Relevant Bleeding Research Articles

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.

A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Population pharmacokinetics and pharmacodynamics of edoxaban in pediatric patients.

Edoxaban is an orally active inhibitor of activated factor X (FXa). Population pharmacokinetic (PK) and pharmacodynamic (PD) analyses were performed to characterize the PK and PK-PD relationships of edoxaban in pediatric patients to identify the covariates that may contribute to inter-subject variability in PK and PD of edoxaban in pediatric patients, and to compare the PK and PD data between pediatric and adult patients. The pediatric PK of edoxaban was best described by a two-compartment model with transit compartments, first-order oral absorption, and linear elimination. The estimated glomerular filtration rate (eGFR), body weight, and post-menstrual age were the significant covariates explaining variability in edoxaban PK among pediatric patients. A function based on renal maturation was applied to edoxaban clearance. The clearance for a 70 kg patient with an eGFR of 110 mL/min/1.73 m2 was estimated to be 42.9 L/h (CV ~ 31.8%). PK simulation showed that exposures across five pediatric age groups were comparable to that in adult patients receiving 60 mg once daily dose. The PK-PD relationship for anti-factor Xa was best fit with an Emax (8.65 IU/mL) model with an EC50 of 631 ng/mL. The PK-PD relationships for activated partial thromboplastin time and prothrombin time were best fit with linear models (slopes of 0.0467, and 0.0415 s mL/ng, respectively). In addition, due to the small number of efficacy and safety events, an exploratory analysis did not detect a correlation between efficacy events (recurrent venous thromboembolism) or safety events (clinically relevant bleeding) and edoxaban exposure.

Direct Oral Anticoagulants Versus Aspirin for Stroke Prevention After Embolic Stroke of Undetermined Source: An Updated Meta-Analysis of Randomized Controlled Trials

Background: Four randomized controlled trials (RCTs) did not show a benefit of direct oral anticoagulant (DOAC) treatment compared with antiplatelet therapy for the prevention of recurrent strokes in patients with embolic stroke of undetermined source (ESUS). However, the balance between efficacy and safety in subgroups needs to be better defined. We aimed to assess the relative benefits of DOACs in key subgroups of adult patients with ESUS. Methods: We searched major databases (PubMed, Embase, CENTRAL, and Web of Science) for RCTs published from inception to 16 June 2024. The primary outcome was recurrent stroke, and the main safety outcomes were major bleeding and clinically relevant non-major bleeding (CRNB). We assessed the risk of bias using the Cochrane Risk of Bias tool 2. Results: We identified four RCTs, involving a total of 13,970 patients with ESUS. Compared to antiplatelet therapy, treatment with DOAC did not reduce the risk of recurrent stroke (RR 0.95, 95% CI 0.83–1.08, p = 0.45) or ischemic stroke (RR 0.92, 95% CI 0.80–1.05, p = 0.22) or increase major bleeding (RR 1.57, 95% CI 0.87–2.83; p = 0.14). DOAC treatment was associated with a significantly higher risk of CRNMB compared to aspirin (RR 1.52, 95% CI: 1.22–1.90; p = 0.0002). The subgroup analysis demonstrated that use of DOACs was associated with a significant protective effect in patients aged 75 or older (RR 0.76, 95% CI 0.60–0.97, p = 0.03) and when the time from index stroke to randomization was ≥8 days (RR 0.80, 95% CI 0.66–0.97, p = 0.02) in preventing recurrency of any type of stroke. Conclusions: Our meta-analysis showed lack of overall benefit of anticoagulation with DOAC compared to antiplatelet therapy for recurrent stroke prevention in adult patients with ESUS. However, the subgroup analyses suggest the possibility of interactions between age and timing of randomization since stroke and treatment with an DOAC in terms of recurrent stroke prevention. Further research toward tailoring the antithrombotic strategy according to patient characteristics is needed.

Temporal modulation (early escalation and late de-escalation) of antiplatelet therapy in patients undergoing complex high-risk PCI: rationale and design of the TAILORED-CHIP trial.

Despite the use of conventional dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), the risk of adverse events remains high among patients with increased thrombotic risk. Until recently, the optimal antiplatelet strategy to balance the ischaemic and bleeding risks in patients who are undergoing complex high-risk PCI has been unclear. The TAILored Versus COnventional AntithRombotic StratEgy IntenDed for Complex HIgh-Risk PCI (TAILORED-CHIP) trial is an investigator-initiated, multicentre, prospective randomised trial to evaluate the efficacy and safety of a time-dependent tailored antiplatelet therapy with an early (<6 months post-PCI) escalation (low-dose ticagrelor at 60 mg twice daily plus aspirin) and a late (>6 months post-PCI) de-escalation (clopidogrel monotherapy) in patients undergoing complex high-risk PCI as compared with standard DAPT (clopidogrel plus aspirin for 12 months). Eligible patients had to have at least one high-risk anatomical or procedural feature or clinical characteristic associated with an increased risk of ischaemic or thrombotic events. The primary endpoint was the net clinical outcome, a composite of death from any cause, myocardial infarction, stroke, stent thrombosis, urgent revascularisation, or clinically relevant bleeding (Bleeding Academic Research Consortium type 2, 3, or 5) at 12 months after randomisation. (ClinicalTrials.gov: NCT03465644).

Strategy Optimization for a Combined Procedure in Patients With Atrial Fibrillation: The COMBINATION Randomized Clinical Trial.

The optimal strategy of combining left atrial appendage occlusion (LAAO) with catheter ablation (CA) in patients with atrial fibrillation (AF) during a single procedure remains unclear. To determine the effects of ablation-first vs occlusion-first strategies on long-term clinical outcomes among patients with atrial fibrillation undergoing a combined LAAO and CA procedure. The prospective, multicenter COMBINATION randomized clinical trial was conducted in 14 high-volume centers in China. Enrollment of patients with nonvalvular AF referred for the combined procedure began on July 24, 2020, and concluded on January 20, 2022. Patients were randomly assigned to either the ablation-first group or the occlusion-first group. Outcomes of LAAO using an occlusion device and CA using a contact force-sensing catheter following different combination strategies during long-term follow-up were evaluated. The primary end point was a composite of thromboembolic events including stroke or transient ischemic attack, device-related thrombus (DRT), clinically relevant bleeding, and cardiovascular rehospitalization or death. Freedom from AF or atrial tachyarrhythmia (ATA) after a single procedure without antiarrhythmic drugs, at both 1 year and long-term follow-up, was also evaluated. Of the 202 patients enrolled, 194 (96.0%) completed the trial (97 in the ablation-first group and 97 in the occlusion-first group). The mean (SD) age of the cohort was 67.3 (9.2) years, and 110 patients (56.7%) were male. All procedures achieved acute successful LAAO and restoration of sinus rhythm, with similar incidences of periprocedural complications. Compared with the ablation-first group, the occlusion-first group exhibited significantly higher event-free survival of the primary end point (83.5% vs 71.1%; hazard ratio [HR], 0.53 [95% CI, 0.29-0.95]; log-rank P = .04) during the median 2.5 (IQR, 2.3-2.8) years of follow-up. Subgroup analysis indicated that male patients and those with higher CHA2DS2-VASc scores (a composite of factors associated with stroke risk; higher scores indicate higher risk) were at lower risk of thromboembolic events. Rates of long-term freedom from AF (77.3% vs 63.5%; HR, 0.58 [95% CI, 0.34-0.97]; log-rank P = .04) and from ATA (70.1% vs 55.7%; HR, 0.62 [95% CI, 0.39-0.99]; log-rank P = .04) were higher in the occlusion-first group vs the ablation-first group. Additionally, a higher incidence of chronic peridevice leak (15 [15.5%] vs 5 [5.2%]; P = .03) and DRT (8 [8.2%] vs 1 [1.0%]; P = .04) was observed in the ablation-first group vs the occlusion-first group. In this randomized clinical trial, the occlusion-first approach was superior due to its higher event-free survival of the primary end point and long-term freedom from ATA. These findings suggest that the occlusion-first approach should be recommended for combined procedures with plug-like device implantation. Chinese Clinical Trial Registry Identifier: ChiCTR2000031486.

Current evidence on the effectiveness and safety of oral anticoagulants in superficial venous thrombosis: a systematic review and meta-analysis.

Previous studies suggest fondaparinux as an effective regimen for superficial venous thrombosis (SVT), but the inconvenience of prolonged parenteral injections has prompted investigations into oral anticoagulants (OACs). This study aims to evaluate the current evidence on the effectiveness and safety of OACs in the treatment of SVT. Following the PRISMA 2020 guidelines, we conducted a systematic review and meta-analysis registered in PROSPERO (CRD42024535625). A comprehensive literature search was performed across multiple databases up to April 2024. Studies were included if they involved adult patients diagnosed with SVT, treated with OACs, and reported relevant efficacy and safety outcomes. Both randomized controlled trials (RCTs) and observational studies were considered. Data extraction and risk of bias assessments were independently performed by two authors. The search identified 1531 studies, with six studies (three RCTs and three prospective cohort studies) meeting inclusion criteria. Meta-analysis for Rivaroxaban-treated group showed DVT occurrence was 1.30% (95% CI 0.17-3.07%), SVT extension was 0.32% (95% CI: 0.00-1.58%), SVT recurrence was 0.75% (95% CI: 0.00-3.30%), clinically relevant non-major bleeding was 1.95% (95% CI: 0.46-4.11%), minor bleeding was 5.68% (95% CI: 3.02-9.01%). These estimates were for patients treated with rivaroxaban 10-20 mg once daily over 42 days to 37 months. No major bleeding was reported with rivaroxaban 10 mg once daily. This systematic review and meta-analysis demonstrate that OACs, especially rivaroxaban, are effective and safe for the treatment of SVT. They offer a convenient alternative to parenteral anticoagulants, potentially improving patient compliance and outcomes. However, further large-scale studies are warranted to confirm these findings.

