Factor Xa Inhibitors Research Articles

Utilising the New Technology Add-on Payment (NTAP): Improving Medicare-insured patients’ access to innovative therapeutics

Andexanet alfa (Andexxa) is the first reversal agent for direct factor Xa inhibitors. It qualified as a new, novel therapeutic for the New Technology Add-on Payment (NTAP) reimbursement from the Centers for Medicare and Medicaid Services (CMS) in October 2018. This paper is the first analysis of a healthcare system (HCS) reporting its implementation and utilisation of the NTAP for a new therapeutic. The number of patients treated with Andexxa at the level 1 trauma centre of southern New Jersey, Cooper University Hospital (CUH) was analysed. This paper highlights the successful implementation of Andexxa as a treatment option for (non)traumatic intracranial haemorrhage and acute, nongastrointestinal haemorrhage requiring surgical management at CUH. This paper looked at how well CUH obtained the Andexxa NTAP from CMS for Medicare patients. During the 4-year reimbursement period, CUH treated a total of 88 patients with Andexxa, of which 53 were Medicare patients treated before the expiry of the Andexxa NTAP. The study found that CUH received NTAP for 81 per cent of Andexxa-treated Medicare patients and that CUH received the maximal NTAP amount of US$18,281.25 for 43 per cent of those same patients. The paper discusses how a large trauma centre implemented and received the NTAP for Andexxa and evaluates the effect of cost on reimbursement amounts during the Andexxa NTAP period. Finally, this paper should help healthcare providers, stakeholders and administrators better understand the process through which to obtain NTAP reimbursements from CMS and improve their HCS with new, innovative therapies for their patients.

Combined drug anti-deep vein thrombosis therapy based on platelet membrane biomimetic targeting nanotechnology

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.

Management of cerebral amyloid angiopathy and atrial fibrillation: We are still far from precision medicine.

The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy (CAA) and atrial fibrillation (AF). In fact, CAA is an age-related cerebral vasculopathy that predisposes patients to intracerebral hemorrhage. Nevertheless, many AF patients require oral systemic dose-adjusted warfarin, direct oral anticoagulants (such as factor Xa inhibitors) or direct thrombin inhibitors to control often associated with cardioembolic stroke risk. The prevalence of both CAA and AF is expected to rise, due to the aging of the population. This clinical dilemma is becoming increasingly common. In patients with coexisting AF and CAA, the risks/benefits profile of anticoagulant therapy must be assessed for each patient individually due to the lack of a clear-cut consensus with regard to its risks in scientific literature. This review aims to provide an overview of the management of patients with concomitant AF and CAA and proposes the implementation of a risk-based decision-making algorithm.

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.

#1313 Dicumarinics and the direct thrombin or factor Xa inhibitors (NOAs) their usefulness in advanced chronic renal disease

Abstract Background and Aims Our population with advanced chronic kidney disease (ACKD), is more prone to thrombotic and hemorrhagic processes so the indication of anticoagulation before the appearance of atrial fibrillation (AF) is complex. Since AF is the most common cardiac arrhythmia, its main complications are thromboembolism and stroke. New treatments are being developed, such as the new oral anticoagulants (NOAs), but their safety in ACKD is still uncertain. To see anticoagulation needs, safety and major adverse effects (major or minor bleeding) in population with ACKD and taking dicumarinics or NOAs. Method Retrospective study of 234 patients followed in our ACKD practice, at least two revisions, with a mean follow-up 25.5 months, in which we recorded cause of anticoagulation, type and major adverse effects. Results 26% of patients have indication for anticoagulation (66 patients), of which 55 remain anticoagulated during follow-up (45% Dicumarinics, 44% NOAs). The indication for anticoagulation was 23% AF (56 patients) and 3% mechanical prostheses (7 patients). Table 1 shows the characteristics of the overall population and the comparison between anticoagulated patients with different types of anticoagulation and non-anticoagulated patients. Non-anticoagulated patients are younger and have less ischemic heart disease, with no differences in the non-anticoagulated population. Throughout follow-up, we found a higher incidence of bleeding with NOAs (compared to the rest) and higher mortality in patients with dicumarinics (compared to the rest). There were no differences in age, sex and ischemic heart disease between the two anticoagulant treatments. Conclusion Our CKD population has a high need for anticoagulation but also a high risk of bleeding. NOAs can be used in ACKD although they are associated with a higher incidence of bleeding than dicumarinics but lower mortality. More studies are needed to conclude which is the best approach for these patients.

