Xa Inhibitors Research Articles

Cleavable Novel Thienopyridine Derivatives as Potent Antithrombotic Agents

AbstractThienopyridine derivatives are specifically designed for utilization in antithrombotic therapy to help combat cardiovascular disorders linked to thrombosis. This study introduces new thienopyridine derivatives with superior therapeutic efficacy through synergies by dual functional compounds, developed as antithrombotic agents. Through computational design, we discovered 32 compounds out of a library of 100 compounds that exhibit efficacy. The compounds are synthesized by multiple steps and subsequently purified using chromatographic procedures to achieve a purity level of >99%. Using the ADP‐induced platelet aggregation assay, we have found 4 active test compounds (ACG‐0173‐19, ACG‐0173‐37, ACG‐A‐04, and ACG‐B‐03) out of a total of 32 compounds. On the other hand, ACG‐0173‐19, ACG‐0173‐37, ACG‐A‐04, and ACG‐B‐03 have demonstrated the highest percentage activity on factor Xa (FXa) inhibition. The ACG‐A‐04 chemical exhibited the highest hydrophilicity, specifically in terms of its aqueous solubility. It had a solubility of 0.44 mg/mL in pH 5.8, 0.29 mg/L in pH 6.2, and 0.145 mg/L in pH 7.4 buffers. In comparison, the standards APX‐01 (apixaban) and PRG‐01(prasugrel) had lower hydrophilicity. Based on cytotoxicity investigations, it was determined that the test substances do not exhibit harmful effects. The results indicated that the test chemicals can undergo hydrolysis in blood plasma rather than in other organs. Among the four test drugs, ACG‐1073‐19 exhibited an unbound fraction of 44.1%, which is twice as high as the standards (apixaban). ACG‐1073‐37 demonstrates superior plasma protein binding (33.2%) compared to all other test compounds. The compounds resulted in a higher expression of CD61, CD42b, and CD62P in platelets compared to the control. The ACG‐1073‐37 molecule had a Caco‐2 permeability of 51%, which is extremely close to the Caco‐2 permeability of the control medicines (55% for APX‐01 and 62% for PRG‐01). Through the assessment of microsomal stability, it was determined that ACG‐1073‐37 and ACG‐A‐04 exhibited metabolic stability for 42.4 and 34.14 min, respectively.

Effects of rivaroxaban on vascular endothelial function and circulating endothelial progenitor cells: a randomized controlled trial

Abstract Background Combination of low dose rivaroxaban with aspirin was shown to reduce major adverse cardiovascular events when compared to aspirin monotherapy in COMPASS trial. The beneficial effect of rivaroxaban beyond factor Xa inhibition remains unknown. Purpose This randomized controlled trial explored the effects of rivaroxaban on vascular endothelial function and circulating endothelial progenitor cells in patients with stable atherosclerotic disease. Methods An investigator-initiated, investigator-blinded, single-center randomized clinical trial was conducted from May 2021 to August 2023. 142 patients were randomized in 1:1 ratio to receive rivaroxaban 2.5mg twice daily plus aspirin 100mg once daily (Treatment Group) or aspirin 100mg once daily (Control Group) and had follow-up for 3 months. The primary outcome was change of flow mediated dilation (FMD) from baseline to 3-month follow-up. Key secondary outcomes included change of circulating endothelial progenitor cells (CD45+/34+/133+, CD45+/34+/KDR+), platelet activation marker (CD41+/62p+), inflammatory marker (CD14+/11b+) and thrombo-inflammatory maker (CD14+/42b+) measured by flow cytometry, as well as platelet function (aspirin reaction unit, ARU) measured by blood biochemistry. Intention-to-treat analysis was performed with analysis of covariance (ANCOVA) and P < 0.05 was considered statistically significant. Results Overall, 142 patients were enrolled in the study. One patient was excluded from analysis due to protocol deviation. Among the remaining 141 patients (78.8% male and mean age 69±9 years), there were 71 in Treatment Group and 70 in Control Group. The recruited patients had a high prevalence of cardiovascular comorbidities including 76.6% with hypertension, 50.4% with hyperlipidemia, 45.4% with diabetes, and 92.2% with percutaneous coronary intervention. At 3 months, Treatment Group had greater FMD improvements (+2.18±5.66% vs +1.57±5.07%, P=0.03), and more reduction in platelet activation marker (-0.33±13.55% vs +5.78±21.60%, P=0.01). There was no significant change in circulating endothelial progenitor cells, inflammatory marker, thrombo-inflammatory maker, and platelet function. Minor bleeding occurred in 2 patients (2.82%) in Treatment Group and none in Control Group (P>0.05). Conclusion In patients with stable atherosclerotic disease, addition of rivaroxaban to aspirin was well tolerated, and it improved vascular endothelial function and reduced platelet activation.

