Oral Anticoagulants Research Articles

Bio-inspired one-pot synthesis of luminescent silver nanoparticles and its significant utility as a fluorescence nano sensor for analysis of two adjunctive COVID-19 drugs

AbstractThis study reveals one-step green synthesis of plant inspired silver nanoparticles (Ag-NPs). The synthesis procedure relies on the bio-reduction of Ag+ to Ag0 using orange waste (orange peel) extract as cheap, readily available, sustainable, biocompatible feedstocks as a reducing and stabilizing agent. The prepared Ag-NPs passed through a full characterization procedure for better confirmation and elucidation of optical and structural properties. The fluorescence of the prepared Ag-NPs has a quantum yield of 17.15% enabling its potential use in chemical sensing of drugs. Ag-NPs are conceived to be used as a fluorescent nano sensor for sensitive, ecofriendly, rapid spectrofluorimetric determination of two recent direct oral anticoagulants, namely, rivaroxaban (RIV) and edoxaban tosylate monohydrate (EDT); COVID-19 adjunctive drugs in their raw materials and pharmaceutical tablets. The fluorescence of the prepared Ag-NPs at 333 nm $${(\uplambda }_{\text{ex}}=258 \text{nm})$$ ( λ ex = 258 nm ) was found to be substantially quenched in existence of increasing concentrations of each drug. The quenching mechanisms were studied and explained. The validation of the method revealed linear correlation over the ranges of 0.5–10 µg/ml with an excellent regression correlation (r = 0.9999) for both drugs with minimum detection limits of 0.14 and 0.16 µg/ml for rivaroxaban and edoxaban tosylate monohydrate, correspondingly. Three different metrics were employed for verifying the greenness profile of the presented study. The findings of the greenness assessment were congruent and compatible with the green synthesis procedure, ecofriendly analysis, and the exclusion of using organic solvents and noxious materials opening an avenue for green synthesis of nanoparticles instead of chemical and physical methods.

How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms

Arterial and venous thromboses are the most significant complications in patients with myeloproliferative neoplasms (MPN), with the primary treatment goal being thrombotic risk reduction. In MPN with no history of thrombosis, primary prevention mainly involves the use of aspirin and cytoreduction is added in high-risk patients. However, thrombotic complications can unveil an MPN in approximately 20% of cases, necessitating the initiation of both antithrombotic therapy for the thrombosis and cytoreductive treatment for the MPN. The duration of anticoagulant therapy following an initial venous thromboembolic event (VTE) is subject to discussion. Furthermore, the occurrence of a thrombotic complication in patients with a known diagnosis of MPN prompts a reconsideration of both antithrombotic and hematological management. This review employs case-based discussions to explore the management of thrombotic complications in MPN patients. It addresses the nature and duration of antithrombotic treatments, as well as the approach to cytoreduction. Special attention is given to the place of direct oral anticoagulants and to the management of MPN patients with splanchnic vein thrombosis, which is disproportionately common in this group.

Urgent Reversal of Direct Oral Anticoagulants in Critical and Life-Threatening Bleeding: A Multidisciplinary Expert Consensus

Direct oral anticoagulants (DOACs) are increasingly being used due to their improved efficacy/safety ratio and lower clinical and economic burden when compared to vitamin K antagonists. However, bleeding is still the most frequent complication associated with DOACs, and although rare, bleeding episodes can be life-threatening or critical. The impact of DOAC anticoagulation activity during a bleeding event must be evaluated according to patient clinical assessment, dosage and time from last intake, the presence of comorbidities (especially kidney and liver dysfunction), and, whenever possible, coagulation tests. Unfortunately, DOACs’ anticoagulation activity is not easily or usually detectable in routine common coagulation testing. Specific DOAC tests allow for specific drug monitoring, but they are too time consuming, and are usually unavailable in routine emergency practice. If a clinically relevant DOAC plasma concentration is assumed or proven in a severe bleeding scenario, DOAC reversal is needed to restore hemostasis. This experts’ consensus provides a narrative review about DOAC reversal and practical life-threatening bleeding management in several scenarios (trauma, intracranial hemorrhage and gastrointestinal bleeding), focusing on the selection of patients to whom specific reversal agents should be given.