Comparative Outcomes of Peripheral Vascular Intervention in Patients Discharged on Clopidogrel in Combination With Factor Xa Inhibitors or Aspirin

Comparative Outcomes of Peripheral Vascular Intervention in Patients Discharged on Clopidogrel in Combination With Factor Xa Inhibitors or Aspirin

Andexanet for Factor Xa Inhibitor–Associated Acute Intracerebral Hemorrhage

BackgroundPatients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied.MethodsWe randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death.ResultsA total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P=0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti–factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P=0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days.ConclusionsAmong patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.)

Is There an Alternative Oral Anticoagulation to Vitamin-K-Antagonists for Patients with Mechanical Aortic Valve Replacement? - A Literature Review.

Current guidelines exclusively recommend vitamin-K-antagonists (VKA) as anticoagulation for patients after mechanical aortic valve replacement due to the increased postoperative risk of valve thrombosis and thrombo-embolism. Strict and regular assessments are mandatory during VKA therapy to ensure a potent anticoagulatory effect within the desired range. From the patients' perspective, VKA are associated with relevant interactions and side effects reducing the quality of life and contributing to a high number of patients not achieving the optimal therapeutic target. Direct oral anticoagulants (DOAC) have replaced VKA therapy in the past for several indications, e.g., atrial fibrillation. However, it is still unclear if DOACs could replace VKA therapy in patients after mechanical aortic valve replacement. While the PROACT-Xa study did not show a sufficient anticoagulatory effect of apixaban plus aspirin compared to VKA therapy in patients after mechanical aortic valve replacement, the direct thrombin inhibitor dabigatran and the oral factor Xa inhibitors apixaban and rivaroxaban showed promising results in comparable patient cohorts in smaller studies and case reports. Factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients after mechanical aortic valve replacement. Therefore, factor Xa inhibitors or factor XI inhibitors could provide a potent alternative to VKA for patients after a mechanical aortic valve replacement.

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.

Trends in Venous Thromboembolism and Chemoprophylaxis Utilization in Elective Total Knee Arthroplasty From 2011 to 2020

BackgroundVenous thromboembolism (VTE) is a feared complication of joint arthroplasty, leading to recent clinical practice guidelines aimed at VTE prevention and prophylaxis. However, limited studies have examined national changes in practice regarding chemoprophylaxis and the resultant changes in VTE rates. The purpose of this study was to identify: (1) the temporal trends in thrombotic complications; and (2) changes in chemoprophylaxis utilization in patients undergoing elective total knee arthroplasty (TKA). MethodsA retrospective study was conducted using a large all-payer claims dataset. Patients who underwent osteoarthritis-indicated TKA between 2011 and 2020 were identified. Annual rates of VTE, including deep vein thrombosis and pulmonary embolism, within 90 days of TKA were determined. Utilization patterns for postoperative aspirin and anticoagulant medications were observed. Temporal trends were analyzed with linear regression and the calculation of the cumulative annual growth rate. Multivariable logistic regression was conducted to account for the effects of age and comorbidities. ResultsA total of 1,263,351 TKA patients were identified between 2011 and 2020. There were significant reductions in VTE rates (2.9% in 2011 to 1.8% in 2020), deep vein thrombosis rates (2.0% in 2011 to 1.3% in 2020), and pulmonary embolism rates (1.1% in 2011 to 0.6% in 2020). Postoperative utilization of aspirin increased from 5.9% in 2011 to 53.2% in 2020, whereas utilization of anticoagulants decreased from 94.1% in 2011 to 46.8% in 2020. Among anticoagulants, direct factor Xa inhibitors had the greatest increase in utilization (4.6 to 69.7%). The average reimbursement associated with VTE after TKA decreased from $18,061 in 2011 to $7,835 in 2020. ConclusionsThe incidence rate and economic burden of VTE after TKA have significantly declined since 2011. There has been a trend toward increased aspirin and direct oral anticoagulant utilization for postoperative chemoprophylaxis. Level of EvidenceLevel III.

Xa inhibitor edoxaban ameliorates hepatic ischemia-reperfusion injury via PAR-2-ERK 1/2 pathway.