Typical profile of a patient with atrial fibrillation in the Russian population based on medical registries. A systematic review

Aim. To compare clinical and anamnestic characteristics of patients with atrial fibrillation (AF) included in three large international stu­dies assessing the efficacy and safety of therapy with direct oral anti­coagu­lants, with the profile of a typical Russian patient with AF in clinical practi­ce, established by medical registries in the Russian Federation (RF).Material and methods. A systematic review of scientific publications was con­ducted. The search was conducted in the E-library and Google Scholar databases. Publications from 8 registries of patients with AF, con­ducted in the Russian Federation from 2012 to 2023, were found, which present the clinical and anamnestic characteristics of patients. All studies included in the analysis meet the generally accepted require­ments for medical registries. The systematic review protocol was pre­viously recorded in the PROSPERO electronic database (CRD42024512425).Results. A Russian patient with AF is a patient with a large number of cardiovascular pathologies and a high risk of thromboembolic events. According to the analysis, Russian patient with AF has an average age of ~70 years. Most patients have a diagnosis of hypertension, heart failure, while from one third to half of patients have a diagnosis of chronic kidney disease. From 20 to 30% of patients have a history of myocardial infarction and every fifth patient has type 2 diabetes.Conclusion. In all countries around the world, including the Russian Fe­deration, for many years, medical registries have been one of the main sources of information on the characteristics of patients with AF and the disease course. They can supplement the available data from randomized clinical trials with real-world data. Comparison of clinical and anamnestic characteristics of patients in randomized clinical trials of direct oral anticoagulants with characteristics of patients in the Russian registries shows that patients included in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K An­tagonism for Prevention of Stroke and Embolism Trial in Atrial Fib­rillation (ROCKET AF trial) were most similar to Russian patients with AF.

Effect of endothelium on the anticoagulant activity of a covalent antithrombin-heparin complex.

We developed a covalent antithrombin-heparin complex (ATH) with superior In vivo anticoagulant efficacy compared to non-covalent antithrombin (AT) + unfractionated heparin (H). Previous in vitro studies of ATH, investigating the mechanisms behind its efficacy, were done in the absence of endothelium. Since the endothelial surface modulates hemostasis, we investigated its impact on the in vitro anticoagulant properties of ATH and AT+H. Discontinuous second order rate constant enzyme inhibition assays, fibrin formation, and plasma clot generation were performed in the presence of ATH or AT+H, with and without endothelium present. ATH had an increased rate of direct inhibition of IIa and Xa, and increased inhibition of IIa-induced fibrin formation, compared to AT+H. When compared at equal anti-Xa levels, ATH was less effective than AT+H at catalyzing inhibition of plasma clot generation. These results were found in both the presence and absence of endothelium. Endothelium decreased the rate of IIa inhibition, and reduced clot time in IIa-induced fibrin formation and plasma clot generation assays, for both ATH and AT+H. Endothelium did not impact the activity of ATH differently to AT+H. This supports the growing body of evidence suggesting ATH may be a beneficial anticoagulant for potential clinical use.

Structural, Biochemical Characterization and Molecular Mechanism of Cerastokunin: A New Kunitz-Type Peptide with Potential Inhibition of Thrombin, Factor Xa and Platelets.

The current investigation focused on separating Cerastes cerastes venom to produce the first Kunitz-type peptide. Based on its anti-trypsin effect, Cerastokunin, a 7.75kDa peptide, was purified until homogenity by three steps of chromatography. Cerastokunin was found to include 67 amino acid residues that were obtained by de novo sequencing using LC-MALDI-MSMS. Upon alignment with Kunitz-type peptides, there was a high degree of similarity. Cerastokunin's 3D structure had 12% α-helices and 21% β-strands with pI 8.48. Cerastokunin showed a potent anticoagulant effect by inhibiting the protease activity of thrombin and trypsin as well as blocking the intrinsic and extrinsic coagulation pathways. In both PT and aPPT, Cerastokunin increased the blood clotting time in a dose-dependent way. Using Lys48 and Gln192 for direct binding, Cerastokunin inhibited thrombin, Factor Xa and trypsin as shown by molecular docking. Cerastokunin exhibited a dose-response blockade of PARs-dependent pathway platelet once stimulated by thrombin. An increased concentration of Cerastokunin resulted in a larger decrease of tail thrombus in the mice-carrageenan model in an in vivo investigation when compared to the effects of antithrombotic medications. At all Cerastokunin doses up to 6mg/kg, no in vivo toxicity was seen in challenged mice over the trial's duration.

