Increased Risk Of Bleeding Research Articles

A Pilot Study on the Replacement of Fibrinogen with Fibrinogen Concentrates During Therapeutic Plasma Exchange with Mild to Moderate Bleeding Risk—A Comparison with Fresh Frozen Plasma and Albumin Replacement

Background: Therapeutic plasma exchange (TPE) removes coagulation factors and leads to depletion coagulopathy. The aim of the study was to compare hemostasis between TPE procedures without coagulation factor replacement (electrolyte group), the partial replacement of fibrinogen with fibrinogen concentrates (fibrinogen group) and partial coagulation factors replacement with fresh frozen plasma (partial FFP group). Methods: A total of 73 TPE procedures in patients with fibrinogen levels 1–2 g/L were divided into three study groups depending on clinically estimated bleeding risk. Standard coagulation and ROTEM® tests were performed before and after TPE. Results: Fibrinogen levels before TPE (p = 0.88) and after TPE (p = 0.33) were comparable between the fibrinogen and partial FFP groups. INR and ROTEM® parameters reflected moderately worse hemostasis after TPE with fibrinogen-only replacement compared to partial FFP replacement, which could result in increased bleeding risk. In the electrolyte group, most laboratory tests confirmed the most deranged hemostasis after TPE, as compared to fibrinogen or partial FFP replacement. A mild allergic reaction to FFP infusion was noted during one TPE. No clinically significant bleeding occurred in any of the study groups. Conclusions: Fibrinogen concentrate supplementation and partial FFP replacement can both maintain fibrinogen levels > 1 g/L after TPE, but modest differences in classical coagulation tests and bedside ROTEM® tests favor FFP replacement (NCT03801135).

Bipolar radiofrequency track cautery during abdominal biopsies: teaching points and lessons learned.

Abdominal percutaneous needle biopsies are commonly performed minimally invasive procedures to obtain tissue samples for histopathological diagnosis. Severe post-biopsy bleeding is uncommon but can be associated with prolonged hospitalization, additional interventions, morbidity, and death. Many factors may increase bleeding risk and various peri-procedural and intra-procedural strategies may minimize bleeding risk. Bipolar radiofrequency track cautery is one method that may reduce the risk of post-biopsy bleeding or tumor seeding. This paper offers an illustrative case-based review of teaching points and lessons learned in our experience using a commercially available bipolar radiofrequency track cautery device during percutaneous image-guided abdominal biopsies.

Intraoperative Epoprostenol in Type II Heparin-Induced Thrombocytopenia During Left-Ventricular Assist Device Implantation: A Case Series and Review of Literature.

Type II heparin-induced thrombocytopenia and thrombosis (type II HITT) is a rare but serious complication in patients receiving heparin for anticoagulation. In type II HITT, an immune-mediated reaction against platelet factor four-heparin complexes results in thrombocytopenia and an elevated risk of thrombosis. This poses significant challenges for patients with advanced heart failure requiring urgent left-ventricular assist device (LVAD) implantation. The use of direct thrombin inhibitors, the typical alternative to heparin, is associated with increased bleeding risk and lacks a reversal agent, limiting their use in cardiac surgery. We present two cases of intraoperative epoprostenol to facilitate implantation of a durable LVAD in type II HITT, of which one case underwent preoperative plasmapheresis and intravenous immunoglobulin (IVIG) therapy. Epoprostenol, a prostacyclin analog, was used intraoperatively during LVAD implantation to inhibit platelet activation and allowed for the safe administration of heparin during cardiopulmonary bypass. Both patients underwent successful LVAD implantation without thrombotic or major bleeding complications. These cases highlight the potential of using intraoperative epoprostenol in conjunction with preoperative plasma exchange (PLEX) and IVIG to mitigate the risks associated with heparin use in patients with type II HITT, offering an alternative approach for this high-risk group requiring urgent cardiac surgery.

Extended Treatment of Venous Thromboembolism with Reduced- Vs Full-Dose Direct Oral Anticoagulants in Patients at High Risk of Recurrence

BACKGROUNDVenous thromboembolism is a common, potentially fatal disease. Beyond the first 3 months of anticoagulation treatment, extending anticoagulation up to 12 or 24 months reduces the risk of recurrence by at least 80% in patients at high risk of recurrence, but this benefit is lost after stopping anticoagulation. Consequently, guidelines recommend indefinite anticoagulation in such patients. However, continued anticoagulation exposes patients to a linear increase in bleeding risk, which is expected to ultimately exceed the risk of recurrent venous thromboembolism after stopping anticoagulation.To address this issue, lower-dose anticoagulation may reduce bleeding risk while maintaining similar efficacy in preventing recurrent venous thromboembolism. In the EINSTEIN-CHOICE and AMPLIFY-EXT studies, extended reduced-dose anticoagulation appeared as effective as and safer than full-dose. However, with the inclusion of a placebo or aspirin control group, both studies enrolled patients in whom physicians were uncertain about continuing anticoagulation. Consequently, robust evidence for recommending reduced- over full-dose anticoagulation in patients with a strong indication for extended treatment is lacking. METHODSThe Reduced Dose Versus Full-Dose of Direct Oral Anticoagulant After Unprovoked Venous Thromboembolism (RENOVE) trial (ClinicalTrials.gov Identifier: NCT03285438) is an academic, multicenter, prospective, randomized, open, blinded end-point (PROBE) trial. In this study, we compared, using hierarchical sequential testing, extended anticoagulation with reduced-dose versus full-dose direct oral anticoagulants in patients with venous thromboembolism at high risk of recurrence initially treated for 6 to 24 months. Primary outcome was recurrent symptomatic venous thromboembolism (noninferiority hypothesis). Key secondary outcomes were clinically relevant bleeding and the composite of recurrent venous thromboembolism and clinically relevant bleeding (superiority hypotheses). Critical events were adjudicated by an independent committee blinded to treatment allocation. RESULTSDuring the 36-month median follow-up, recurrent venous thromboembolism occurred in 19 of 1383 patients in the reduced-dose group versus 15 of 1385 patients in the full-dose group (5-year cumulative incidence 2.2%; 95% confidence interval [CI], 1.1 to 3.3 versus 1.8%; 95% CI, 0.8 to 2.7; hazard ratio, 1.32; 95% CI, 0.67 to 2.60; P=0.23 for noninferiority). Clinically relevant bleeding occurred in 96 and 154 patients in the reduced- and full-dose groups, respectively (5-year cumulative incidence 9.9%; 95% CI, 7.7 to 12.1 versus 15.2%; 95% CI, 12.8 to 17.6). The composite outcome occurred in 113 and 166 patients in the reduced- and full dose groups, respectively (5-year cumulative incidence 11.8%; 95% CI, 9.4 to 14.3 versus 16.5%; 95% CI, 14.0 to 19.0). All-cause death occurred in 35 (4.3%) and 54 (6.1%) patients in the reduced- and full-dose groups, respectively. CONCLUSIONSIn patients with venous thromboembolism who need extended anticoagulation, the noninferiority of a reduced-dose versus a full-dose of direct anticoagulants to prevent recurrent venous thromboembolism could not be proven. In the reduced-dose group, clinically relevant bleeding and the composite of recurrent venous thromboembolism or clinically relevant bleeding were lower than in the full-dose group and did not appear to be offset by an increased risk of death or arterial thromboembolic events.

Practical guide to the diagnosis and management of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune reaction to heparin associated with thrombocytopenia, thrombotic risk, and a high risk of morbidity and mortality. Given the frequent use of heparin and the common occurrence of thrombocytopenia in hospitalized patients, the diagnosis and management of HIT is a recurrent challenge in everyday inpatient care. This article presents practical guidance and tools to support the individual clinician providing evidence-based care to patients with suspected or confirmed HIT. The optimal diagnostic evaluation requires the stepwise use of risk-stratification tools and laboratory assays. Management requires the selection and use of nonheparin anticoagulation in these complex patients with both increased thrombotic risk and possible concurrent increased bleeding risk due to thrombocytopenia. Each step in the diagnostic and management process has important nuances and complexities, many of which vary based on patient characteristics and institutional resources. Given the many challenges of HIT care, truly practical management is best achieved when tools are implemented to support the delivery of consistent, high quality, and cost-effective care across health systems.