Hepatic ischemia-reperfusion injury causes liver damage during surgery. In hepatic ischemia-reperfusion injury, the blood coagulation cascade is activated, causing microcirculatory incompetence and cellular injury. Coagulation factor Xa (FXa)- protease-activated receptor (PAR)-2 signaling activates inflammatory reactions and the cytoprotective effect of FXa inhibitor in several organs. However, no studies have elucidated the significance of FXa inhibition on hepatic ischemia-reperfusion injury. The present study elucidated the treatment effect of an FXa inhibitor, edoxaban, on hepatic ischemia-reperfusion injury, focusing on FXa-PAR-2 signaling. A 60 min hepatic partial-warm ischemia-reperfusion injury mouse model and a hypoxia-reoxygenation model of hepatic sinusoidal endothelial cells were used. Ischemia-reperfusion injury mice and hepatic sinusoidal endothelial cells were treated and pretreated, respectively with or without edoxaban. They were incubated during hypoxia/reoxygenation in vitro. Cell signaling was evaluated using the PAR-2 knockdown model. In ischemia-reperfusion injury mice, edoxaban treatment significantly attenuated fibrin deposition in the sinusoids and liver histological damage and resulted in both anti-inflammatory and antiapoptotic effects. Hepatic ischemia-reperfusion injury upregulated PAR-2 generation and enhanced extracellular signal-regulated kinase 1/2 (ERK 1/2) activation; however, edoxaban treatment reduced PAR-2 generation and suppressed ERK 1/2 activation in vivo. In the hypoxia/reoxygenation model of sinusoidal endothelial cells, hypoxia/reoxygenation stress increased FXa generation and induced cytotoxic effects. Edoxaban protected sinusoidal endothelial cells from hypoxia/reoxygenation stress and reduced ERK 1/2 activation. PAR-2 knockdown in the sinusoidal endothelial cells ameliorated hypoxia/reoxygenation stress-induced cytotoxicity and suppressed ERK 1/2 phosphorylation. Thus, edoxaban ameliorated hepatic ischemia-reperfusion injury in mice by protecting against micro-thrombosis in sinusoids and suppressing FXa-PAR-2-induced inflammation in the sinusoidal endothelial cells.

Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations.

The majority of drug-like molecules contain at least one ionizable group, and many common drug scaffolds are subject to tautomeric equilibria. Thus, these compounds are found in a mixture of protonation and/or tautomeric states at physiological pH. Intrinsically, standard classical molecular dynamics (MD) simulations cannot describe such equilibria between states, which negatively impacts the prediction of key molecular properties in silico. Following the formalism described by de Oliveira and co-workers (J. Chem. Theory Comput. 2019, 15, 424-435) to consider the influence of all states on the binding process based on alchemical free-energy calculations, we demonstrate in this work that the multistate method replica-exchange enveloping distribution sampling (RE-EDS) is well suited to describe molecules with multiple protonation and/or tautomeric states in a single simulation. We apply our methodology to a series of eight inhibitors of factor Xa with two protonation states and a series of eight inhibitors of glycogen synthase kinase 3β (GSK3β) with two tautomeric states. In particular, we show that given a sufficient phase-space overlap between the states, RE-EDS is computationally more efficient than standard pairwise free-energy methods.

Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors

BackgroundDirect oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. ObjectivesThe ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. MethodsHuman FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. ResultsF174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. ConclusionThese human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.

The Heidelberg registry of atrial fibrillation. a summary in the era of transition of oral anticoagulation regimes over an 11-year period