Prothrombin complex concentrate for emergency surgery in patients on oral Xa-inhibitors

BackgroundIt is uncertain whether prothrombin complex concentrate (PCC) improves hemostasis in patients on treatment with oral factor Xa-inhibitors (XaI) who require emergency surgery. ObjectivesTo evaluate whether, in patients with therapeutic levels of oral XaI, preoperative PCC prevents excessive bleeding during and after emergency surgery and is not associated with thrombotic complications. MethodsWe conducted a prospective cohort study wherein a fixed 2000 IU dose of 4-factor PCC was given to patients taking oral XaI with plasma XaI levels of at least 75 ng/mL before the emergency surgery with an expected blood loss of at least 50 mL. Patients were followed for 30 days. The primary efficacy outcome was the incidence of normal or mildly abnormal surgical hemostasis, as assessed by the surgeon; primary safety outcome was the incidence of thromboembolic events within 7 days. ResultsWe included 20 patients, of which 50% were female, on apixaban (75%) or rivaroxaban (25%) with median XaI level of 128 ng/mL (range, 77-497 ng/mL). The median duration of surgery was 2 hours 42 minutes (range, 15 minutes to 8 hours 17 minutes). Normal or mildly abnormal hemostasis was observed in 16 patients (80%); 2 patients had moderately abnormal and 2 had severely abnormal hemostasis, 1 each of those was considered due to local or technical factors. There were 4 deaths (20%) secondary to underlying disease and 1 incidental pulmonary embolism in a patient with cancer. ConclusionA fixed dose of PCC appears to control hemostasis in patients with therapeutic plasma levels of apixaban or rivaroxaban requiring emergency surgery.

Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation

In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. ClinicalTrials.gov Identifier: NCT00781391.

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF

BackgroundThe extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition...

Minimal interference of concizumab with standard clinical coagulation laboratory assays - An in vitro study.

Non-factor replacement therapies are emerging as prophylactic treatment options in haemophilia A or B (HA/HB) with and without inhibitors. Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody preventing factor (F)Xa inhibition and enhancing thrombin generation. Based on experience with other non-factor therapies and extended half-life products, there is a focus on potential interference with common clinical coagulation assays used to monitor patients treated with concizumab. To evaluate the impact of concizumab on standard clinical coagulation assays. Plasma samples (normal, HA/HB with/without inhibitors) in the presence/absence of added concizumab (250-16,000ng/mL) were analysed in clinical assays including activated partial thromboplastin time (aPTT), prothrombin time (PT), FVIII and FIX one-stage clot and chromogenic substrate assay, assays for detecting FVIII or FIX inhibitors and other assays for coagulation factors. Concizumab did not impact PT assays, but resulted in a small shortening of aPTT (up to 5 s in haemophilia plasma and 0.4 s in normal plasma). Concizumab had no, or only a minor impact on FVIII and FIX activity assays or Bethesda inhibitor assays. FXI and FXII activity in normal plasma, as measured by single factor aPTT-based assay, was significantly increased in the presence of concizumab (+11% each). This was also the case for FVII and FX measured by PT-based assays using plasma with 25% of FVII or FX (+64% and +22%, respectively). The presence of concizumab did not, or only slightly, influence the outcome of standard clinical coagulation assays relevant for HA and HB.

Assessment of Days Alive Out of Hospital as a Possible End Point in Trials of Stroke Prevention for Atrial Fibrillation: A ROCKET AF Analysis.

Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Factor XI inhibitors: a new option for the prevention and treatment of cancer-associated thrombosis

Venous thromboembolism (VTE) is a relatively common complication in cancer patients with potentially dire consequences. Anticoagulants are the mainstay of treatment of cancer-associated VTE. The anticoagulants most often used are low-molecular-weight heparin (LMWH) and direct oral factor (F) Xa inhibitors, which include apixaban, edoxaban, and rivaroxaban. Most guidelines recommend primary VTE prophylaxis with LMWH, apixaban, or rivaroxaban after abdominal or pelvic cancer surgery, or in high-risk ambulatory cancer patients. Both oral FXa inhibitors and LMWH have limitations. LMWH requires daily subcutaneous injections, and because of its renal clearance, its use may be problematic in patients with severe kidney disease. The risk of bleeding with oral FXa inhibitors may be higher than with LMWH in patients with intraluminal gastrointestinal or genitourinary cancers. Other problems with oral FXa inhibitors include potential drug-drug interactions and dosing issues in patients with thrombocytopenia or severe kidney or liver disease. Therefore, there remains a need for convenient and safer anticoagulants for VTE treatment in cancer patients. FXI has emerged as a potentially safer target for anticoagulants than FXa because FXI is essential for thrombosis, but mostly dispensable for hemostasis. This review summarizes the currently available therapeutic options for cancer-associated VTE, highlights knowledge gaps, and discusses the potential of FXI inhibitors to address key unmet clinical needs in this vulnerable patient population.

Abstract 136: Protease-activating Receptor-4 Antagonism In Coronary Artery Disease

Background: BMS-986141 is a novel potent highly selective antagonist of protease-activated receptor type 4 (PAR4). PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. Aim: To determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. Methods: Forty-five patients with stable coronary heart disease and ten healthy volunteers completed a phase 2a open-label four-arm single-center study. Patients were allocated to one of three treatment arms for seven days: (i) ticagrelor (90 mg twice daily), (ii) aspirin (75 mg once daily) or (iii) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before, 2 and 24 hours after a single oral 4-mg dose of BMS-986141 in all participants. Results: BMS-986141 demonstrated highly selective inhibition of PAR4-agonist peptide (AP) induced platelet aggregation, p-selectin expression, and platelet-monocyte aggregate expression (p≤0.001 for all) which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%, p=0.001) and in patients receiving ticagrelor alone (-28%, p=0.001), aspirin alone (-23%, p=0.018), or both in combination (-24%, p≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (p≤0.001 for all) and total thrombus area under high shear stress conditions (p≤0.01 for all). Conclusions: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin or their combination, in patients with stable coronary artery disease.

The Effect of 4-Factor Prothrombin Complex Concentrate to Reverse Factor Xa Inhibitors in Patients With Traumatic Intracranial Hemorrhage.

The utility of 4-factor prothrombin complex concentrate (4F-PCC) for reversal in patients on factor Xa inhibitors (XaI) is unclear, specifically in mild traumatic brain injury (mTBI). This is a retrospective review over 6 years at a level 1 trauma center of patients presenting with mTBI on XaI comparing outcomes for those that received 4F-PCC to those that did not. 140 patients were included, 103 (74%) of these patients received 4F-PCC while 37 (26%) did not. There was no significant difference in neurologic decline within 48 hours of admission or need for neurosurgical intervention. Interestingly, there was no difference in ICH progression (16% vs 14%, P = .77). In this study, 4F-PCC given after mild traumatic brain injury did not impact ICH progression, neurologic decline, or need for neurosurgical intervention. Although limited in numbers, this study suggests that 4F-PCC is not necessarily required in mTBI and further studies are indicated.

PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies.

BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants. BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)-induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (P≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%; P=0.001) and in patients receiving ticagrelor alone (-28%; P=0.001), aspirin alone (-23%; P=0.018), or both in combination (-24%; P≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (P≤0.001 for all) and total thrombus area under high shear stress conditions (P≤0.01 for all). PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.

New anticoagulant protein from medicinal leech

The saliva of the medicinal leech contains various anticoagulants. Some of them, such as hirudin, are well known. However, it is reasonable to believe that not all anticoagulant proteins from medicinal leech saliva have been identified. We previously performed a comprehensive study of the transcriptome, genome, and proteome of leech salivary gland cells, which led to the discovery of several previously unknown hypothetical proteins that may have anticoagulant properties. Subsequently, we obtained a series of recombinant proteins and investigated their impact on coagulation in in vitro assays. We identified a previously undescribed protein that exhibited a high ability to suppress coagulation. The His-tagged recombinant protein was expressed in Escherichia coli and purified using metal chelate chromatography. To determine its activity, commonly used coagulation methods were used: activated partial thromboplastin time, prothrombin time, and thrombin inhibition clotting assay. Clotting and chromogenic assays for factor Xa inhibition were performed to evaluate anti-Xa activity. We used recombinant hirudin as a control anticoagulant protein in all experiments. The new protein showed significantly greater inhibition of coagulation than hirudin at the same molar concentrations in the activated partial thrombin time assay. However, hirudin demonstrated better results in the direct thrombin inhibition test, although the tested protein also exhibited the ability to inhibit thrombin. The chromogenic analysis of factor Xa inhibition revealed no activity, whereas the clotting test for factor Xa showed the opposite result. Thus, a new powerful anticoagulant protein has been discovered in the medicinal leech. This protein is homologous to antistatin, with 28 % identical amino acid residues. The recombinant protein was expressed in E. coli. This protein is capable of directly inhibiting thrombin, and based on indirect evidence, other proteases of the blood coagulation cascade have been identified.