Management of giant left atrial thrombus late after transcatheter mitral valve-in-ring replacement using a transcatheter aortic valve: a case report

Abstract Background In symptomatic high-risk patients with severe mitral valve regurgitation (MR), who are not eligible for surgery, Transcatheter edge-to-edge repair (TEER) or transcatheter mitral valve replacement (TMVR) may be an option, especially when surgical mitral valve repair by annuloplasty has been performed earlier. After TMVR, the appropriate anticoagulation regimen is still matter of debate. Case presentation We here report on a 78-year-old frail lady with heart failure and atrial fibrillation who underwent surgical reconstruction of the mitral valve nine years ago. Due to high surgical risk and after heart team discussion, TMVR using a transcatheter aortic valve prosthesis (valve-in-ring concept) was performed successfully via the transapical access route. Several months later, an excellent result could be confirmed. Since surgical excision of the left atrial appendage was carried out during first surgery, oral anticoagulation was withdrawn. Two months later, the patient presented with a massive LA thrombus mass and severe stenosis of the mitral valve prosthesis requiring re-do surgery. Conclusions Management of anticoagulation in patients with atrial fibrillation and successfully performed LAA excision is still a matter of debate, in particular after transcatheter heart valve implantation in mitral position. TMVR devices may be very thrombogenic. Thus, caution should be used whenever discontinuing oral anticoagulation in these patients. Despite the lack of evidence, withdrawal of anticoagulation should be avoided here, especially in the absence of bleeding complications. Left atrial appendage closure or excision should not influence this decision.

The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID‐19 Patients: A Physiologically Based Pharmacokinetic Modeling Study

Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen‐dependent COVID‐19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P‐glycoprotein (P‐gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P‐gp, such as direct oral anticoagulants (DOAC). Currently, there is limited robust evidence to support a clinically significant interaction between DEX and DOAC. Using physiologically based pharmacokinetic modeling (PBPK), we investigated the impact of DEX administered in the context of SARS‐CoV‐2 infection on the pharmacokinetics of apixaban (APX) and rivaroxaban (RVX). After validating the induction effect of the DEX compound on two CYP3A4 substrates using the limited available studies, we optimized the compound in a COVID‐19 patient population, where significantly higher DEX plasma concentrations were observed compared to healthy volunteers. Our PBPK‐based PK simulations showed a 20% decrease in the AUC of APX and RVX in a worst‐case scenario and when DEX was administered at 6 mg PO for 10 days. This finding confirms the limited clinical data currently available and supports the use of APX and RVX with DEX in COVID‐19 patients at low‐risk for thrombo‐embolism. In addition, our results suggest that prednisone (PRED), when used at an equipotent dose, could serve as a viable alternative to DEX, given its less pronounced induction effect on APX and RVX. Further research is needed to validate these findings and to explore the clinical implications of using PRED in place of DEX in such scenarios.

Abstract 4136743: Current Oral Anticoagulation Use Among Patients With Atrial Fibrillation and Risk Factors Associated With Inadequate Treatments: A Report From a UK Population Cohort Study

Background: The worldwide prevalence of atrial fibrillation (AF) continues to grow with approximately 60 million cases each year. Aim: To understand demographic and clinical attributes of patients receiving adequate DOAC (direct oral anticoagulant) treatment, DOAC undertreatments, or no OAC (oral anticoagulant) treatments, thus providing valuable perspectives into the current landscape of stroke prevention in AF within the UK. Methods: We used the Clinical Practice Research Datalink (CPRD) Aurum database from January 2020 to March 2021 for this retrospective observational study. Patients’ characteristics from various cohorts (standard dose [SD], low dose [LD] per label, LD inconsistent per label prescribing, and untreated) were evaluated based on OAC treatment. Duration of index OAC treatment, time to discontinuation and incidence rates across OAC treated cohorts were assessed. A machine learning method (Elastic Net) identified factors associated with being undertreated or untreated. Results: The final sample included 13,341 patients (mean age 78.5 and female 47%). Within a 180-day timeframe post-diagnosis, 76% of patients received OAC treatment, while 24% did not receive any OAC therapy. Among those treated with DOAC (n=9947), 74% were administered SD (n=7238), 18% received LD per labels (n=1756) and 10% were inappropriately prescribed LD of DOACs (n=953). Both LD cohorts tended to have shorter duration of OAC therapy (figure) and higher discontinuation rates (per 100 person-years; LD per label: 42.97; LD not per label: 39.11) compared to the SD cohort (SD: 31.67). Patients who were untreated were associated with elevated bleeding risk factors such as renal disease and prior bleeding history; patients who received inappropriate LD were associated with age above 75, renal disease, GI conditions with PPI (proton pump inhibitor) concomitant treatments when compared to SD cohort. Conclusions: In our study, a considerable proportion of AF patients remained untreated/undertreated and were associated with bleeding risk factors, highlighting the unmet needs within this population. Exploring potential alternative treatment options with enhanced safety profiles could offer substantial benefits to patients in need.

Abstract 4137927: Physicians’ Misrecognition of Stroke Risk in Patients with Atrial Fibrillation

Background: Current clinical practice guidelines for atrial fibrillation (AF) recommend stroke risk stratification and the use of oral anticoagulants (OACs) for patients at risk. However, physicians’ recognition of patients’ stroke risk may differ from the calculated risk, and the effect of this discrepancy on subsequent care remains unknown. Aims: We aimed to document treating physicians’ estimations of individual patients' stroke risk and assess its association with OAC utilization. Methods: A multicenter, prospective cohort study was conducted in two outpatient practices in Tokyo, Japan, between 2018 to 2020. Participants included patients with newly diagnosed AF or those referred for initial treatment for AF. Treating physicians were asked to document the patient's estimated risk of stroke in numbers. The estimations were categorized as low risk (<1.0%/year), intermediate risk (1.0%≤ to <2.0%/ year), and high risk (2.0%≤/year). We then calculated patients’ baseline CHA 2 DS 2 -VASc scores and divided them into three risk groups: 0 or 1 point as low risk, 2 points as intermediate risk, and 3 or more points as high risk. Higher risk categorization by physicians was defined as "overestimation," while lower risk categorization was defined as "underestimation." The independent association of physician-patient risk concordance with OAC use was explored by multivariable Logistic regression models. Results: Among the 285 patients enrolled in this study (mean age 68±12 years, male 72.6%), the mean CHA 2 DS 2 -VASc score was 2.3±1.6. Physicians correctly estimated stroke risk in 147 patients (51.6%), underestimated it in 25 patients (8.8%) and overestimated it in 113 patients (39.6%). OACs were used in 89.8% of patients whose stroke risk was correctly estimated, 72.0% of those whose stroke risk was underestimated, and 84.1% of patients whose health status was overestimated. After multivariable adjustment, the underestimation of stroke risk was independently associated with less use of OACs (adjusted odds ratio 0.23, 95% CI 0.061-0.85, P=0.028). Conclusions: In this cohort study, physician underestimation of stroke risk was not rare and associated with less use of OACs.

Abstract 4143224: Feasibility of Left Atrial Appendage Occlusion with Dual-Seal Technology without Pre-Procedural CT: Early Single-Center Experience

Background: Left Atrial Appendage (LAA) Occlusion with Amulet has shown promising results in achieving complete closure with minimal periprocedural leak. Amulet’s dual-sealed technology and numerous sizing options provide versatility for different LAA morphologies. Pre-procedural CT is routinely recommended for pre-procedural planning. However, this brings risks including use of contrast, risk of renal failure, radiation exposure, and patient inconvenience. Here, we share initial results of our Amulet implantation protocol without pre-procedural CT: 83 cases were reviewed; number of devices used, procedural time, periprocedural bleeding complications, success in coming off oral anticoagulation, and incidences of stroke and embolism were followed. Methods: We followed 83 AF patients who underwent LAA closure with Amulet, implanted with intraprocedural TEE, intracardiac left atrial echocardiography, and intraprocedural angiography. Pre-procedural CT was not used. Patients were followed to assess safety and efficacy of this protocol. Safety endpoints included rates of procedural and bleeding complications. Efficacy endpoints included rates of stroke and embolism, and number of devices used. Results: All 83 procedures were successfully completed with no perioperative procedural complications and no documented leaks on follow-up TEE. Patients had early ambulation with closure. On average, 1.14 devices were used per case: 88% of cases required 1 device, and nine cases required 2 devices; one case required 4 devices to fit as patient was noted to have an interrupted IVC, requiring implantation via right IJV. There were no cases of stroke or embolism following implantation, and all patients were safely able to come off oral anticoagulation. Conclusions: Results demonstrate that Amulet with its dual-sealed technology can be effectively and safely implanted without pre-procedural CT. No perioperative complications were observed. 88% of cases closed with single device usage. No post-procedure leaks were noted on follow-up TEE. Safety endpoints revealed minimal adverse events, with 2 cases of late pericardial effusion managed without long-term consequences. This protocol demonstrated high efficacy, as all patients were successfully able to come off oral anticoagulation with no reported strokes or embolic events. Intraprocedural TEE, intracardiac left atrial echocardiography, and intraprocedural angiography are typically appropriate for periprocedural sizing of the device.

Abstract 4118668: Understanding Medication Adherence to Oral Anticoagulants in Atrial Fibrillation Management: Patient and Provider Perspectives in a Mixed Methods Study

Background: Atrial fibrillation (AF) increases risk of stroke. National guidelines recommend oral anticoagulant (OAC) use to reduce this risk. Medication adherence is pivotal for effective AF management, necessitating an understanding of adherence barriers. Aims: This mixed-methods study aimed to identify patient and provider factors influencing OAC adherence. Methods: Patients with nonvalvular AF and OAC prescriptions were sampled from a large community health system serving seven states. A stratified random sample of 2,000 patients was surveyed by mail, achieving a 13.3% response rate (266 patients). Twenty-eight semi-structured interviews were conducted with a purposive sample of patient survey respondents. Eligible providers were surveyed by email, resulting in a 3% response rate (78 providers). Survey data were analyzed descriptively and using multivariable regression models. Interview data were analyzed thematically. Results: Of 213 patients with an adherence score available, 31.5% reported non-adherence. Nonadherent patients were more likely to report poor healthcare experiences, including discrimination in a healthcare setting and poorer mental/emotional health. Receiving information from providers was significantly associated with adherence, especially among younger patients and those with fewer chronic conditions. High self-efficacy score was associated with adherence, particularly among older and rural patients. Interview analyses showed provider communication about AF medications, perceptions of AF as a serious illness, and a sense that medication was helping manage AF were all important for medication adherence. In contrast, most providers (87%) perceived high non-adherence among AF patients, citing forgetfulness, cost, and side effects as the main reasons. Providers’ responses indicate a need for improving communication and support for addressing adherence barriers. Conclusion: Most patients reported adherence to their medications, with adherence being associated with positive healthcare experiences and better mental/emotional health. Providers perceived relatively low adherence among their patients but aligned with patients on the need for improved communication and shared decision making. Tools that encourage discussion with patients and open communication between providers and patients are pivotal for optimizing patient care and enhancing medication adherence and treatment outcomes.

Abstract 4119189: Imaging practices prior to cardioversion in patients presenting post percutaneous left atrial appendage occlusion.

Background: Direct current cardioversion (DCCV) carries a risk for stroke in AF patients, for that reason there are guidelines for mitigating this risk in AF patients on oral anticoagulation (OAC). Meanwhile, no consensus on the best approach for cardioverting patients with an appendage occlusion device in situ. This led to a very wide variation in pre and post DCCV practices in these patients. Aims: We aim to explore different factors that might be associated with the variation seen in pre-DCCV imaging practices in patients presenting post- percutaneous LAAO. Methods: This was a multi-center retrospective cohort study of patients who received DCCV for AF or AFL during follow up after LAAO procedure within a single healthcare system from 2016-2024. Results: A total of 119 patients were included, there were more females 70 (59%), with more than half (64 (54%)) receiving a first-generation WATCHMAN™ 2.5, while the rest had WATCHMAN FLX™. Median age at presentation was 77 years (72,82), BMI of 31 kg/m 2 (26,37), average CHADSVASC score of 4.5 and HASBLED score of 3. A median duration of 10 months (3,21) between LAAO to presentation for DCCV . Forty-four (37%) patients had pre-DCCV imaging (imaging cohort). Number of males was significantly higher in the imaging cohort (24 (54.5%) vs 25 (33.3%), p=0.038), compared to those without imaging. There was a significant difference (p<0.001) between the two cohorts in the location (center) where DCCV was done. The site with the highest number of pre-DCCV imaging cases had an equal gender ratio of patients presenting for DCCV. Patients who received imaging presented earlier (11.2 months vs 15.8 months, p=0.068) compared to those without imaging, though the difference was not significant. Between the two groups, there was no significant difference in OAC (VKA-antagonist/DOAC) usage prior to presentation (8 (18.6%) vs 12 (16.4%), P=0.9). There was no significant difference in baseline CHADSVASC score, HASBLED score, age, LVEF. Higher percentage of patients were discharged on OAC post DCCV in the imaging arm (13 (30.2%) vs 14 (19.4%), p=0.27), but the difference was non-significant. No Device related thrombus nor significant PDL was detected on imaging. Conclusion: There was male preference in providing pre-DCCV imaging for ruling out DRT. Location of care was also associated with the variation in pre-DCCV protocols. Additional research is needed to understand other factors associated with variation seen in pre-DCCV practices.

Abstract 4141454: Atrial Fibrillation in American Indians: Comparative Analysis of Characteristics and Anticoagulation Use for Stroke Prevention of Atrial Fibrillation

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States, affecting individuals of all races. Anticoagulation (AC) therapy is recommended by the guidelines to reduce the risk of stroke in AF patients. Previous reports indicate that American Indians (AI) have a higher risk of AF and an increased risk of stroke from AF. Aim: To describe the demographic and clinical characteristics of the AI population with AF and compare their AC status with other racial groups. Methods: We retrospectively analyzed AF patients age >18 years hospitalized between January 2022 and October 2023 in two hospitals serving a large Navajo Nation AI population in rural Northern Arizona. We compared baseline characteristics, AC status and direct oral anticoagulant (DOAC) use between AI and other races. Between group statistical analysis was completed using a chi-square for categorical variables and a Mann-whiney U test for continuous variables, with statistical significance defined as a p-value ≤ 0.05. Results: In total, 9255 patients were admitted with AF: 871 (9.4%) were AI, with 696 (79.9%) being Navajo Nation AI and 8284 (89.5%) from other non-AI races. AI patients with AF were younger (average age 65±15.9 vs 75±11.2; p <0.0001), had fewer female patients (30.5% vs 39.3%; p <0.0001), and were less likely to be treated with oral anticoagulation (40.5% vs 50.9%; p <0.0001; OR 0.66; 95% CI: 0.57 to 0.76) compared to non-AI races (table 1). Among those anticoagulated, AI patients were less likely to receive a DOAC (38.0% vs 44.7%; p = 0.0002; OR 0.76; 95% CI: 0.66 to 0.88) compared to non-AI races (table 2). Conclusions: Our analysis, with a significant number of AI pts, reveal that AI patients develop AF at a younger age and despite an increased risk of stroke, have significantly lower rates of anticoagulation use, particularly with DOACs. Our findings underscore the need for guideline-adherent AC use in this AI population.