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The study was supported by a research grant from Daiichi Sankyo and Bayer diagnostics. The sponsor had no influence on the study concept, data collection, or interpretation. Background Management of patients with atrial fibrillation (AF) has improved in recent years. Particularly, the shift from vitamin-k containing (VKA) oral anticoagulation (OAC) regimes to factor Xa or thrombin inhibitor containing non-vitamin K regimes (NOAC) regimes has revolutionized stroke prevention in AF patients. Purpose This study aimed to illustrate the shift from VKA to NOAC regimes over an 11-year period in an emergency department (ED) setting. Methods The Heidelberg Registry of Atrial Fibrillation (HERA-FIB) is a retrospective, observational single-center study and collected data from patients with AF presenting to the ED of our hospital between 2009 and 2020. Inclusion criteria were (a) diagnosis of AF and (b) age &amp;gt;18 years. Exclusion criteria were (a) non-availability of at least one high sensitive troponin T value and (b) lost to follow-up for all-cause mortality. Repeated visits to the ED were also excluded. Clinical data was accessed retrospectively from available medical records. A sequential follow-up was performed for all-cause mortality, stroke, major bleeding and myocardial infarction. This study was conducted according to ethical principles stated in the Declaration of Helsinki (2008). Results Within the inclusion period of HERA-FIB a total of 76,528 visits to CPU were screened over an 11-year time period. 24.4% were excluded for other diagnosis than AF, resulting in a total of 12,279 visits to ED within the inclusion period. Here, a total of 5.4% of the patients were excluded after re-adjustment of AF diagnosis, 1,5% for non-sufficient laboratory values and 10% for lost-to follow-up. The total study population of HERA-FIB included 10,222 patients with the diagnosis of AF. Within the inclusion period of HERA-FIB, a significant change form VKA containing to NOAC containing anticoagulation regimes could be detected among patients presenting to the ED. Additionally, the number of patients on OAC compared to the number of patients without any OAC regime increased over time. Within the inclusion period, a total of 69.7% received an OAC regime. Here 59.5% of the AF patients received a NOAC and 40.5% VKA at discharge. Hazard ratio for patients on VKA for all-cause mortality was 1.25 (95%CI: 1.11-1.41), p=0.0003. Conclusions HERA-FIB is one of the largest real-world retrospective single-center databases for patients with AF, reflecting the shift from NOAC to VKA containing anticoagulation regimes in AF patients presenting to an ED over an 11-year period.

Factor Xa inhibitors versus low-molecular-weight heparin for preventing coagulopathy following COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Hospitalized patients with COVID-19 have shown a significant occurrence of thromboembolism and a heightened risk of death. It remains unclear whether factor Xa inhibitors are superior to enoxaparin in this context. Hence, there is a need for a direct comparison to assess the preventive effects and safety of factor Xa inhibitors versus enoxaparin in hospitalized COVID-19 patients. MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) or retrospective studies that compared the effectiveness or safety of factor Xa inhibitors and enoxaparin in preventing thromboembolism in hospitalized patients with COVID-19. Embolic incidence, incidence of bleeding, and all-cause mortality were among the outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95 percent CIs. The analysis included six RCTs and two retrospective studies containing 4048 patients. Meta-analysis showed a statistically significant reduction among patients on factor Xa inhibitors compared with low-molecular-weight heparin (LMWH) in the embolic incidence [risk ratio (RR) 0.64 (95%, CI 0.42, 0.98); P=0.04, I2=12%]. Upon subgroup analysis by type of study design, no significant reductions were noted in patients on factor Xa inhibitors in RCTs (RR: 0.62; 95% CI: 0.33-1.17; P=0.14) or observational studies (RR: 0.53; 95% CI: 0.23-1.26; P=0.15) when compared with enoxaparin Factor Xa inhibitors were not significantly associated with incidence of bleeding [RR 0.76 (95% CI 0.36, 1.61); P=0.47, I2=0%] or all-cause mortality (RR: 0.81; 95% CI: 0.48-1.36; P=0.43). Consistent results were obtained upon subgroup analysis by the type of study design. Factor Xa inhibitors are more effective than enoxaparin in preventing thromboembolism among patients with COVID-19 who are not acutely ill and are hospitalized. Additional rigorous RCTs comparing factor Xa inhibitors with enoxaparin are warranted.

Perioperative Management in Patients with Atrial Fibrillation Treated with Non-Vitamin K Antagonist Oral Anticoagulants Undergoing Minor Bleeding Risk Procedure: Rationale and Protocol for the PERIXa Study.

While treatment interruption of non-vitamin K antagonist oral anticoagulants (NOACs) for elective surgery or procedures among patients with atrial fibrillation (AF) is becoming more prevalent, there remains insufficient evidence regarding the optimal perioperative management of NOACs, particularly procedures with minor bleeding risks. This study aims to evaluate the safety and effectiveness of a simplified, standardized protocol for perioperative management of direct factor Xa inhibitors in patients, with AF undergoing procedures associated with minor bleeding risk. This multicenter, prospective single-arm registry study plans to enroll patients undergoing procedures with minor bleeding risk who were prescribed direct factor Xa inhibitors for AF. The procedures with minor bleeding risk will include gastrointestinal endoscopy for diagnostic purposes, selected dental procedures, and ocular surgery for cataracts or glaucoma. For apixaban, patients will withhold the last evening dose and resume either from the evening dose of the procedure day or the following morning, depending on the bleeding risk of the patient. For edoxaban or rivaroxaban, patients will withhold only a single dose on the procedure day. The primary outcome is the occurrence of major bleeding events within 30 days. Secondary outcomes include systemic thromboembolism, all-cause mortality, and a composite of major and clinically relevant non-major bleeding events. This study has the potential to generate evidence regarding the safety of perioperative management for patients, with AF undergoing procedures associated with minor bleeding risk. Clinicaltrials.gov: NCT05801068.