SAFETY OF DIRECT ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION 80 YEARS AND OLDER: CLINICAL RISK FACTORS

BACKGROUND: Direct oral anticoagulants (DOACs) use is complicated by bleeding, especially in the geriatric population. Most studies focus on predicting major bleeding, while clinically relevant non-major bleeding (CRNMB) is no less important for practice. АIM: of the study was to evaluate the ability of clinical factors to predict the risk of CRNMB while taking DOACs in patients with atrial fibrillation (AF) aged 80 years and older. MATERIALS AND METHODS: 367 patients were examined with non-valvular AF aged 80 years and older (median age 84 [82; 88] years) taking DOACs. The main population parameters (gender and age composition of groups, body mass index), risk of ischemic stroke according to the CHA2DS2-VASc scale, risk of bleeding according to the HAS-BLED scale, comorbidity, Charlson comorbidity index, risk factors for chronic non-communicable diseases, number of medications taken, objective examination data, vascular wall stiffness, and laboratory test results were assessed. RESULTS: In univariate analysis, significant risk factors for developing CRNMB with all DOACs were: higher frequency of walking (p=0.022), lower heart rate (p=0.08), and history of gastric and duodenal ulcer (GDU) (odds ratio (OR) 5.34 [95% confidence interval (CI): 2.31; 12], p0.001). As a result of multivariate analysis, a model for predicting CRNMB was developed, with age, type of DOAC, liver disease, acute cerebrovascular accident, history of GDU selected as predictors. The resulting model was characterized by 62.6% [95% CI: 57.4; 67.6] predictive accuracy, 66.5% [95% CI: 59.4; 73.1] sensitivity and 58.2% [95% CI: 50.4; 65.7] specificity. CONCLUSION: The study identified specific modifiable, potentially modifiable, and non-modifiable risk factors for the development of CRNMB in patients with AF over 80 years of age taking DOACs. The results of the study can be used to create an electronic system to support medical decision-making, manage risk factors, and improve the quality of life of the population.

The role of comorbidities for hospital outcome of patients with severe acute pulmonary embolism treated with thrombolytic therapy

Abstract Background The association between the outcome of severe acute pulmonary embolism treated with thrombolytic therapy and the presence of common comorbidities is fairly known. Methodology In this study we investigated the influence of common comorbidities (arterial hypertension, atrial fibrillation, heart failure, coronary disease, diabetes mellitus, active malignant disease, chronic obstructive lung disease, chronic renal failure, anemia and previous stroke) to hospital mortality and the composite of major and clinically relevant non-major bleeding at 7 days from hospital admission in patients with severe acute PE treated with thrombolytic therapy enrolled in the Regional PE Registry from the 4 west-Balkan countries. Univariate and multivariable regression analysis (adjusted to age and the presence of arterial hypotension – systolic blood pressure below 90 mmHg) was used to establish association between comorbidities and hospital outcome of acute PE treated with thrombolysis. Results 2068 patients enrolled with computed tomography pulmonary angiography proven acute, symptomatic PE, and of them 645 patients had features of intermediate-high PE (right ventricle dysfunction with positive biomarkers without severe hypotension) and 283 patients had high-risk PE with arterial hypotension. Of them, 394 (42.5%) were treated with thrombolytic therapy (245 with intermediate-high and 149 with high-risk PE). Overall hospital mortality was 17.0% and the composite of major and clinically relevant non-major bleeding at 7 days was 17.5% (11.2% was major bleeding). Among all tested comorbidities, only 3-staged renal failure (OR 3.56, 95%CI 1.78-7.15, p&amp;lt;0.001 for creatinine clearance 30-59 ml/min compare to clearance ≥ 60 ml/min; and OR 6.01, 95%CI 2.35-15.37, p&amp;lt;0.001 for creatinine clearance &amp;lt;30 ml/min versus ≥ 60 ml/min), and the presence of either paroxysmal or chronic atrial fibrillation had significant higher risk for hospital mortality adjusted to age and the presence of arterial systolic hypotension (OR 2.11, 95% 1.03-4.29, p=0.04). Between all presented comorbidities only the presence of diabetes mellitus type 2 was independently associated with the higher risk for bleeding on thrombolytic therapy OR adjusted to age 2.03, 95%CI 1.126-3.659, p=0.019. Conclusion Creatinine clearance and atrial fibrillation were the independent predictors of hospital death and diabetes mellitus type 2 for bleeding in patients with severe acute PE who were treated with thrombolysis.