Abstract 4136632: Impact of Postoperative Atrial Fibrillation on Long-term Clinical Outcomes in Patients after Coronary Artery Bypass Grafting

Background: The impact of postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) on long-term clinical outcomes has not been adequately evaluated yet. Methods: Among consecutive 14927 patients who underwent their first coronary revascularization in the CREDO-Kyoto PCI/CABG Registry Cohort-3 (2011-2013), the study population consisted of 1483 patients who underwent CABG after excluding those with prior AF. POAF was defined as newly documented AF during hospitalization for CABG. The primary outcome measure was all-cause death after discharge. The median clinical follow-up was 5.7 (interquartile range, 4.4-6.6) years. Results: POAF was observed in 337 patients (23%). Multivariable logistic regression analysis indicated that age >=75 years (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.24-2.10; P<0.001) and cardiopulmonary bypass (CPB) use (OR, 1.40; 95%CI, 1.09-1.79; P=0.01) were independent predictors of POAF. Of the 1400 patients discharged alive among the study population, the POAF group included more older patients, patients with prior stroke, and patients prescribed beta-blockers and oral anticoagulants than the non-POAF group. The cumulative 5-year incidence of all-cause death was 15.9% in the POAF group and 13.0% in the non-POAF group (Log-rank P=0.38). After adjusting for confounders, the adjusted risk for all-cause death was almost neutral (adjusted HR, 0.96; 95%CI, 0.70-1.31; P=0.81). The cumulative 5-year incidence of stroke was significantly higher in the POAF group than in the non-POAF group (8.0% versus 4.2%; Log-rank P=0.02), and the adjusted risk of stroke in the POAF group relative to the non-POAF group tended to be higher (adjusted HR: 1.58, 95%CI, 0.99-2.53; P=0.057). However, the cumulative 5-year incidence of major bleeding was significantly higher in the POAF group than in the non-POAF group (14.6% versus 10.7%; Log-rank P=0.01). Even after adjusting for confounders, the excess risk of major bleeding in the POAF group was significant (adjusted HR, 1.42; 95%CI, 1.01-2.00; P=0.041). Conclusions: Advanced age and CPB use were associated with POAF occurrence. POAF was not associated with long-term mortality after discharge. However, it tended to be associated with a higher risk for stroke and was associated with a significantly higher risk for major bleeding. Further study would be needed to clarify the appropriate management of POAF after CABG.

Abstract 4131630: Comparative Outcomes of Left Atrial Appendage Occlusion Device Implantation in Atrial Fibrillation Patients with a Lower Stroke Risk

Introduction: Current guidelines recommend oral anticoagulation in atrial fibrillation (AF) patients with a CHA 2 DS 2 -VASc score ≥ 2 for stroke prevention. Left atrial appendage occlusion (LAAO) devices serve as alternatives to reduce stroke risk in select AF patients that are unable to tolerate long-term oral anticoagulation. However, Centers for Medicare&Medicaid Services reimburses left atrial appendage occlusion (LAAO) for patients with CHA 2 DS 2 -VASc score ≥ 3. Objective: To evaluate differences in outcomes and complications of LAAO therapy in AF patients with a CHA 2 DS 2 -VASc score of ≥ 3 versus < 3. Methods: National Inpatient Sample and International Classification of Diseases, 10th Revision codes were used to identify AF patients who underwent LAAO device implantation in the U.S. from 2016−2020. The study population was stratified by stroke risk into two groups, CHA 2 DS 2 -VASc ≥ 3 and < 3. Study endpoints assessed included procedural complications, inpatient outcomes and resource utilization. A multivariable logistic regression model was used to assess the independent association of CHA 2 DS 2 -VASc score with study outcomes. Results: A total of 73,795 and 15,500 LAAO devices were implanted in patients with CHA 2 DS 2 -VASc ≥ 3 and < 3, respectively. Compared to patients with CHA 2 DS 2 -VASc score of ≥ 3, patients with CHA 2 DS 2 -VASc < 3 had lower overall (6.9% vs 9.9%, P< 0.01) and major (4.5% vs 6.2%, P< 0.01) complications in the crude analysis. After multivariable adjustment for potential confounders, CHA 2 DS 2 -VASc < 3 was associated with lower overall complications (aOR 0.84, 95% CI 0.78 – 0.91), major complications (aOR 0.90, 95% CI 0.81-0.99) and cost of hospitalization (aOR 0.95, 95% CI 0.91-0.99). Conclusions: Patients with CHA 2 DS 2 -VASc < 3 had lower complications and hospitalization costs after LAAO device implantation than patients with CHA 2 DS 2 -VASc ≥ 3 . These data, if redemonstrated in a large randomized trial can have important clinical implications for stroke prevention in AF patients.

Abstract 4138781: Neuro-specific biomarkers for risk assessment of ischemic stroke and death in patients with atrial fibrillation not receiving oral anticoagulation

Background: Biomarkers measured in plasma reflecting cardiorenal dysfunction and inflammation are associated with clinical outcomes in atrial fibrillation (AF). We recently showed an association between the plasma level of the neuronal biomarker neurofilament light chain (NFL) and subsequent stroke and death in patients with AF not receiving oral anticoagulation (OAC). Purpose: We aimed to compare NFL with other circulating neuro-specific biomarkers, specifically glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), concerning associations with the risk of stroke and other outcomes in patients with AF. Methods: Concentrations of NFL, GFAP, tau, and UCHL1 were determined with Single Molecule Array (Simoa®) in plasma samples obtained at baseline from 967 patients with AF randomized to aspirin in the ACTIVE A trial. Median follow-up was 3.6 years. Associations between baseline biomarker concentrations, clinical variables (age, sex, body mass index, smoking, alcohol consumption, type of AF, cardiac rhythm at baseline, heart failure, hypertension, diabetes, prior stroke/transient ischemic attack, peripheral arterial disease, and myocardial infarction), and outcomes (ischemic stroke, cardiovascular and all-cause death) were analysed with Cox regression, adjusting for clinical variables and other biomarkers. Results: Increasing age and female sex were associated with elevated levels of all four biomarkers. Plasma levels of NFL were positively correlated with those of GFAP (r=0.67, p<0.001), tau (r=0.12, p<0.001), and UCHL1 (r=0.37, p<0.001). NFL was independently associated with subsequent ischemic stroke (HR 1.27, 95% CI 1.03–1.56 for a doubling of NFL), cardiovascular death (HR 1.37, 95% CI 1.13–1.64 for a doubling of NFL), and all-cause death (HR 1.46, 95% CI 1.25–1.70 for a doubling of NFL) after adjustment for clinical factors and other biomarkers. In unadjusted analyses, GFAP was associated with ischemic stroke and death; tau and UCHL1 with death only, however, these associations were not significant after adjusting for clinical variables (Table). Conclusions: In patients with AF not receiving OAC, NFL was independently associated with ischemic stroke and death. Further investigation of NFL and its association with clinical outcomes in patients with cardiovascular disease is therefore warranted.

Abstract 4145883: Elevated International Normalized Ratio Is Associated with Severity of Intracerebral Hemorrhage for Patients Taking Direct Oral Anticoagulants

Introduction/Background: While the international normalized ratio (INR), a marker of functioning of the extrinsic and final common pathways of the coagulation cascade is associated with increased intracerebral hemorrhage (ICH) mortality for patients taking warfarin, it is not understood how it might be associated with outcomes in patients taking direct oral anticoagulants (DOACs), given the inconsistent and variable effect of DOACs on INR. Research Questions/Hypothesis: To determine whether INR is associated with increased ICH severity in patients with recent exposure to a DOAC. Methods/Approach: We included patients taking Apixaban or Rivaroxaban prior to acute presentation with ICH to hospitals participating in the Get With the Guidelines - Stroke registry, a nationwide quality improvement registry. The primary exposure was INR, which we modeled as a continuous variable with restricted cubic splines. The primary endpoint was stroke severity on presentation, measured by the National Institutes of Health Stroke Scale (NIHSS). Secondary endpoints included Glasgow Coma Scale (GCS) <=8 on admission, in-hospital mortality, composite of in-hospital mortality and discharge to hospice, and modified Rankin Scale (mRS) at discharge. We adjusted for key confounding factors, specifically age, sex, race/ethnicity, insurance status, and medical history, while taking into account within-hospital clustering. Results/Data: In total, 13,251 patients were included of whom 7,545 were exposed to apixaban and 5,706 were exposed to rivaroxaban. As shown in Table 1, for patients taking Apixaban, elevated INR was associated with increased likelihood of NIHSS >=21 (aOR 1.02 [95% CI 1.00-1.04, p=0.03] per 0.1 above 1.1) and in-hospital mortality (aOR 1.11 [95% CI 1.05-1.16, p<.001) per 0.1 above 1.1). For patients taking Rivaroxaban, similar trends were seen (aOR 1.21 [95% CI 1.08-1.35, p<.001] per 0.1 up to 1.2 for NIHSS >=21, aOR 1.13, [95% CI 1.09-1.16, p<.001] per 0.1 up to 1.6, for in-hospital mortality). Conclusion(s): Elevated INR at admission is associated with worsened ICH severity for patients taking Apixaban or Rivaroxaban.