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.

Concizumab improves clot formation in hemophilia A under flow

BackgroundInhibition of tissue factor pathway inhibitor (TFPI) is an emerging therapeutic strategy for treatment of hemophilia. Concizumab is a monoclonal antibody that binds TFPI and blocks its inhibition of factor (F)Xa thereby extending the initiation of coagulation and compensating for lack of FVIII or FIX. ObjectivesThe objective of this in vitro study was to evaluate how concizumab affects clot formation in hemophilia A under flow. MethodsBlood was collected from normal controls or people with hemophilia A. An anti-FVIII antibody was added to normal controls to simulate hemophilia A with inhibitory antibodies to FVIII. Whole blood and recombinant activated FVII (rFVIIa, 25 nM) or concizumab (200, 1000, and 4000 ng/mL) were perfused at 100 s−1 over a surface micropatterned with tissue factor (TF) and collagen-related peptide. Platelet and fibrin(ogen) accumulation were measured by confocal microscopy. Static thrombin generation in plasma was measured in response to rFVIIa and concizumab. ResultsConcizumab (1000 and 4000 ng/mL) and rFVIIa both rescued (93%-101%) total platelet accumulation, but only partially rescued (53%-63%) fibrin(ogen) incorporation to normal control levels in simulated hemophilia A. Results using congenital hemophilia A blood confirmed effects of rFVIIa and concizumab. While these 2 agents had similar effect on clot formation under flow, concizumab enhanced thrombin generation in plasma under static conditions to a greater extent than rFVIIa. ConclusionTFPI inhibition by concizumab enhanced activation and aggregation of platelets and fibrin clot formation in hemophilia A to levels comparable with that of rFVIIa.

Four-factor prothrombin complex concentrate is not inferior to andexanet alfa for the reversal or oral factor Xa inhibitors: An Eastern Association for the Surgery of Trauma multicenter study.

Andexanet alfa (AA) is the only FDA-approved reversal agent for apixaban and rivaroxaban (DOAC). There are no studies comparing its efficacy with four-factor prothrombin complex concentrate (PCC). This study aimed to compare PCC to AA for DOAC reversal, hypothesizing noninferiority of PCC. We performed a retrospective, noninferiority multicenter study of adult patients admitted from July 1, 2018, to December 31, 2019, who had taken a DOAC within 12 hours of injury, were transfused red blood cells (RBCs) or had traumatic brain injury, and received AA or PCC. Primary outcome was PRBC unit transfusion. Secondary outcome with intensive care unit length of stay. MICE imputation was used to account for missing data and zero-inflated Poisson regression was used to account for an excess of zero units of RBC transfused. Two units difference in RBC transfusion was selected as noninferior. Results: From 263 patients at 10 centers, 77 (29%) received PCC and 186 (71%) AA. Patients had similar transfusion rates across reversal treatment groups (23.7% AA vs. 19.5% PCC) with median transfusion in both groups of 0 RBC. According to the Poisson component, PCC increases the amount of RBC transfusion by 1.02 times (95% confidence interval, 0.79-1.33) compared with AA after adjusting for other covariates. The average amount of RBC transfusion (nonzero group) is 6.13. Multiplying this number by the estimated rate ratio, PCC is estimated to have an increase RBC transfusion by 0.123 (95% confidence interval, 0.53-2.02) units compared with AA. PCC appears noninferior to AA for reversal of DOACs for RBC transfusion in traumatically injured patients. Additional prospective, randomized trials are necessary to compare PCC and AA for the treatment of hemorrhage in injured patients on DOACs. Therapeutic/Care Management; Level III.

Total intracranial hemorrhage volume measurement summating all compartments best in traumatic and nontraumatic intracranial bleeding.

The ANNEXA-4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume. Thirty patients were randomly selected from the ANNEXA-4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty-eight different ANNEXA-4 subjects were also randomly selected to assess intra-rater reliability of total ICrH volume measurement change at baseline and 12-h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA-4. Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader. Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes.