apixaban at the approved dose of 5 mg BID achieved maximum and minimum plasma concentration of 373 nM (95% CI: 198 – 699 nM) and 224 nM (95% CI 89–501 nM), respectively, in patients with nonvalvular atrial fibrillation (AF). We calibrated the rabbit model of electrolytic‐mediated arterial thrombosis (ECAT) against apixaban and correlated the potencies derived from the rabbit ECAT to in vivo efficacious exposure levels in AF patients. Vehicle and apixaban at multiple doses were infused IV in ECAT rabbits and their effects on thrombus weight were measured. Apixaban exhibited dose‐related efficacy in preventing thrombosis in ECAT rabbits with EC20, EC50, EC60, EC70 and EC80 of 18, 101, 169, 296, and 585 nM, respectively. After correcting for the human‐to‐rabbit potency based on FXa Ki and plasma protein binding, we estimated a rabbit‐equally‐effective plasma concentration of 157 and 259 nM to the trough and peak plasma concentration in AF patients treated with 5 mg BID of apixaban. These rabbit‐equally‐effective plasma concentrations matched well with the rabbit ECAT EC60 and EC70. This study supports the potential of the rabbit ECAT to predict in vivo therapeutic drug exposure of FXa inhibitors. Achieving human‐equally‐effective plasma concentrations to the rabbit ECAT EC60 and EC70 may produce clinical efficacy in patient populations like AF.

Post-thrombotic syndrome (PTS) is common in patients with deep vein thrombosis (DVT). It is unclear if different types of anticoagulant therapies (e.g. vitamin K antagonists (VKA), direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH)) are associated with different risks of PTS. We sought to assess the incidence rates of PTS development following a proximal DVT of the lower extremity managed with different types of anticoagulation regimens. A systematic search of MEDLINE, EMBASE and PubMed, from inception to June 2023 was performed. The primary outcome was development of PTS. The secondary outcomes included severe PTS, venous ulcers, and major bleeding. Incidence rates were pooled using the random effects model and expressed as event per 100 patient-years with its associated 95 % confidence intervals (CI) using R software. A total of 21 (4342 patients) articles were included in the analysis. The adjusted pooled incidence of PTS was 15.1 (95 % CI: 8.7 to 26.1), 18.2 (95 % CI: 9.4 to 35.1) and 24.6 (95 % CI: 9.2 to 65.5) per 100 patient-years patients managed with VKA, DOAC and LMWH, respectively. The adjusted pooled incidence of severe PTS was 5.1 (95 % CI: 2.6 to 10.0) and 0.2 (95 % CI: 0.01 to 2.7) per 100 patient-years for VKAs and DOACs, respectively. The development of PTS is common in patients with proximal lower extremity DVT. The incidence rates of PTS seem to be similar across the different anticoagulation regimens, but severe PTS may be lower among patients receiving a DOAC. • Post-Thrombotic Syndrome (PTS) is a common complication following deep vein thrombosis (DVT). • Different types of anticoagulant therapies are associated with similar risk of PTS. • Direct oral anticoagulants may be associated with a lower risk of severe PTS compared to vitamin-K antagonist. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Until recently, guidelines recommended the use of low-molecular weight heparin (LMWH) as standard of care for VTE in patients with cancer. Despite the proven efficacy of direct oral anticoagulants (DOACs) for treatment of VTE, there is equipoise supporting their use in cancer patients.Methods: A systematic review of PubMed, Medline and EMBASE identified four randomised controlled trials (RCTs) in patients with cancer and VTE comparing a factor Xa inhibitor (FXaI) to LMWH. A meta-analysis was performed with a primary outcome of VTE recurrence and key secondary outcomes of major bleeding, clinically relevant non-major bleeding (CRNMB) and gastrointestinal (GI) bleeding.Results: Four RCTs with 2,907 patients were included. 1,451 patients were randomised to FXaI and 1,456 to LMWH. VTE recurrence was lower in the FXaI group (RR 0.62, 95%CI 0.44-0.87; p=0.01; I2=24.90), with an absolute risk difference of -4% equating to a number needed to treat of 25 for prevention of recurrent VTE with FXaI. No significant difference in major bleeding was noted between groups (RR 1.33, 95%CI 0.84-2.11; p=0.23). Rates of GI bleeding (RR 1.87, 95%CI 1.06-3.29; p=0.03) and CRNMB (RR 1.57, 95%CI 1.11-2.23; p=0.01) were greater with FXaIs.Conclusion: In patients with cancer and VTE, the rate of VTE recurrence was significantly lower with FXaI than with LMWH without an increased risk of major bleeding. Our data supports the use of FXaIs as the standard of care for the treatment of VTE in this population. [ABSTRACT FROM AUTHOR]

Background: Existing research recommends either andexanet alfa (AA) or four-factor prothrombin complex concentrate (4F-PCC) as an antidote for major bleeding events due to apixaban or rivaroxaban. Currently, there is limited published research that directly compares the risks and benefits of the two agents in patients with oral factor Xa inhibitor related traumatic and spontaneous intracerebral hemorrhages. Additional head-to-head data is needed to support favoring either AA or 4F-PCC when it comes to efficacy, safety, and cost.Methods: A retrospective chart review was conducted to assess patients admitted to a multi-center healthcare system and a stand-alone teaching hospital in central Florida from June 2016 to December 2020. Patients included in the study were at least 18 years of age, taking apixaban or rivaroxaban prior to admission, had radiographical evidence of an intracranial hemorrhage, and received either AA or 4F-PCC as a reversal agent. The primary outcome analyzed was the level of excellent hemostasis achieved, based on a standardized rating system for effective hemostasis defined by the International Society of Thrombosis and Hemostasis (ISTH), after administration of AA or 4F-PCC. Secondary outcomes analyzed included changes in the initial hemorrhage volume as reported on computed tomography (CT) scan and at 12 to 24 h post treatment, rate of thromboembolic events, rate of inpatient mortality, and total cost of treatment after AA or 4F-PCC administration.Results: A total of 109 patients were included in the study with 47 in the AA group (43.1%) and 62 in the 4F-PCC group (56.9%). There were no statistically significant differences between AA and 4F-PCC in terms of the primary and secondary outcomes with the exception of total cost of treatment. The level of excellent hemostasis achieved after reversal administration of AA was seen in 27 patients (71.1%) and 41 patients (70.7%) after 4F-PCC administration (p = 1, p adjusted = 0.654 after controlling for age, ICH score, regional mass effect, and midline shift). There was no statistically significant difference in the median percentage change in hemorrhagic volume from baseline to 12-24 h after reversal treatment (0 [-0.17--0.24] vs. 0 [-0.021-0.29], p = 0.439, adjusted p = 0.601) in the AA and 4F-PCC groups, respectively. The total incidence of thromboembolic events (4 [8.5%] vs. 6 [9.7%], p = 1, adjusted p = 0.973) and rate of inpatient mortality was similar between the two groups (16 [34.0%] vs. 13 [21.0%], p = 0.134, adjusted p = 0.283). A statistically significant difference was observed with the total cost of reversal treatment: $23,602 for treatment with AA and $6692 for treatment with 4F-PCC.Conclusions: No statistically significant differences were identified in primary or secondary outcomes between the two agents with the exception of total treatment cost. There is insufficient evidence based on this study to recommend AA over 4F-PCC for patients with intracranial hemorrhages associated with the use of apixaban or rivaroxaban. [ABSTRACT FROM AUTHOR]

Objectives: Feline arterial thromboembolism (ATE), an often devastating outcome, was recently shown to affect 11.3% of cats with hypertrophic cardiomyopathy over 10 years. Current American College of Veterinary Internal Medicine guidelines recommend the use of clopidogrel in cats at risk for ATE, with addition of a factor Xa inhibitor in very high risk or post-ATE cases. To date, no studies have examined the safety or efficacy of this combined antithrombotic therapy. This retrospective case series aimed to assess the frequency and type of adverse events that occurred in cats prescribed dual clopidogrel and rivaroxaban therapy. Secondary aims were to evaluate indications for dual therapy and clinical outcome. Methods: The study included 32 cats prescribed clopidogrel (18.75 mg PO q24h) and rivaroxaban (2.5 mg PO q24h) on an outpatient basis over a 5-year period. Results: Cats were prescribed dual therapy for at least one of the following: ATE event (n = 18), presence of an intracardiac thrombi (n = 17) or presence of spontaneous echocardiographic contrast (SEC) (n = 16). Five cats experienced adverse effects that could be attributed to medications, a median of 13 days from initiation (epistaxis, hematemesis, hematochezia or hematuria). No cat required hospitalization as a result of these events. Median survival time from onset of therapy was 257 days (interquartile range [IQR] = 38–497) for all cats, 502 days (IQR = 171–663) for ATE cats, 725 days (IQR = 133–856) for cats with an ATE to two or more limbs and 301 days (IQR = 221–431) for cats with only one limb affected. Recurrence rate of ATE while on dual therapy was 16.7%; no cat newly developed an ATE while on dual therapy. Conclusions and relevance: Dual antithrombotic therapy with clopidogrel and rivaroxaban resulted in a low reported incidence of adverse events. Cats placed on dual therapy for an ATE event experienced a low rate of recurrence and effective thromboprophylaxis was achieved in cats with intracardiac thrombi or SEC. [ABSTRACT FROM AUTHOR]

Purpose: The use of direct oral Xa inhibitors (DXaIs) to prevent venothrombotic events is increasing. However, gastrointestinal bleeding, including that related to endoscopic resection, is a concern. In this study, we evaluated bleeding and coagulation times during the perioperative period of gastric endoscopic submucosal dissection (ESD). Materials and Methods: Patients who consecutively underwent gastric ESD from August 2016 to December 2018 were analyzed. Bleeding rates were compared among the 3 groups (antiplatelet, DXaIs, and control). DXaI administration was discontinued on the day of the procedure. Prothrombin time (PT), activated partial thromboplastin time, and the ratio of inhibited thrombin generation (RITG), which was based on dilute PT, were determined before and after ESD. Results: During the study period, 265 gastric ESDs were performed in 239 patients, where 23 and 50 patients received DXaIs and antiplatelets, respectively. Delayed bleeding occurred in 17 patients (7.4%) and 21 lesions (7.1%). The bleeding rate in the DXaI group was significantly higher than that in the other groups (30.4%, P<0.01), and the adjusted odds ratio of bleeding was 5.7 (95% confidence interval, 1.4–23.7; P=0.016). In patients using DXaIs, there was a significant (P=0.046) difference in the median RITG between bleeding cases (18.6%) and non-bleeding cases (3.8%). Conclusions: A one-day cessation of DXaIs was related to a high incidence of bleeding after gastric ESD, and monitoring of residual coagulation activity at trough levels might enable the predicted risk of delayed bleeding in patients using DXaIs. [ABSTRACT FROM AUTHOR]

Background: An earlier systematic review reported no differences in the incidence of recurrent venous thromboembolism and major bleeding between factor Xa inhibitors and standard anticoagulation. The present meta-analysis aimed to assess the effectiveness of factor Xa inhibitors for the management of venous thromboembolism (VTE), specifically in patients with cancer, as there were more randomized clinical trials (RCTs) available. Methods: The PubMed and Cochrane Library databases were systematically screened for all RCTs assessing factor Xa inhibitor efficacy for VTE management in cancer patients. Using RevMan 5.3, we performed a Mantel–Haenszel fixed-effects meta-analysis of the following outcomes: recurrent VTE, VTE events, and major bleeding rates. Results: We identified 11 studies involving 7,965 patients. Factor Xa inhibitors were superior in preventing VTE recurrence, compared to low-molecular-weight heparin (LMWH) (OR 0.60; 95% CI 0.45–0.80; P < 0.01) and vitamin K antagonists (VKA) (OR 0.51; 95% CI 0.33–0.78; P < 0.01). As prophylaxis, factor Xa inhibitors had a similar rate of VTE compared to VKAs (OR 1.08 [95% CI 0.31–3.77]; P = 0.90) and a lower rate compared to placebo (OR 0.54 [95% CI 0.35–0.81]; P < 0.01). Major bleeding rates were higher with factor Xa inhibitors than with LMWHs (OR 1.34 [95% CI 0.83–2.18]; P = 0.23), but significantly lower than VKAs (OR 0.71 [95% CI 0.55–0.92]; P < 0.01). Conclusions: Factor Xa inhibitors are effective for VTE management in patients with cancer; however, they are also associated with an increased bleeding risk compared to LMWH, but decreased when compared to VKA.