Abstract 4125076: Catheter Ablation Alone Versus Catheter Ablation With Combined Percutaneous Left Atrial Appendage Closure For Atrial Fibrillation: A Systematic Review and Meta-analysis

Background: Combined catheter ablation (CA) with left atrial appendage closure (LAAC) may produce comprehensive treatment for atrial fibrillation (AF) whereby rhythm control is achieved and stroke risk is reduced without the need for chronic oral anticoagulation. However, the efficacy and safety of this strategy is still controversial. Aim: To investigate the efficacy and safety of a combined CA with LAAC approach to treat AF in patients moderate-to-high-risk for bleeding. Methods: This meta-analysis was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Medline, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. Risk of bias was assessed using the Modified Newcastle-Ottawa scale and Cochrane risk of bias tool. Eligible studies reported outcomes in patients with AF who underwent combined CA and LAAC versus CA alone. Studies performing CA without pulmonary vein isolation were excluded. Results: Eight studies comprising 1878 patients were included (2 RCT, 6 observational). Pooled results showed no difference in arrhythmia recurrence (risk ratio [RR] 1.05; 95% confidence interval [CI] 0.84-1.30), stroke or systemic embolism (RR 0.71; 95% CI 0.26-1.94), total procedure time (mean difference 31.45 minutes; 95% CI -5.91-68.81), or major periprocedural complications (RR 1.28; 95% CI 0.28-5.89) when comparing combined CA and LAAC versus CA alone. Conclusion: Combined CA with LAAC for AF is associated with similar rates of arrhythmia free survival, stroke, major periprocedural complications, and procedure time when compared to CA alone. A combined strategy may be as safe and efficacious for patients moderate-to-high-risk for bleeding events to negate the need for chronic oral anticoagulation.

Off-Label Dosing of Direct Oral Anticoagulants: Prescribing Error or Opportunity in Treating Patients with Atrial Fibrillation?

Off-Label Dosing of Direct Oral Anticoagulants: Prescribing Error or Opportunity in Treating Patients with Atrial Fibrillation?

Abstract 4138813: The Use of Direct Oral Anticoagulants for Valvular Atrial Fibrillation in Central Australia

Background: In developed countries, valvular atrial fibrillation (vAF) in the setting of rheumatic heart disease (RHD) disproportionately impacts minority groups. In Australia, Indigenous Australians account for 92% of cases despite only representing 3.8% of the population. Studies to date, such as the INVICTUS trial, support the use of Vitamin K antagonists (VKAs) over direct oral anticoagulants (DOACs) in vAF. However, this assumes consistent adherence and regular clinic follow up. Reduced access to monitoring and dispensing clinics in Central Australia remains a challenge in the provision of VKAs and the use of DOACs may address this. Hypothesis: DOACs may be comparably effective with VKAs in preventing major adverse cardiac and cerebrovascular events (MACCE) in a real-world vAF population. Aim: To conduct a real-world retrospective observational study examining rates of MACCE for patients on VKAs or DOACs for vAF in Central Australia over a five-year period. Methods: The Northern Territory RHD Register was accessed to identify patients with RHD and vAF in January 2019. Demographic and five-year outcome data (until January 2024) were collected. The primary outcome was MACCE, a composite of ischaemic stroke, systemic embolism, non-fatal myocardial infarction, cardiovascular death and all-cause mortality. The primary safety endpoint was major bleeding. Statistical analyses were conducted as both intention-to-treat (ITT) based on initial anticoagulation and as-treated (AT) based on anticoagulation prior to MACCE or trial endpoint, each excluding patients without anticoagulation. Results: 61 patients were included. The mean age was 61.9 ± 13.9 years and 68.9% were female. At baseline, 65.6% received VKA, 14.8% DOAC and 19.7% were not anticoagulated. 30.6% of patients crossed over from the ITT analysis, with a non-significant trend favouring switch to DOAC (11 vs 0, p=0.09). In the ITT analysis (n=49), there was no significant difference in MACCE (25.0% vs 22.2%, p=0.86) or major bleeding (20.0% vs 11.1%, p=0.53) between VKA and DOAC groups. In the AT analysis (n=51), there was no significant difference in MACCE (27.3% vs 16.7%, p=0.39) or major bleeding (18.2% vs 22.2%, p=0.73) between VKA and DOAC groups. Conclusion: Over a five-year period, there was a trend towards use of DOACs over VKAs in vAF. This study demonstrates that DOACs may be as effective as VKAs for reducing MACCE in a real-world vAF population however further investigation is required.