Expedited surgery does not increase transfusion rates for patients with geriatric hip fracture taking factor Xa inhibitors.

Geriatric patients who sustain hip fractures and are taking factor Xa inhibitors (Xa-I) experience surgical delay. Our institution developed a pharmacokinetic protocol to formally guide and expedite surgical timing for these patients. The protocol is based on the patient's renal function and timing of last Xa-I dose. For patients with impaired renal function, longer wait times are recommended. The purpose of this study was to determine the effects of this protocol for patients with geriatric hip fracture taking Xa-I. Retrospective cohort study. Level 1 trauma center. A total of 164 patients aged 65 and older who were taking Xa-I before admission and underwent hip fracture surgery; 68 patients in the Standard group (2014-2018) and 96 patients in the Expedited group (2020-2022, after protocol implementation). Hip fracture surgery. Time to surgery (TTS), transfusion rate, blood loss, 90-day complication rates. The median TTS was significantly shorter in the Expedited group (28.6 hours, interquartile range 21.3 hours) than in the Standard group (44.8 hours, interquartile range 21.1 hours) (P < .001). There were no differences in overall transfusion rates. Multivariable regression analysis demonstrated that time to surgery was not predictive of transfusion rate in all patients (OR 1.00, 95% CI 0.99-1.02, P = .652). There were no differences in blood loss or rates of 90-day complications. Geriatric patients with hip fractures and taking factor Xa inhibitors may warrant earlier surgery without an increased risk of transfusion or bleeding. Therapeutic Level III.

Risk Profiles and Treatment Patterns in Atrial Fibrillation Patients with Chronic Kidney Disease Receiving or not Receiving Anticoagulation Therapy.

Background Patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are at high risk for both thromboembolism and bleeding events. The latter induces a potential reason for withholding oral anticoagulation (OAC) despite an indication for prophylaxis of thromboembolic events. Methods AF patients with CKD (estimated glomerular filtration [eGFR] rate between 15 and 49 mL/min per 1.73 m 2 ) were included in a prospective international registry in Europe between 2016 and 2020, that is, XARENO (factor XA inhibition in renal patients with nonvalvular atrial fibrillation observational registry). The study enrolled adult patients treated at the discretion of physicians with rivaroxaban, vitamin K antagonists (VKA), or without OAC (w/oOAC). Here, we report a prespecified explorative baseline comparison between patients receiving OAC or no OAC within XARENO. Results In total, 1,544 patients (mean age: 78.2 years, mean eGFR: 36.2 mL/min) were studied (rivaroxaban n = 764, VKA n = 691, w/oOAC n = 89). Patients in the w/oOAC group were older and had a similar stroke (mean CHA 2 DS 2 -VASc score 4.0) but higher bleeding risk (mean modified Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score 2.5 vs. 1.8) compared with the OAC groups. The distribution of comorbidities including hypertension, diabetes, and heart failure was similar. Treatment with antiplatelet drugs was fivefold more frequent in the w/oOAC group. Conclusion Only 5.8% of the overall population of AF patients with advanced CKD received no OAC. These patients were older and had a higher bleeding risk, which might explain this decision, but which contrasts with the more frequent use of antiplatelet drugs in this vulnerable group of patients.

Efficacy and Safety of Direct Oral Anticoagulants for Stroke Prevention in Older Patients With Atrial Fibrillation: A Network Meta-Analysis of Randomized Controlled Trials.