Background: Several recent randomised controlled trials (RCT) have investigated the use of direct oral anticoagulants (DOAC) in the treatment of malignancy‐associated venous thromboembolism (VTE). Aims: This meta‐analysis combines all RCT data to determine the risks of recurrent VTE and bleeding with DOAC in patients with malignancy‐associated VTE compared with low‐molecular‐weight heparin (LMWH). Methods: The study followed PRISMA guidelines. MEDLINE, EMBASE and CENTRAL were systematically searched from inception to 1 April 2020. References of reviews and relevant conference proceedings were searched by hand. Two authors independently evaluated study eligibility, extracted data and assessed risk of bias. Direct and indirect meta‐analyses were performed. Results: In four RCT with low risk of bias (2907 patients), high certainty evidence suggested that DOAC had a 37% reduction in risk of recurrent VTE compared with LMWH (direct pooled risk ratio (RR) 0.63; 95% confidence interval (CI) 0.44–0.91; I2 = 28%). No significant difference was observed in the risk of major bleeding with DOAC compared with LMWH (RR 1.31; 95% CI 0.83–2.07; I2 = 22%; moderate certainty evidence), including in patients in gastrointestinal and genitourinary malignancy. An increased risk of combined major or clinically relevant non‐major bleeding was seen with DOAC (RR 1.52; 95% CI 1.09–2.12; I2 = 51%; low certainty evidence). Apixaban had the highest probability of being ranked the most effective and least bleeding risk among the DOAC. Conclusion: DOAC are effective in treating malignancy associated VTE; however, caution is required in patients with high risk of bleeding. Apixaban had lower risk of bleeding compared to other DOAC in this population. [ABSTRACT FROM AUTHOR]

All patients had an isolated SVT confirmed by compression ultrasonography.8 The primary efficacy outcome was SVT, DVT, or PE within 90 days of diagnosis. Keywords: rivaroxaban; superficial vein thrombosis; anticoagulants; factor Xa inhibitor EN rivaroxaban superficial vein thrombosis anticoagulants factor Xa inhibitor e3 e6 4 12/27/21 20220101 NES 220101 The precise incidence of superficial vein thrombosis (SVT) is unknown. Bleeding was defined using the International Society on Thrombosis and Haemostasis criteria.9 Baseline characteristics and outcome data were extracted from the local hospital electronic patient record (EPR; Allscripts Sunrise™, Chicago, IL, USA), and anti-coagulation clinic database (DAWN xs) for each patient. [Extracted from the article]

Purpose Oral factor Xa inhibitors (FXaIs) are increasingly utilized for outpatient anticoagulation therapy; however, laboratory monitoring is not routinely used to assess the safety and efficacy of these agents. We aimed to evaluate the role of chromogenic anti–factor Xa (anti-Xa) assays in the emergency department (ED) in the setting of patients with an acute bleed or requiring emergent procedures. Methods A retrospective review of anti-Xa levels obtained in the ED between June 1, 2019, and April 30, 2020, was completed. Data were collected to describe the clinical setting of anti-Xa level collection, oral FXaIs used before admission, administration of reversal agents, and patient disposition to further characterize the role of anti-Xa levels in the management of rivaroxaban and apixaban reversal. Results Thirty anti-Xa levels were included in the final analysis. The median time from sample collection to anti-Xa assay result was 45.9 minutes (interquartile range, 35.3-54.7 minutes). Eleven patients (37%) received anticoagulation reversal after their anti-Xa levels were determined. Anticoagulation reversal agents included either activated prothrombin complex concentrates (aPCCs) or prothrombin complex concentrates (PCCs). Anti-Xa levels were collected in 2 patients who had received PCCs before arrival at our ED. Of the patients with anti-Xa levels below 30 ng/mL, none received aPCCs or PCCs after their anti-Xa levels were determined. Anti-Xa assays were used to rule out the presence of FXaIs in 3 patients. Conclusion This study illustrates the novel role of anti-Xa levels in managing patients with an emergent need for reversal in the ED. The assay may be used to rule out the presence of oral FXaIs and avoid unnecessary administrations of anticoagulation reversal agents. [ABSTRACT FROM AUTHOR]

To conduct a cost-effectiveness analysis (CEA) on the use of andexanet alfa for the treatment of factor Xa inhibitor-related intracranial hemorrhage (ICH) from the US third-party payer and societal perspectives. CEA compared andexanet alfa to prothrombin complex concentrate for the treatment of patients receiving factor Xa inhibitors admitted to hospital inpatient care with an ICH. The model comprised two linked phases. Phase 1 utilized a decision tree to model the acute treatment phase (admission of a patient with ICH into intensive care for the first 30 days). Phase 2 modeled long-term costs and outcomes using three linked Markov models comprising the six health states defined by the modified Rankin score. The analysis showed that the strategy of using andexanet alfa for the treatment of factor Xa inhibitor-related ICH is cost-effective, with incremental cost-effectiveness per quality-adjusted life-year gained of $35,872 from a third-party payer perspective and $40,997 from a societal perspective over 20 years. (1) Absence of head-to-head trials comparing therapies included in the economic model, (2) lack of comparative long-term data on treatment efficacy, and (3) bias resulting from the study designs of published literature. Given these results, the use of andexanet alfa for the reversal of anticoagulation in patients with factor Xa inhibitor-related ICH may improve quality of life and is likely to be cost-effective in a US context. [ABSTRACT FROM AUTHOR]

4-factor prothrombin complex concentrate (4FPCC) is used off-label for factor Xa (FXa) inhibitor-associated intracranial hemorrhage (ICH). Guideline recommendations provide various 4FPCC dosing regimens for FXa inhibitor reversal in this setting. We evaluated 4FPCC weight-based dosing and outcomes in FXa inhibitor-associated ICH. We conducted a multi-center, retrospective, cohort study of ICH patients between July 2017 and February 2020. Patients were greater than 18 years of age, received 4FPCC, and were taking apixaban, rivaroxaban, or edoxaban. Patients were separated into high- (≥35 units/kg) or low-dose (<35 units/kg) 4FPCC groups. The primary outcome was hemostasis achievement. Secondary outcomes included in-hospital mortality, intensive care unit and hospital length of stay, discharge disposition, and thrombotic events. Outcomes were evaluated with binary logistic regression. Of 390 patients identified, 89 were included with 74 and 15 in the high- vs low-dose groups, respectively. Mean (SD) age was 76.6 (±10.8) years. Most were taking a FXa inhibitor for atrial fibrillation (76.4%) and apixaban was the most common FXa inhibitor (65.2%). Hemostasis achievement was greater in the high- vs low-dose group (89.2% vs 46.7%; OR 11.2; 95% CI 2.4–52.6, P = 0.002). Thrombotic events were 8.2% and 6.7% in the high vs low-dose groups, respectively (OR 0.8; 95% CI 0.08–8.2, P = 0.87). No statistically significant differences were found in secondary outcomes. In patients with FXa inhibitor-associated ICH, high-dose 4FPCC was associated with increased odds of hemostasis achievement. There was no difference in thrombotic events. • Weight-based dosing of 4FPCC should be used in FXa inhibitor-associated ICH. • ≥35 units/kg of 4FPCC is most effective for hemostasis achievement. • ≥35 units/kg of 4FPCC is not associated with increased thrombosis. [ABSTRACT FROM AUTHOR]

Abstract Background Venous Thromboembolism (VTE) in cancer patients is associated with increased mortality and morbidity. While newer data on use of direct oral anticoagulants (DOACs) in treating cancer associated thrombosis (CAT) is promising; its data is still few and inconsistent across literature. We designed the study to assess if rivaroxaban would be an appealing alternate choice to treat CAT. Methods We conducted a retrospective study to evaluate the efficacy and safety profile of rivaroxaban versus enoxaparin in cancer patients after developing a symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE). Baseline patient characteristics and laboratory values were assessed in each arm. Primary efficacy outcome was measured by radiographically confirmed VTE recurrence at different intervals. Primary safety outcome was measured by presence of major and minor bleeding using the ISTH scale. Results Our study recruited 150 cancer patients with radiologically confirmed DVT and PE; 80 patients were evaluated in enoxaparin arm and 70 patients in rivaroxaban arm. Our results showed that there was no statistically significant difference between the incidence of VTE recurrence at 6 months between the enoxaparin and rivaroxaban arm (10% vs 14.2%, p = 0.42). Historically significant risk factors for VTE in cancer patients such as high platelet count, high leukocyte count, low hemoglobin level, high risk gastrointestinal, genitourinary and lung cancers were not found to be significantly associated with the risk of VTE recurrence. Primary safety outcome analysis also showed no statistically significant difference in major (11.2% vs 11.4%) and minor (15% vs 10%) bleeding between enoxaparin versus rivaroxaban arm respectively (p = 0.65). Conclusion We conclude that there was no significant difference seen between the efficacy and safety profile of enoxaparin and rivaroxaban in our cancer patient population.

Abstract Background The optimal method of detecting a lupus anticoagulant (LA) for patients taking direct factor Xa inhibitor (DFXaI) direct oral anticoagulants (DOACs) remains controversial. Methods include charcoal adsorption of the DOACs to allow testing with the activated partial thromboplastin time (APTT) and dilute Russell viper venom time (dRVVT), or use of the DFXaI‐insensitive Taipan snake venom time (TSVT) and Ecarin time (ET) assays on neat plasma. Objectives The objective was to compare the utility of APTT and dRVVT analysis following DOAC Remove against TSVT/ET on untreated plasma for LA detection in spiked plasmas and routine clinical samples for patients on DFXaIs. Patients/methods Various LA‐negative and LA‐positive samples were assayed by APTT, dRVVT, and TSVT/ET, and then separately spiked with rivaroxaban, apixaban, and edoxaban calibrators to a concentration of ~190 ng/ml and the assays repeated on spiked plasma before and after DOAC Remove treatment. Testing of 284 consecutive samples from DFXaI‐anticoagulated patients by APTT/dRVVT and TSVT/ET before and after DOAC Remove treatment was undertaken. Results In the spiking model, we found that both TSVT/ET and DOAC Remove strategies generally distinguished LA‐negative and LA‐positive samples, but some false‐positive LA results occurred. In the investigation of 284 consecutive patient samples on DFXaIs, the percentage agreement for LA detection in neat samples tested by TSVT/ET versus APTT and dRVVT after DOAC Remove treatment was 90% (Cohen kappa 0.12). Conclusion Our data highlight uncertainty and disagreement for testing LA in patients on DFXaI. Further studies are required.

Background: An earlier systematic review reported no differences in the incidence of recurrent venous thromboembolism and major bleeding between factor Xa inhibitors and standard anticoagulation. The present meta-analysis aimed to assess the effectiveness of factor Xa inhibitors for the management of venous thromboembolism (VTE), specifically in patients with cancer, as there were more randomized clinical trials (RCTs) available. Methods: The PubMed and Cochrane Library databases were systematically screened for all RCTs assessing factor Xa inhibitor efficacy for VTE management in cancer patients. Using RevMan 5.3, we performed a Mantel–Haenszel fixed-effects meta-analysis of the following outcomes: recurrent VTE, VTE events, and major bleeding rates. Results: We identified 11 studies involving 7,965 patients. Factor Xa inhibitors were superior in preventing VTE recurrence, compared to low-molecular-weight heparin (LMWH) (OR 0.60; 95% CI 0.45–0.80; P < 0.01) and vitamin K antagonists (VKA) (OR 0.51; 95% CI 0.33–0.78; P < 0.01). As prophylaxis, factor Xa inhibitors had a similar rate of VTE compared to VKAs (OR 1.08 [95% CI 0.31–3.77]; P = 0.90) and a lower rate compared to placebo (OR 0.54 [95% CI 0.35–0.81]; P < 0.01). Major bleeding rates were higher with factor Xa inhibitors than with LMWHs (OR 1.34 [95% CI 0.83–2.18]; P = 0.23), but significantly lower than VKAs (OR 0.71 [95% CI 0.55–0.92]; P < 0.01). Conclusions: Factor Xa inhibitors are effective for VTE management in patients with cancer; however, they are also associated with an increased bleeding risk compared to LMWH, but decreased when compared to VKA.