Direct oral anticoagulants exhibit lower risks of mortality and bleeding compared to vitamin-k antagonists in atrial fibrillation patients on chronic hemodialysis: a meta-analysis

Abstract Background Atrial fibrillation (AF) is a common arrhythmia in patients with chronic kidney disease (CKD). Although direct oral anticoagulants (DOACs) are equally or more effective than vitamin K antagonists (VKAs) in patients with moderate CKD, evidence claiming the benefits of DOACs over VKAs in patients on hemodialysis (HD) is scarce. Purpose This meta-analysis aimed to assess the outcomes of patients with AF on chronic HD by comparing the clinical outcomes of DOACs versus VKAs. Methods A systematic literature search was conducted across various databases to retrieve studies focusing on efficacy and safety outcomes in patients with AF on chronic hemodialysis comparing DOACs and VKAs. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using the Mantel-Haenszel random-effects model in Review Manager 5.4. Statistical significance was set at p &amp;lt;0.05. Results Nine studies with 39, 831 patients were included. The risk of all-cause mortality [RR: 0.73; 95% CI: 0.60, 0.88; p=0.001], major bleeding [RR: 0.63; 95% CI: 0.52, 0.76; p&amp;lt;0.00001], gastrointestinal bleeding [RR: 0.67; 95% CI: 0.53, 0.85; p=0.0009], intracranial hemorrhage [RR: 0.57; 95% CI: 0.38, 0.84; p=0.004], all-cause stroke [RR: 0.64; 95% CI: 0.51, 0.81; p=0.0001], and ischemic stroke [RR: 0.53; 95% CI: 0.29, 0.96; p=0.04] were lower in the DOAC group than in the VKA group. The risk of cardiovascular-related death [RR: 1.34; 95% CI: 0.69, 2.60; p=0.39], and clinically relevant non-major bleeding [RR: 0.90; 95% CI: 0.75, 1.08; p=0.26] showed no significant differences. Conclusion The risks of all-cause stroke, ischemic stroke, all-cause mortality, major bleeding, gastrointestinal bleeding, and intracranial hemorrhage in the patients with AF undergoing chronic HD were lower in the DOAC group than in the VKA group. Further large-scale RCTs are needed to generate more robust evidence through adequately powered studies, leading to conclusive results that are applicable to real-world scenarios.

Switching from warfarin to a DOAC in frail elderly asian patients with atrial fibrillation: a nationwide population-based study

Abstract Background Recently, switching international normalized ratio guided warfarin management to a direct oral anticoagulant (DOAC) was associated with more bleeding complications than maintaining warfarin in frail elderly patients with atrial fibrillation (AF). However, there is a paucity of information on whether these results could be applied to Asian patients with AF, who are known to have relatively low time in therapeutic range (TTR) levels. Purpose To evaluate the safety and effectiveness of switching from warfarin to a DOAC in frail elderly Asian patients with AF. Methods Using a Korean health insurance database, we included patients with AF who were prescribed warfarin between January 2013 and August 2015 without significant bleeding or thromboembolic events during the window period, specifically those aged 75 or older with a Hospital Frailty Risk Score of 5 or more. Those who switched to DOACs during the window period were categorized as the DOAC group and those who continued with warfarin were categorized as the warfarin group. The primary outcome was defined as the composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB), and secondary outcomes were defined as thromboembolic events, all-cause death, the composite of MB, CRNMB and ischemic stroke (so-called net clinical outcome [NCO]). The propensity score weighting method was utilized to compare the two groups. Results A total of 12,162 patients were included (8,108 with maintaining warfarin, 4,054 with switching to a DOAC). Baseline characteristics were well-balanced after the inverse probability of treatment weighting (mean age, 80 years; men, 50%; and mean CHA₂DS₂-VASc score, 5.6). Compared with maintaining warfarin, switching to a DOAC was associated with significantly higher risks of the primary outcome (hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.09-1.87, p=0.01), thromboembolic events (1.28, 1.01-1.62, p=0.039), all-cause death (1.38, 1.15-1.66, p&amp;lt;0.001) and the NCO (1.26, 1.01-1.58, p=0.04). (Figure A, Figure B), whereas there was no difference in the risk of intracerebral hemorrhage (0.90, 0.50-1.60, p=0.7157). When comparing each DOAC with maintaining warfarin, switching to rivaroxaban was associated with a higher risk of the composite of MB and CRNMB (1.91, 1.38-2.64, p&amp;lt;0.001) and thromboembolic events (1.40, 1.03-1.91, p=0.034) than maintaining warfarin. Conclusion In line with the non-Asian population, switching to a DOAC was associated with a significantly higher risk of MB or CRNMB, thromboembolic events, all-cause death and NCO compared with maintaining warfarin in frail elderly Asian patients with AF. Therefore, even in Asians, switching to a DOAC should be considered more cautiously in patients who are stably managed on warfarin.

Characterisation of the pharmacokinetic and pharmacodynamic relationship of milvexian in total knee replacement patients