Abstract 4136721: Reducing the Use of Transesophageal Echocardiogram Prior to Cardioversion Using Machine Learning

Introduction/Background: Direct current cardioversion (DCC) is used to terminate atrial fibrillation and atrial flutter. Due to increased stroke risk post DCC, a transesophageal echocardiogram (TEE) is performed in selected patients to rule out left atrial appendage thrombus (LAAT) prior to DCC. The prevalence of LAAT is around 2.5% in the era of direct oral anticoagulants. This is a large proportion of patients with no LAAT on TEE and calls for strategies to improve patient selections for TEE before DCC. Research Questions/Hypothesis: In this study we aimed to determine if the use of machine learning could accurately predict the presence of LAAT among patients with nonvalvular atrial fibrillation and atrial flutter. Methods/Approach: We collected demographic, comorbid, and transthoracic echocardiographic data on 795 patients who underwent TEE prior to DCC for nonvalvular atrial fibrillation and atrial flutter. We developed and validated an explainable machine learning model using the eXtreme Gradient Boosting algorithm with 5x5 nested cross-validation. The algorithm used 37 variables to predict the probability of LAAT. Results/Data: The prevalence of LAAT in our cohort was 11.3%. Our model achieved an area under the curve (AUC) of 0.79 in predicting LAAT, figure 1A. In comparison, CHA2DS2-VASc score performed poorly in our cohort with an AUC of 0.48, figure 1B. The ranking of variables most strongly predictive of LAAT is shown in figure 1C, with left ventricle ejection fraction as the most instrumental. Patients were categorized into 10 groups based on the percentile of their predicted probability of having a thrombus. A lower percentile (e.g., 10%) indicates a lower probability of having a thrombus. By utilizing a cutoff point of 0.16, which includes 10.0% of the patients, we can exclude the presence of thrombus with 100% certainty. Conclusion: Machine learning, compared to traditional risk scores, offers enhanced predictive model for identifying LAAT and provides better guidance for TEE and anticoagulation therapy before DCC.

Abstract 4113263: Serum Metabolomics Adds Predictive Value to Clinical and Polygenic Risk Scores for Atrial Fibrillation: A UK Biobank study of >240,000 Patients

Background: Atrial fibrillation (AF) poses substantial morbidity and mortality burdens globally. It is critical to identify individuals at high-risk for AF to implement both lifestyle modifications and close monitoring for initiation of oral anticoagulants. Currently, risk prediction in AF relies on clinical scores such as CHARGE-AF. Small molecule metabolites are thought to play a role in AF pathogenesis, but the additional predictive value of metabolomics over clinical and genetic risk factors is unknown. Using the UK Biobank (UKBB), we sought to perform this evaluation. Methods: We included all UKBB participants with complete 1 H-NMR metabolite measurements. We excluded participants with prior history of AF or with incomplete AF Polygenic Risk Score (AF-PRS) or CHARGE-AF components. The final cohort included 240,628 patients. In-patient records, primary care notes, and death registries were queried to identify patients who had developed incident AF within 5 years of enrollment. The cohort was divided into a 80/20:Train/Test split. We compared the performance of an Elastic-Net regularized Cox Proportional Hazards (EN-CPH) model trained on CHARGE-AF, AF-PRS, and the full 170 metabolite panel to a CPH model trained only on CHARGE-AF and AF-PRS. Results: Within 5 years, 4,174 (1.7%) patients developed AF. Compared to the control population, the incident AF cases were more likely to be older (62 vs. 56, p<0.001), male (65% vs 45%, p<0.001), and have higher CHARGE-AF and AF-PRS scores (p<0.001). After training the EN-CPH model on CHARGE-AF, AF-PRS, and 170 metabolites, the final model included 8 metabolites on top of CHARGE-AF (HR: 1.28) and AF-PRS (HR: 1.11). After adjusting for CHARGE-AF and AF-PRS, creatinine level was associated with increased risk of AF (HR: 1.01) while linoleic acid level (HR: 0.985) was associated with decreased risk. Furthermore, total cholesterol, esterified cholesterol, free cholesterol, cholesteryl esters in IDL, omega-6 fatty acids, and cholesterol in large LDL were associated with HR 0.993-0.999. The EN-CPH model out-performed the CPH model without metabolomics on the test set (AUC 0.786 vs 0.753, p < 0.001). Conclusions: The addition of metabolomics to clinical and genomic risk scores improves prediction of 5-year incident AF within a general population. This study highlights the significance of the metabolome as an independent prognosticator of AF risk. Further study of the mechanisms by which selected metabolites alter AF risk is needed.