Although older patients with atrial fibrillation are at heightened risk of thromboembolic and bleeding events, their optimal treatment choice remains uncertain. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that compared thromboembolic or bleeding outcomes between a direct oral anticoagulant (DOAC) and a vitamin K antagonist (VKA) and reported outcomes for patients aged ≥75 years with atrial fibrillation. The efficacy outcome was the composite of stroke and systemic embolism. Safety outcomes included major bleeding, any clinically relevant bleeding, and intracranial hemorrhage. Each DOAC and VKA was compared pairwise in a network meta-analysis. High- and low-dose regimens and factor IIa and Xa inhibitors were also compared. Seven randomized controlled trials were included in the analysis. Stroke and systemic embolism risks did not differ significantly among DOACs. There were no significant differences in major bleeding between each DOAC and VKA. Intracranial hemorrhage risk was significantly lower with dabigatran, apixaban, and edoxaban than with VKA and rivaroxaban, which had similar risks. High-dose regimens led to lower risks of stroke or systemic embolism compared with VKA and low-dose regimens, with both doses having similar bleeding risks. In patients aged ≥75 years with atrial fibrillation, DOACs were associated with fewer thromboembolic events compared with VKA, whereas dabigatran, apixaban, and edoxaban were associated with lower risks of intracranial hemorrhage compared with VKA and rivaroxaban. URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42022329557.

Variation in coagulation factor activity levels cause discrepancies between activated partial thromboplastin time and anti-Xa activity for heparin monitoring: a retrospective observational study

BackgroundUnfractionated heparin (UFH) is primarily monitored using activated partial thromboplastin time (APTT). However, the recent introduction of anti-activated factor X (anti-Xa) activity testing has provided a direct evaluation of Xa inhibition by anticoagulants. This study aimed to investigate discrepancies between APTT and anti-Xa activity during UFH monitoring in critically ill patients and explore their underlying causes.MethodsThis study analyzed 271 pairs of laboratory test results from blood samples of 99 critically ill patients receiving continuous intravenous UFH. Theoretical APTT values were calculated using fitted curve equations from spiked sample measurements with anti-Xa activity. Samples were categorized into three groups based on the measurement of the APTT/theoretical APTT ratio: the lower group (< 80%), the concordant group (80–120%), and the upper group (> 120%).ResultsThe overall concordance rate between APTT and anti-Xa activity was 45%, with a 55% discrepancy rate. The lower group frequently showed apparent heparin overdoses, while coagulation factor activities in the lower and upper groups were higher and lower, respectively, than those in the concordant group. Particularly, the lower group exhibited higher factor VIII activity levels than the upper and concordant groups.ConclusionsDiscrepancies between APTT and anti-Xa activity were frequently observed, influenced by changes in coagulation factors activity levels. The lower and upper groups were classified as pseudo-heparin-resistant and coagulopathy types, respectively. Accurate monitoring of heparin in critically ill patients is crucial, especially in cases of pseudo-heparin resistance, where APTT values may wrongly indicate inadequate heparin dosing despite sufficient anti-Xa activity. Understanding these discrepancies is important for managing heparin therapy in critically ill patients.Trial registration: Not applicable.

Abstract 11876: Impact of Online Continuing Medical Education on Advancing Physician Knowledge and Confidence Around Dual-Pathway Inhibition for Patients With Peripheral Artery Disease

Background: Patients with PAD are at risk for MACE and MALE. Antithrombotic therapy, including DPI can improve patient outcomes. Physicians who care for patients with PAD may require education to improve knowledge and confidence around employing newer treatments. Purpose: This study was conducted to determine if online CME could improve physician knowledge and confidence of advances in DPI for the treatment of patients with PAD. Methods: The educational program consisted of a 15-minute online video-based rapid-fire discussion between 2 experts that launched March 24, 2021-March 24, 2022. Data were collected from participants on March 24, 2022. Four multiple choice questions were used; 3 assessed knowledge and 1 determined confidence with Likert-type scale. Endpoints were assessed using a repeated-pair design with pre-/post-assessment. A paired samples t-test was conducted on overall average number of correct responses for physician knowledge, and a McNemar’s test was conducted at the question level (significance level, P &lt; .05) for confidence. Results: 855 physicians completed the pre-/post-assessment out of 3,825 total physician learners (22%). Physician specialties included general cardiology (28%), vascular cardiology (15%), vascular surgery (15%), other surgery (20%), and primary care (22%). Overall, significant improvements were seen in knowledge of medical treatment for PAD (P&lt;.001), data for the use of factor Xa inhibition to treat PAD (P&lt;.001), and confidence in selecting antithrombotic therapy (P&lt;.001) (Table). Gains in knowledge and confidence were highest amongst vascular specialists compared with non-vascular specialists (Table). Conclusion: This study demonstrates the effect of a 15-minute online video-based CME discussion between 2 expert faculty on knowledge and confidence among providers caring for patients with PAD related to advances in antithrombotic therapy. Continued gaps were identified for future educational targets.