Abstract Background Milvexian, an oral factor XIa inhibitor, is currently being evaluated in patients at risk for thrombotic events due to atrial fibrillation, ischaemic stroke, or acute coronary syndrome. The exposure-response relationship between clinical efficacy and safety endpoints and milvexian pharmacokinetic (PK) metrics was recently submitted as a separate publication. Characterisation of the relationship between the coagulation pharmacodynamic (PD) markers versus milvexian PK metrics at the patient level has yet to be reported. Purpose This analysis characterised the relationship between the coagulation biomarkers, activated partial thromboplastin time (aPTT) and prothrombin time (PT), and milvexian systemic exposure in patients undergoing total knee replacement (TKR) evaluated in the AXIOMATIC-TKR study. Methods A population pharmacokinetic (PopPK) model was previously developed and characterised the PK of milvexian in TKR patients well. The PK/PD relationships between observed aPTT and PT versus PopPK model estimated time-matched milvexian plasma concentrations via nonlinear mixed effects modeling. The relationship between key clinical safety endpoints (e.g., any bleeding or clinically relevant non-major bleeding) and individual PD marker change (e.g., aPTT ratio to baseline) was also explored. Results The aPTT increased with increasing plasma concentration of milvexian over the range of doses evaluated in the study (25mg QD to 200mg BID). An Emax type of model reasonably characterised the PK/PD relationship between the aPTT and model predicted time-matched milvexian plasma concentration, which is consistent with previously observed relationships in healthy volunteers. No change was observed in PT with increased milvexian exposure. No obvious relationship was identified between any (including clinically relevant non-major) bleeding and aPTT ratio to baseline. Conclusions Increased milvexian exposure is directly correlated with aPTT prolongation over the range of doses evaluated in the TKR study. There was no obvious relationship between any (including clinically relevant non-major) bleeding and aPTT ratio. The PK/PD relationship of aPTT without a parallel relationship in PT distinguishes milvexian, a FXIa inhibitor, from previously studied FXa inhibitors. These analyses were a complementary component in dose selection for the milvexian Phase 3 program. Figure 1. PK/PD relationship between aPTT (left) and PT (right) and estimated time-matched plasma concentration (AXIOMATIC-TKR study)

Monitoring anti-factor Xa activity in patients with chronic thromboembolic pulmonary hypertension treated with factor Xa inhibitors

Direct oral anticoagulants (DOACs) have been used clinically in patients with chronic thromboembolic pulmonary hypertension (CTEPH) for secondary prevention after acute venous thromboembolism, although the data are limited. We evaluated the effects of DOACs—especially factor Xa (FXa) inhibitors—by measuring anti-factor Xa activity (AXA). Fifty consecutive CTEPH patients treated with rivaroxaban, apixaban, or edoxaban were enrolled. Heparin-calibrated AXA was measured at peak and trough. The median peak heparin-calibrated AXA across all 50 patients was 1.90 IU/mL and was comparable among the three FXa inhibitors. At trough, heparin-calibrated AXA was significantly higher in apixaban-treated patients (median 0.70 IU/mL) than in those given rivaroxaban (median 0.11 IU/mL) or edoxaban (median 0.11 IU/mL, p < 0.001). Peak heparin-calibrated AXA was significantly lower with reduced-dosage FXa inhibitor (edoxaban 30 mg/day) than with the reference dosage (edoxaban 60 mg/day, apixaban 10 mg/day, or rivaroxaban 15 mg/day, p = 0.01). The heparin-calibrated AXA of both rivaroxaban and apixaban was strongly significantly correlated with the plasma concentration of each drug. The cumulative rate of major and clinically relevant non-major bleeding was significantly higher in patients with peak heparin-calibrated AXA ≥ 2.09 IU/mL. Heparin-calibrated AXA could provide useful information for treating CTEPH patients with FXa inhibitors.

The initial high-dose versus maintenance-dose anticoagulation therapy with direct oral anticoagulants for cancer-associated venous thromboembolism: from the COMMAND VTE Registry-2

Abstract Background/Introduction Initial high-dose anticoagulation therapy with rivaroxaban and apixaban has been a standard treatment for venous thromboembolism (VTE), although there could be concerns of an increased risk of bleeding events especially among high bleeding-risk patients including those with active cancer. Purpose The present study aimed to evaluate the clinical outcome of initial high-dose anticoagulation therapy comparing to maintenance-dose anticoagulation therapy in patients with cancer-associated VTE using propensity score-matching analysis. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. Among 1507 patients with cancer-associated VTE, we evaluated 180-day clinical outcomes before discontinuation of anticoagulation therapy using a 1:1 propensity score-matching model with 21 risk-adjusting variables Results After the propensity score-matching, we enrolled 324 patients with initial high-dose anticoagulation therapy and 324 patients with initial maintenance dose anticoagulation therapy. Of patients with initial high-dose anticoagulation therapy, rivaroxaban and apixaban were administered in 198 and 126 patients, respectively. Of those with initial maintenance-dose anticoagulation therapy, rivaroxaban, apixaban, and edoxaban were administered in 34, 46 and 244 patients, respectively. The median durations of initial high-dose anticoagulation therapy were 18 [IQR: 15-21] days for rivaroxaban and 7 [IQR: 7-7] days for apixaban. In the current study population, the mean age was 67±12 years, 346 were women, and the mean body weight was 58±12 kg. There was no significant difference in the distribution of gastrointestinal cancer such as stomach and colorectal cancer between the 2 groups (4.6% vs. 4.9%, P=1.0, 8.3% vs. 11.4%, P=0.22). The cumulative 180-day incidence of discontinuation of anticoagulation was not significantly different between the 2 groups (27.8% vs. 30.5%, P=0.50). There were no significant differences in the cumulative 180-day incidences of recurrent VTE (3.1% vs. 1.0%, P=0.08), nor major bleeding (8.1% vs. 7.0%, P=0.66), nor all-cause death (25.1% vs. 21.6%, P=0.33) between the 2 groups. There were also no significant differences in the cumulative 180-day incidences of all clinically relevant bleeding (14.9% vs. 13.3%, P=0.72), gastrointestinal bleeding (8.4% vs. 5.4%, P=0.15), nor major gastrointestinal bleeding (5.4% vs. 2.7%, P=0.10). Conclusions There was no signal of an increased risk of recurrent VTE in the initial maintenance-dose anticoagulation therapy. Considering a numerically slightly higher incidence of gastrointestinal bleeding in the initial high-dose anticoagulation therapy for cancer-associated VTE, the initial maintenance-dose anticoagulation therapy could be a potential treatment option for selected patients including patients at a high risk of gastrointestinal bleeding.Study flow chartResults