Purpose: Whether direct oral anticoagulants (DOACs) are more effective and safer than warfarin among Asian patients with non-valvular atrial fibrillation (NVAF) undergoing dialysis remains unclear. Methods: We first compared the risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding associated with DOACs compared with warfarin, in NVAF Asians undergoing dialysis using the Taiwan National Health Insurance Research Database (NHIRD) (Aim 1). Next, we searched PubMed and Medline from January 1, 2010 until January 31, 2020, to perform a systematic review and meta-analysis of all observational real-world studies comparing DOACs with warfarin specifically focused on NVAF patients with stage 4 or 5 chronic kidney disease undergoing dialysis (Aim 2). Finally, we tested the hypothesis whether AF patients undergoing dialysis treated with OACs (warfarin and DOACs) would be associated with lower risk of adverse clinical outcomes as compared to those without OACs using the Taiwan NHIRD (Aim 3). Results: From June 1, 2012, to December 31, 2017, a total of 3237 and 9263 NVAF patients comorbid with ESRD receiving oral anticoagulant (OACs) (490 on DOAC, 2747 on warfarin) or no OACs, respectively, were enrolled. Propensity score matching was used to balance covariates across the study groups. For the comparison of DOAC vs. warfarin (Aim 1), DOACs had comparable risks of IS/SE and major bleeding to warfarin in our present cohort. From the original 85 results retrieved, nine studies (including our study) with a total of 6490 and 22,494 patients treated with DOACs and warfarin were included in the meta-analysis, respectively. There were 5343 (82%) and 20,337 (90%) patients treated with DOACs and warfarin undergoing dialysis, respectively. The pooled meta-analysis also indicated no difference of the effectiveness (HR:0.90; [95%CI:0.74–1.10]; P = 0.32) and safety outcomes (HR:0.75; [95%CI:0.54–1.05]; P = 0.09) between DOACs and warfarin (Aim 2). For the comparison of OAC (+) vs. OAC (−) (Aim 3), OAC-treatment was associated with a higher risk of IS/SE (hazard ratio (HR):1.54; [95% confidential interval (CI):1.29–1.84];P < 0.0001) and comparable risk of major bleeding compared to those without OAC treatment. Conclusions: DOACs did not provide benefit over warfarin regarding effectiveness and safety in AF patients undergoing dialysis. The use of OAC was not associated with a lower risk of IS/SE in ESRD AF patients when compared to those without OAC use. [ABSTRACT FROM AUTHOR]

Over the past few decades, drug discovery directed at the treatment and prevention of thromboembolic diseases has been challenged by the need to balance robust efficacy with improved safety relative to the standard of care. To this end, the most impactful advance to date has been the discovery and development of oral factor Xa inhibitors. In this essay, a brief account of the program that culminated in the discovery of Eliquis (apixaban) and the commitment to identify a compound with an optimal profile are described. [ABSTRACT FROM AUTHOR]

Background: Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low‐molecular‐weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized. Methods: Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups. Results: Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow‐up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28‐4.69 [P =.007]) and first‐onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13‐4.42 [P =.02]). Analysis of 6‐month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone. Conclusions: Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone. The results of the current study suggest that there is an increased risk of bleeding with the concurrent use of vascular endothelial growth factor receptor tyrosine kinase inhibitors and factor Xa inhibitors in patients with metastatic cancer. Careful monitoring is required and future studies are warranted to further understand and assess how to safely administer concurrent treatment in this at‐risk population. [ABSTRACT FROM AUTHOR]

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date.Design: COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771).Conclusion: In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes. [ABSTRACT FROM AUTHOR]

X-ray powder diffraction data, unit-cell parameters, and space group for rivaroxaban, C19H18ClN3O5S, are reported [a = 9.010(3) Å, b = 10.986(6) Å, c = 11.230(1) Å, α = 63.439(5)°, β = 74.355(4)°, γ = 78.133(3)°, unit-cell volume V = 952.87 Å3, Z = 2, ρcal = 1.519 g cm−3, and space group P1]. All measured lines were indexed and are consistent with the P1 space group. No detectable impurities were observed. [ABSTRACT FROM AUTHOR]