Direct Oral Anticoagulants Research Articles

Perioperative direct oral anticoagulant management during cardiac implantable electronic device surgery: an updated systematic review and meta-analysis.

Patients undergoing cardiovascular implantable electronic device (CIED) implantation are often on direct oral anticoagulation (DOAC). However, the evidence on whether to continue or temporarily discontinue DOAC therapy during the perioperative period in these patients is unclear. We conducted a comprehensive literature review using PubMed, Embase, and Cochrane databases through July 2024. We included studies comparing uninterrupted versus interrupted perioperative DOAC therapy in patients undergoing CIED procedure- primary implants, pulse generator replacement, and device upgrades. Primary outcomes were clinically significant device-pocket hematoma and thromboembolic events. Secondary outcomes included any device-pocket hematoma, all-cause mortality, major bleeding, and any bleeding. A total of 1,607 patients from 8 studies were included. The mean age was 73.2years, with atrial fibrillation as the indication for DOAC therapy in most patients. The mean CHA2DS2-VASc was 3.4. Among the included studies, 2 were randomized control trials (RCTs), while the others were observational cohort studies, including one that was propensity score matched. Our meta-analysis found both strategies to be similar in terms of clinically significant pocket hematoma (RR 1.70; 95%CI 0.84-3.45; p = 0.14; I2 = 0%), thromboembolic complications (RR 0.35; 95%CI 0.04-3.32; p = 0.36; I2 = 19%), any pocket hematoma, all-cause mortality and any bleeding with a higher risk of major bleeding with uninterrupted anticoagulation. This meta-analysis shows that uninterrupted DOAC therapy is comparable to interrupted therapy for CIED procedures, with a potential increase in major bleeding risk but low overall complication rates. Further research is needed to confirm the best approach of periprocedural anticoagulation in these patients.

Comparative safety and effectiveness of oral anticoagulants in patients with non-valvular atrial fibrillation and high risk of gastrointestinal bleeding: A nationwide French cohort study.

This observational study compared effectiveness and safety of direct oral anticoagulants (DOACs; apixaban, rivaroxaban, dabigatran) or vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) at high risk for gastrointestinal bleeding (GIB). Anticoagulant-naïve adults with NVAF with ≥1 GIB risk factor, initiating anticoagulant treatment January 2016-December 2019, and covered by the French national health data system were eligible. Outcomes included major bleeding (MB) and stroke/systemic embolism (SE). Patient characteristics were balanced using propensity score matching. A total of 314,184 patients were identified with 162,150 (51.5%) in the apixaban cohort, 88,427 (28.1%) in the rivaroxaban cohort, 16,465 (5.2%) in the dabigatran cohort, and 47,142 (15.0%) in the VKA cohort (mean age 79.0 years, standard deviation 10.5; 51.0% female). A total of 45,124 apixaban-VKAs, 38,737 rivaroxaban-VKAs, 16,415 dabigatran-VKAs, 88,414 apixaban-rivaroxaban, 16,464 apixaban-dabigatran, and 16,459 rivaroxaban-dabigatran pairs were retained after propensity score matching. Apixaban had lower risk of MB versus dabigatran (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.63-0.83) and rivaroxaban (HR, 0.63; 95% CI, 0.59-0.66). Apixaban had lower risk of GIB versus dabigatran (HR, 0.46; 95% CI, 0.37-0.56) and rivaroxaban (HR, 0.54; 95% CI, 0.49-0.59). Risk of GIB was similar with dabigatran versus rivaroxaban (HR, 1.05; 95% CI, 0.89-1.24). Apixaban had lower risk of stroke/SE versus rivaroxaban (HR, 0.90; 95% CI, 0.84-0.96), while risk was similar versus dabigatran (HR, 1.1; 95% CI, 0.9-1.3). All DOACs had lower risk of MB and stroke/SE versus VKAs (p<0.001 for all). DOACs had improved safety and effectiveness from bleeding and stroke/SE, respectively, versus VKAs among patients with NVAF at high risk for GIB. Apixaban was associated with lower MB and GIB risk versus other DOACs. For stroke/SE, apixaban was associated with reduced risk versus rivaroxaban and similar risk versus dabigatran.

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.

Direct Oral Anticoagulants Versus Warfarin in Patients With Isolated Heparin-Induced Thrombocytopenia or Heparin-Induced Thrombocytopenia With Thrombosis.

No existing studies compare oral anticoagulants to treat heparin-induced thrombocytopenia with or without thrombosis (HIT/HITT). This retrospective study evaluated thrombotic and bleeding outcomes in adults treated for HIT/HITT with a direct oral anticoagulant (DOAC) or warfarin between 2012 and 2023 within the Ochsner Health System. Patients with mechanical heart valves, valvular atrial fibrillation, antiphospholipid syndrome, active malignancy, or venous thromboembolism (VTE) within the previous 6 months were excluded. The primary outcome was a composite of new or progressive VTE or arterial thromboembolism. Secondary outcomes included major and clinically relevant non-major bleeding, duration of hospitalization, time to platelet recovery, and incidence of skin necrosis, gangrene, and amputation. Forty-nine patients receiving a DOAC and 30 patients receiving warfarin were included. Baseline characteristics were similar between cohorts. There were non-statistically significant increased rates of both the primary outcome (8.9% vs. 4.3%, p = 0.65) and the composite bleeding outcome (32.7% vs. 23.3%, p = 0.37) in the DOAC cohort. Larger, prospective studies are needed to confirm these findings.

Management of venous aneurysms and the vascular surgical treatment options : Selection of representative case constellations illustrating experiences at acenter for vascular surgery

Venous aneurysms are arare entity in vascular surgery, which are mostly described in individual case series and meta-analyses generated from them. The treatment concepts are diverse and surgical treatment is highlighted due to the risk of thrombosis and pulmonary embolism. There is still an ongoing debate regarding the postoperative necessity and duration of anticoagulation. Case series of aconsecutive patient cohort with venous aneurysms from the last 18years in acenter of (highly specialized care) vascular surgery including i)own experiences obtained in daily vascular surgical practice and ii)aselected and current literature search of relevant references on possible and, in particular, established diagnosis-specific therapeutic concepts. Between 2005 and 2023, atotal of 11cases of venous aneurysms were reported in patients aged 30-84years (mean: 52.5, median: 50), with 1 patient requiring surgery for a recurrence after 2years. The gender ratio was 7:3 (m:f) and the popliteal vein was the most frequently affected anatomical region with 36.4%, followed by the internal jugular vein and axillary/subclavian vein each with 18.2%. Aneurysms of the inferior vena cava, the common iliac vein and the cubital vein occurred only once. Surgical treatment of the aneurysms was performed in 9cases. The surgical methods used were i)tangential resection of the aneurysm wall and continuous purse-string suture, ii)resection of the aneurysm and interposition of an 8‑mm GORE-TEX® vascular graft prosthesis (Gore, Putzbrunn, Germany), iii)ligation of the aneurysm and iv)ligation with subsequent resection of the aneurysm. The rarity of venous aneurysms should be a reason to register these cases centrally (possibly, nationwide diagnosis-related register). Surgical treatment is usually unproblematic and associated with few complications. The risk of pulmonary embolism appears to be significantly increased in venous aneurysms of the extremities, pelvic veins and inferior vena cava, while venous aneurysms of the head and neck are significantly less prone to this. Perioperative and postoperative anticoagulation has been adapted to the development of specific anticoagulants and novel drugs, in favor of treatment with direct oral anticoagulants (DOAC). In personal experience, immediate postoperative heparin perfusion (low dose) and subsequent therapeutic bridging with low-molecular-weight heparin before switching to an anticoagulant for outpatient clinic-based care appears to safeguard the perioperative phase with respect to keeping the surgery-related complication rate (e.g., thrombosis, bleeding) low.

Real world application of the 2023 ACR/EULAR antiphospholipid antibody syndrome classification criteria in a pharmacist directed anticoagulation clinic.

To determine the number of patients that met classification for antiphospholipid antibody syndrome (APS) after applying the 2023 American College of Rheumatology and the European Alliance for Associations of Rheumatology (ACR/EULAR) classification criteria, to identify reasons patients did not meet the new criteria, and determine the number of patients who were single, double, or triple positive based on laboratory criteria. A single center, retrospective chart review of patients with APS on anticoagulation managed by ambulatory care clinical pharmacists. Data collected included patient demographics, type of anticoagulation, and clinical and laboratory criteria for APS as defined by the 2023 ACR/EULAR criteria. Data is presented using descriptive statistics. A total of 51 patients previously diagnosed with APS were included. There were 42 patients on warfarin (82.3%), 4 patients on direct oral anticoagulants (19%), 3 patients on low molecular weight heparin (5.8%), and 2 patients on fondaparinux (3.9%). Of the 51 patients, 12 (23.5%) met classification criteria, 33 (64.7%) did not meet classification criteria and 6 (11.7%) had insufficient data. Of the 27 patients that did not meet criteria, 13 patients did not meet the laboratory criteria (39.4%), 6 patients did not meet the clinical criteria (18.2%) and 14 patients did not meet both laboratory and clinical criteria (42.4%). Of the 12 patients that met classification criteria, 2 patients were triple positive (16.7%), 3 were double positive (25%), and 7 were single positive (58.3%). Results from this study indicate that APS continues to be a complex disease state with challenges in diagnosis and classification. Since only a small number of patients in our clinic continued to meet the classification criteria, opportunities for patient re-evaluation of management strategies at our institution could be considered.

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.

This 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 333nm 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 0.5-10µg/ml with an excellent regression correlation (r=0.9999) for both drugs with minimum detection limits of 0.14 and 0.16µg/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.

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 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 4135327: Long-term Bleeding Events after Percutaneous Coronary Intervention in Patients with Malignancy with and without Anticoagulant Therapy

Background: With the aging population, the prevalence of malignancies in patients undergoing percutaneous coronary intervention (PCI) is increasing. Active malignancy is increasingly recognized as a significant contributor to high bleeding risks. In cases where anticoagulant (AC) therapy is required, it becomes crucial to determine which is the optimal choice for cancer patients, direct oral anticoagulants (DOACs) or warfarin. The aim of this study was to investigate long-term bleeding events in patients with malignancy undergoing PCI. Methods: CLIDAS (Clinical Deep Data Accumulation System) is a multicenter database with 7 tertiary medical hospitals in Japan. This retrospective analysis using CLIDAS database included 6838 patients who underwent PCI during April 2014 and March 2020 and also who have completed 3-year follow-up were divided into two groups; No malignancy group (n=6155) and malignancy group (n=683). Malignancy was defined as patients with treatment history of malignancy. Furthermore, these patients were categorized into six groups based on the presence of malignancy and the type of AC therapy; 1) No malignancy without AC (n=5369), 2) No malignancy with DOAC (n=294), 3) No malignancy with warfarin (n=492), 4) Malignancy without AC (n=586), 5) Malignancy with DOAC (n=44), and 6) Malignancy with warfarin (n=53). The primary outcome was the incidence of bleeding events, defined according to the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries classification of moderate and severe bleeding. Results: During the 3-year follow-up period, 260 (3.8%) patients experienced major bleeding events after PCI. Among these patients, 180 (3.4%) were in group 1, 9 (3.1%) in group 2, 33 (6.7%) in group 3, 27 (4.6%) in group 4, 2 (4.5%) in group 5, and 9 (17.0%) in group 6. Multivariate Cox regression analysis showed that patients in the malignancy group had a significantly higher rate of bleeding events (HR, 1.50; 95% CI, 1.03-2.18). Furthermore, only the malignancy with warfarin group showed a significantly higher rate of bleeding events compared to the no malignancy without AC group (HR, 4.03; 95% CI, 1.94-8.37). Conclusions: Patients with malignancies receiving warfarin were associated with a higher risk of bleeding events. DOACs may be a safer alternative to warfarin in reducing bleeding risk in this population.

Evaluation of Drug–Drug Interactions Between Clarithromycin and Direct Oral Anticoagulants Using Physiologically Based Pharmacokinetic Models

Objective: This study assessed the pharmacokinetic (PK) interactions between clarithromycin (a P-glycoprotein [P-gp] inhibitor) and four direct oral anticoagulants (DOACs) (P-gp substrates) using physiologically based PK (PBPK) models to elucidate the influence of P-gp in the interaction between them. Methods: PBPK models for clarithromycin, DABE–dabigatran (DAB), rivaroxaban, apixaban, and edoxaban were constructed using GastroPlus™ (version 9.9), based on physicochemical data and PK parameters from the literature. The models were optimized and validated in healthy subjects. We evaluated the predictive performance of the established model and further assessed the impact of P-gp on the PK of the four DOACs. Successfully validated models were then used to evaluate potential drug–drug interactions (DDIs) between clarithromycin and the DOACs. Results: The established PBPK models accurately described the PK of clarithromycin, DABE–DAB, rivaroxaban, apixaban, and edoxaban. The predicted PK parameters (Cmax, Tmax, AUC0-t) were within 0.5–2 times the observed values. A sensitivity analysis of P-gp parameters indicated that an increase in P-gp expression was reduced by in vivo exposure to DOACs. The models demonstrated good predictive ability for DDIs between clarithromycin and the anticoagulants, and the ratio of the predicted values to the observed values of Cmax and the area under the curve (AUC) in the DDI state was within the range of 0.5–2. Conclusions: Comprehensive PBPK models for clarithromycin, DABE–DAB, rivaroxaban, apixaban, and edoxaban were developed, which can effectively predict DDIs mediated by P-gp’s function. These models provide theoretical support for clinical dose adjustments and serve as a foundation for future PBPK model development for DOACs under specific pathological conditions.

Abstract 4116285: Safety and Efficacy of Early Direct Oral Anticoagulants Versus Low Molecular Weight Heparin in Patients with Ischemic Stroke and Immobility: A Multi-National Database Study

Background: Low molecular weight heparin (LMWH) is the preferred anticoagulant for venous thromboembolism (VTE) prophylaxis in patients with ischemic stroke and reduced mobility. However, some patients may have indications for early direct oral anticoagulants (DOACs) and are continued on this therapy rather than transitioning to LMWH. Whether outcomes differ between these groups is unknown. We compared the safety and efficacy of early DOACs versus LMWH from a large retrospective database. Methods: Patients within the TriNetX Research Network receiving either DOACs or LMWH within 72 hours of ischemic stroke and a Modified Rankin Scale of 4-5 were included. A 1:1 propensity score matching analysis was performed using 27 covariables including demographic information, comorbidities, and medications. Chi-square and independent t -tests were used in bivariable analyses. Outcomes were all-cause mortality, VTE, intracranial and extracranial hemorrhage at 30 and 90 days. Results: Of 5,492 propensity-matched patients, mean age was 73±13, and 43% were male. Mortality in the DOAC group was significantly lower than in the LMWH group at 30 days (RR=0.59, 95% CI: 0.51-0.69) and 90 days (RR=0.63, 95% CI: 0.56-0.71). Risk of VTE was not significantly different at 30 days (RR=0.80, 95% CI: 0.43-1.50) or 90 days (RR=0.74, 95% CI: 0.45-1.22). Risk of intracranial hemorrhage was not significantly different at 30 days (RR=0.81, 95% CI: 0.36-1.80) or 90 days (RR=0.62, 95% CI: 0.34-1.15). Conclusions: In patients with acute ischemic stroke and reduced mobility, early use of DOACs was associated with lower mortality compared to early use of LMWH.

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 4144581: Diltiazem, Direct Oral Anticoagulants and Risk of Major Bleeding in Patients with Atrial Fibrillation

Background: Existing research suggests a potential increase in bleeding risk associated with the combined use of calcium channel blockers (CCBs) and direct oral anticoagulants (DOACs). However, the evidence remains inconclusive and conflicting. To clarify this relationship, we conducted a meta-analysis to investigate the risk of major bleeding in patients with atrial fibrillation (AF) using diltiazem. Methods: We conducted a comprehensive search of major electronic databases, including PubMed, Embase, and the Cochrane Library, from their inception through April 20, 2024 for relevant studies. The primary endpoint was major bleeding, defined as a composite of bleeding-related hospitalization, requiring blood transfusion, or fatal bleeding. We conducted a conventional meta-analysis using the Hartung-Knapp-Sidik-Jonkman random-effects model. Endpoints are expressed as hazard ratio (HR) and their corresponding confidence intervals (CI). Results: A total of 5 studies with 488,884 patients with AF were included in our study, of which 23.4% of patients were on diltiazem. All patients were also on DOACs. Results of the meta-analysis showed that there was no statistically significant difference between use of diltiazem and the risk of major bleeding (HR 1.16 ; 95% CI 0.94-1.42). Sensitivity analysis showed that this result remained unaltered in terms of magnitude and direction after excluding one study at a time. When stratified by type of control group, both active comparator (HR 1.09 ; 95% CI 0.92-1.30) and non-use subgroups (HR 1.24 ; 95% CI 0.87-1.77) showed that there was no significant difference in the risk of major bleeding with diltiazem use respectively. Conclusion: We observed that there was no significant difference in the risk of major bleeding in diltiazem use compared to controls in AF patients on DOACs. Further large-scale, longitudinal, and prospective studies are essential to validate these findings.

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) &lt;=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 &gt;=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&lt;.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&lt;.001] per 0.1 up to 1.2 for NIHSS &gt;=21, aOR 1.13, [95% CI 1.09-1.16, p&lt;.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 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 &gt;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 &lt;0.0001), had fewer female patients (30.5% vs 39.3%; p &lt;0.0001), and were less likely to be treated with oral anticoagulation (40.5% vs 50.9%; p &lt;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 4135975: Anticoagulation versus Antiplatelets in Coronary Artery Ectasia and Acute Coronary Syndrome: A Systematic Review and Meta-analysis

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

Abstract 4120515: Impact of 2022 AHA/ACC/HFSA Heart Failure Guideline Value Statement Publication on Medicare Drug Coverage Policies

Background: Patients with heart failure (HF) often have difficulty obtaining life-saving medications due to coverage barriers, such as prior authorizations (PA) and high out of pocket (OOP) costs. To promote better insurance coverage of high value therapies, the AHA/ACC/HFSA added Value Statements to HF guidelines to inform policymakers about medication cost effectiveness. We assessed whether these guidelines influenced Medicare drug coverage policies for two life-saving, costly HF medications: angiotensin receptor neprilysin inhibitors (ARNI – guideline “high value”) and sodium glucose cotransporter 2 inhibitors (SGLT2i – guideline “intermediate value”). Methods: We performed an observational study of Medicare drug plans from 4/2020-4/2023 to assess for changes in ARNI and SGLT2i coverage after Value Statement publication (4/2022), and subsequent Medicare plan online update (10/2022). The primary outcome was any barrier to drug coverage (PA, tier ≥ 3 OOP cost-sharing, step therapy, or no coverage). Analysis utilized interrupted time series and difference-in-difference (DiD) approaches. DiD analyses used direct oral anticoagulants as a control due to similar cost and utilization as ARNI and SGLT2i, but with no Value Statement. Results: Among 7,396 Medicare drug plans, 94.3%-97.4% had coverage barriers to ARNI and 93.2%-96.6% to SGLT2i. The majority of barriers were due to tier ≥ 3 OOP cost-sharing requirements (ARNI: 94.3%-95.8%; SGLT2i: 93.2%-95.6%). Coverage barriers remained stable in 4/2022, and declined slightly in 10/2022 (Figure). In DiD analyses, the presence of a Value Statement was associated with a ~1 percentage point decline in coverage barriers for ARNI and SGLT2i. Conclusion: Coverage barriers to ARNI and SGLT2i were common and did not change much in response to Value Statements in HF Guidelines. Increased consideration for Value Statements by Medicare policy-makers is needed to meaningfully improve access to high value therapies.

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?