Impact of neutrophil-to-lymphocyte ratio on clinical outcomes in patients with or without chronic kidney disease undergoing percutaneous coronary intervention

Abstract Background Neutrophil-to-lymphocyte ratio (NLR) has recently emerged as inexpensive inflammatory biomarker associated with worse cardiovascular outcomes. However, little is known about its role in risk stratification of patients with both chronic kidney disease (CKD) and coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Purpose We aimed to evaluate the clinical impact of baseline NLR in patients with and without CKD undergoing PCI. Methods We retrospectively evaluated all consecutive patients undergoing PCI between 2012-2022 in a large tertiary US center. We excluded patients without available NLR and those who were deemed to have active hematological or infective diseases, including patients with extremely low or high lymphocyte and neutrophil counts or with hs-CRP above 10 mg/L. Quartiles of NLR were derived in the overall population and patients were stratified according to presence of CKD (eGFR &amp;lt; 60 ml/min). Within each group, we estimated the risk of adverse events using the lowest NLR quartile as reference. The primary endpoint was 12-month incidence of major adverse cardiovascular events (MACE), defined as the composite of all-cause death, myocardial infarction, or stroke. Secondary endpoints included incidence of clinically relevant bleeding and contrast-associated acute kidney injury (CA-AKI), defined as ≥ 0.3 mg/dL or ≥ 50% serum creatinine increase from baseline. Results A total of 7,287 patients were included in the analysis; of these 2,008 (27.6%) had CKD and 5,279 (72.4%) did not. CKD patients (mean eGFR 40.8±16.1 ml/min) were older, had more comorbidities, and presented with higher hs-CRP levels and a greater estimated risk of CA-AKI. Overall, patients with elevated NLR had more severe CAD and underwent more complex PCI. In CKD patients, incidence of adverse events increased stepwise and those in the 4th NLR quartile had the highest adjusted risks of MACE (HRadj 1.86, 95% CI 1.12-3.08; P=0.012), all cause death (HRadj 2.44, 95% CI 1.18-5.05; P=0.003) and bleeding (HRadj 1.74, 95% CI 1.07-2.84; P=0.002) at 1 year, as compared to those in the lowest quartile (Table 1). In patients without CKD, MACE and all-cause death incidences were numerically higher in the 4th quartile but risk estimates were no longer statistically significant after adjustment. The overall incidence of CA-AKI was much greater in the CKD group. When compared to the lowest quartile, patients in the 4th NLR quartile showed a trend for higher risk of CA-AKI in CKD group, while they had a significant increased risk in non-CKD group (Figure 1). Conclusions Elevated NLR is strongly associated with higher risk of MACE and all-cause mortality in CKD patients. Conversely, the risk of bleeding and CA-AKI is increased with elevated NLR in both CKD and non-CKD patients. Thus, NLR may further inform risk stratification of CKD patients undergoing PCI.

Impact of neutrophil-to-lymphocyte ratio on clinical outcomes in patients with acute or chronic coronary syndrome undergoing percutaneous coronary intervention

Abstract Background Neutrophil-to-lymphocyte ratio (NLR) has recently emerged as an inflammatory biomarker associated with atherosclerosis and cardiovascular events. However, its role in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains unclear. Purpose We aimed to evaluate the clinical impact of baseline NLR in patients undergoing PCI for acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). Methods We retrospectively evaluated all consecutive patients undergoing PCI between 2012-2022 in a large tertiary US hospital. We excluded patients for whom NLR was not available and those who were deemed to have active hematological or infective diseases, including patients presenting with extremely low or high lymphocyte and neutrophil counts or with hs-CRP above 10 mg/L. Quartiles of NLR were derived in the overall population and patients were stratified according to clinical presentation. Within each group, we estimated the risk of 12-month adverse events using the lowest NLR quartile as reference. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause death, myocardial infarction (MI), or stroke. Secondary endpoints were MACE individual components and any periprocedural or post-discharge clinically relevant bleeding. Results A total of 7,201 patients were included in the analysis; of these 3,975 (55.2%) had ACS and 3,226 (44.8%) CCS. Patients in the 4th quartile (NLR &amp;gt; 5.0) were more frequently male, older, and presented more often with chronic kidney disease and complex coronary artery disease. Smoking, diabetes and history of CAD, as well as triglycerides, LDL, non-HDL and total cholesterol levels were lower in the 4th NLR quartile. In patients presenting with CCS, the risk of MACE, all-cause death, MI was similar across NLR quartiles, while the risk of bleeding increased stepwise (Figure 1). In patients presenting with ACS, the 4th NLR quartile had the highest adjusted risk of MACE (HRadj 1.82, 95% CI 1.25-2.67; P=0.002), all cause death (HRadj 2.56, 95% CI 1.41-4.66; P&amp;lt;0.001), and bleeding (HRadj 1.82 95% CI 1.25-2.63, P&amp;lt;0.001) at 1 year, as compared to the lowest quartile (Table 1). Conclusions Among patients undergoing PCI, elevated NLR is strongly associated with risk of MACE and all-cause mortality in patients presenting with ACS but not in those with CCS. Conversely, the risk of bleeding was augmented with higher NLR in both ACS and CCS patients undergoing PCI. In this setting, NLR may inform risk stratification at the time of PCI.

First-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of RBD4059, a GalNAc-siRNA drug targeting coagulation factor XI (FXI), in healthy subjects

Abstract Background Patients at risk of thrombosis/thromboembolism, require effective and safe anti-coagulation with high compliance. Inhibiting FXI has emerged as a promising strategy with potential for lower bleeding risk compared to currently approved anti-coagulants. Here we report on the safety, PK and PD effects of the GalNAc-conjugated siRNA RBD4059, specifically targeting and repressing FXI protein synthesis in the liver. Purpose Investigate safety, PK, and PD of first-in-human dosing of RBD4059 in healthy subjects. Methods A randomized, single-blind, placebo-controlled, single ascending dose (SAD) phase I study in healthy subjects (NCT05653037), in cohorts of eight randomized 3:1 to receive escalating doses of RBD4059 (50, 150, and 400 mg) or placebo administered subcutaneously. Results As of January 25, 2024, 24 subjects (with follow-up to week 24) with demographics and baseline clinical characteristics shown in Table 1 were enrolled. RBD4059 was well tolerated (Table 2), all related AEs were grade 1. There was no evidence of any clinically relevant bleeding events. Plasma exposure of RBD4059 tended to increase in proportion to the dose. Maximum concentration in plasma (Cmax) was reached in 2 to 4 h and then declined in line with one-compartment kinetics. The mean plasma half-life (t1/2) ranged from 3.2 to 7.0 h. RBD4059 treatment resulted in dose dependent and sustained reductions in FXI activity and FXI antigen (Figure 1A, B, D). Observed mean maximum percentage change from baseline in FXI activity from the 50 mg, 150 mg, and 400 mg SAD cohorts were 67.5%, 81.0%, and 85.8%, respectively, recovering with a maintained effect observed on D141 (50mg: 50.6% inhibition; 150mg: 68.2% inhibition). The reduction in FXI antigen showed a very similar pattern as the reduction in FXI activity, and reductions were accompanied by a concomitant increase in APTT. (Figure 1C, D). PKPD modelling supports that RBD4059 may be dosed every 3 months or less frequent with a &amp;gt;90% FXI reduction throughout the dosing interval, and will be tested in the upcoming phase 2 study. Conclusion(s) RBD4059 demonstrated favorable safety, predictable PK, and pronounced durable PD effect in the dose range of 50 mg - 400 mg. This first-in-human SAD study supports the further development of RBD4059 as an anticoagulant that can maintain a high level of PD effect with a once every 3 month or less frequent dosing regimen, with potential for enhanced compliance in chronic anti-coagulant therapy.Table 1 &amp; Table 2Figure 1.Panels A-D

Efficacy and safety of long-term edoxaban treatment for low body weight cancer patients with isolated distal deep vein thrombosis: a post-hoc subgroup analysis of the ONCO DVT study

Abstract Background Low body weight is known to be a bleeding risk in the anticoagulation treatment. ONCO DVT study revealed that 12-month edoxaban treatment for cancer patients with isolated distal deep vein thrombosis (DVT) reduced a composite outcome of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death compared with 3-month edoxaban treatment. However, the efficacy and safety of long-term edoxaban treatment for cancer patients with low body weight is unclear. Purpose In this subgroup analysis, we assessed the efficacy and safety of 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT. Methods We conducted a post-hoc subgroup analysis of the ONCO DVT study in the low body weight patients. ONCO DVT study was a multicenter, open-label, adjudicator-blinded, randomized clinical trial. Cancer patients with isolated distal DVT were assigned to 12-month or 3-month edoxaban treatment. The primary endpoint was a composite outcome of a symptomatic recurrent VTE or VTE-related death at 12 months. The major secondary endpoint was major bleeding at 12 months. We enrolled patients who met low body weight defined in Japanese Version of High Bleeding Risk criteria (&amp;lt;55 kg for men, &amp;lt;50 kg for women) and evaluated the efficacy and safety of 12-month edoxaban treatment using logistic regression models and log-rank test. Results Among 601 patients in the intention-to-treat population of ONCO DVT study, 322 patients (53.6%) met low body weight: 151 patients were in 12-month edoxaban group and 171 patients were in 3-month edoxaban group. The body weight was similar between two group (47.1±5.2 kg in 12-month edoxaban group vs. 46.9±5.4 kg in 3-month edoxaban group; P=0.77). All of them used a lower dose edoxaban (30 mg once daily) following the dose reduction criteria. 12-month edoxaban group had lower rates of the primary endpoint compared with 3-month edoxaban group (2 patients (1.3%) vs. 10 patients (5.8%); Odds ratio 0.22 [95% CI, 0.05–1.00]; Log-rank P=0.036). There was no significant difference in the major secondary endpoint of major bleeding (12 patients (7.9%) in 12-month edoxaban group vs. 16 patients (9.4%) in 3-month edoxaban group; Odds ratio 0.83 [95% CI, 0.38–1.83]; Log-rank P=0.65). All clinically relevant bleeding events occurred in 22 patients (14.6%) in 12-month edoxaban group and in 27 patients (15.8%) in 3-month edoxaban group (Odds ratio 1.40 [0.90–2.19]; Log rank P=0.13), resulting in the comparable risk of bleeding in the 12-month edoxaban group. Conclusions Our study suggests that 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT prevents recurrent VTE or VTE-related death without increasing the risk of bleeding compared to 3-month edoxaban treatment.primary endpointsecondary endpoint

Bleeding and Thrombotic Events in Hemodialysis Patients with Atrial Fibrillation on Anticoagulation and Antiplatelet Therapy: A 24-Month Cohort Study

Background and Objectives: Patients undergoing chronic hemodialysis (HD) are predisposed to both thrombotic and bleeding complications due to the complex interplay of end-stage renal disease (ESRD), cardiovascular comorbidities, and the routine use of anticoagulant and antiplatelet therapies. This study aimed to investigate the incidence of bleeding and thrombotic events in chronic HD patients receiving anticoagulant and antiplatelet therapy, with a specific focus on those with atrial fibrillation (AF). Materials and Methods: A total of 224 patients, with 43 (19%) of them diagnosed with AF, were included in this single-center, observational cohort study conducted over 24 months. The cohort was divided into three groups: patients without anticoagulation, those on warfarin monotherapy, and those on combined warfarin and aspirin therapy. Bleeding events were classified as major, clinically relevant non-major bleeding (CRNMB), or minor bleeding, while thrombotic events included ischemic stroke, myocardial infarction, pulmonary embolism, and arteriovenous fistula thrombosis. Results: Overall, 35.7% of patients experienced a bleeding event, with major bleeding occurring in 9.4%. Patients with AF had significantly higher rates of major bleeding (18.6%) compared to those without AF (7.18%; p = 0.043), especially in the combined therapy group. Mortality due to bleeding was also higher in AF patients (14%). In contrast, thrombotic events occurred in 26.8% of patients, with AF patients experiencing significantly more events (48.8%) compared to non-AF patients (21.5%; p = 0.0006). The hazard ratio (HR) for major bleeding in patients on combined warfarin and aspirin therapy was 2.56 (p = 0.016), while the HR for thrombotic events was 2.34 (p = 0.0202). Conclusions: These findings highlight the increased risks of both bleeding and thrombosis in chronic HD patients with AF, particularly those on combined anticoagulation and antiplatelet therapy.

Patients treated with vitamin K oral anticoagulants in family practice: a new approach to bleeding risk assessment. An ancillary study by the CACAO prospective general practice cohort.

The ability of bleeding risk scores to predict major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) remains a topic of contention, particularly in nonselected patients in family practice. In addition, the capacity to predict bleeding risk using simple variables has yet to be established. The main objective was to confirm that severe anemia was the most predictive factor for the estimation of bleeding risk in patients treated with vitamin K antagonists (VKAs). Secondary objectives were to test the capacity of different bleeding scores to detect high-risk patients. Subsequently, the impact of functional decline on bleeding incidence was explored. The CACAO study was a multicenter prospective cohort study of patients who, due to nonvalvular atrial fibrillation (NVAF) and/or venous thromboembolism (VTE), had been prescribed an oral anticoagulant by their general practitioner (GP) as a prophylactic measure. Patient characteristics were collected at the time of inclusion by GPs, who then monitored them in accordance with standard practice for one year. MB and CRNMB were the main outcomes for one year. By applying this approach, a total of 13 scores were analyzed. Aaemia was found to be strongly associated with MB (HR: 2.77, 95% CI: 1.2-6.36), with a particularly pronounced association observed in cases of severe anemia (HR: 12.9, 95% CI: 2.76-60.35). Twelve out of 27 MB cases were not identified by at least half of the scores. By contrast, functional decline was identified as a novel factor associated with MB (HR: 2.45, 95% CI: 1.13-5.31). Preexisting anemia is a major prognostic factor associated with the occurrence of bleeding. It seems relevant to suggest that functional decline should be considered by GPs when assessing bleeding risk.