MANAGEMENT OF ANTICOAGULATION IN ATRIAL FIBRILLATION: MINIMIZING DRUG INTERACTIONS WITH DOACS

Introduction: Atrial fibrillation (AF) is a common cardiac arrhythmia that elevates the risk of thromboembolic events, necessitating effective anticoagulation strategies. Direct oral anticoagulants (DOACs) have become the preferred choice due to their safety profiles; however, drug interactions can compromise their efficacy and safety. Objective: This study aims to assess the impact of drug interactions on the efficacy and safety of DOACs in patients with AF. Method: A literature review was conducted using databases such as the Virtual Health Library, LILACS Plus, and Medline, focusing on articles published from 2019 to 2024. Inclusion criteria emphasized studies related to drug interactions involving DOACs and AF, resulting in the selection of 13 relevant articles. Results: The analysis revealed a significant prevalence of drug interactions among patients treated with DOACs. Co-prescription with CYP3A4 inhibitors and P-glycoprotein modulators was linked to increased bleeding risks. Factors such as age, renal function, and the presence of comorbidities were crucial in determining appropriate dosing and the risk of adverse events. Conclusion: Careful management of AF patients on DOACs is vital to mitigate risks associated with drug interactions. Personalized treatment approaches that consider individual clinical profiles and ongoing education for healthcare providers are essential to optimize anticoagulation therapy.

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 4127931: Chronic Steroid Use is Associated with Increased Readmission Rates in Patients Admitted with Acute Coronary Syndromes

Introduction: Acute coronary syndrome (ACS) is associated with significant morbidity and mortality. Management of ACS includes percutaneous coronary intervention (PCI) and requires the use of antithrombotic therapy, which increases bleeding risk. Chronic steroid use (CSU) is common for many diseases and is also associated with bleeding risk and impaired wound healing. However, data on outcomes of patients with CSU and AMI are sparse. Methods: Patients admitted for ACS and managed with PCI from 2014 to 2020 with and without CSU were identified using the National Readmissions Database (NRD). In-hospital outcomes include death, arterial thrombosis (composite of ischemic stroke and arterial thromboembolism), and major bleeding (composite of gastrointestinal, intracranial, or post-procedure bleeding or transfusion). Ninety-day readmission outcomes were cardiovascular (CV)-related, bleeding-related and all-cause. Multivariable logistic or Cox proportional hazards were utilized. Results: A total of 1,087,357 patients with ACS were included, of whom, 9,864 (0.9%) had CSU. After multivariable adjustment, there was no significant difference in in-hospital mortality (3.1% vs 3.2%; OR 1.09, 95% CI 0.93-1.26) or risk of arterial thrombosis (3.3% vs 2.8%; OR 0.91, 95% CI 0.81-1.02) between patients with and without CSU. CSU was associated with an increased risk of major bleeding events (8.3% vs 6.0%; OR 1.15, 95% CI 1.06-1.25). CSU was associated with a higher risk of CV-related (10.7% vs 7.5%; HR 1.10, 95% CI 1.02-1.18), bleeding-related (2.3% vs 1.2%; HR 1.28, 95% CI 1.09-1.51), and all-cause 90-day readmissions (23.9% vs 14.9%; HR 1.28, 95% CI, 1.22-1.34). Conclusion: Among patients admitted with ACS who underwent PCI, CSU was associated with increased risk of bleeding during index hospitalization and readmissions for bleeding. Furthermore, CSU was associated with increased risk of 90-day CV and all-cause readmission. Further studies are needed to better characterize this risk.

Abstract 4134630: Focal Delivery of Antiplatelet Therapy to Prevent Post-Stent Bleeding in High-Risk Patients

Background: Over 3 million percutaneous coronary interventions (PCI) are performed yearly to treat coronary artery stenosis. Stent thrombosis is a catastrophic complication associated with high morbidity and mortality, and its prevention requires the use of prolonged dual antiplatelet therapy (DAPT), which increases bleeding risk. Within the first 30 days after PCI, the mortality of DAPT-associated major bleeding is on par with recurrent myocardial infarction. Research question: No stent system that provides focal antiplatelet activity to prevent stent thrombosis exists, eliminating the need for systemic DAPT and subsequent bleeding risk. Aim: To address this unmet need, we have developed such a stent, termed “the ticagrelor coated stent” (TCS). Methods: Self-assembled monolayers (SAMs) of 12-aminododecylphosphonic acid (ADPA) were formed on cobalt-chromium stents. The amine tail group of ADPA was used to link the ticagrelor molecule through a Mitsunobu reaction and confirmed via infrared spectroscopy. Coating uniformity was validated via atomic force microscopy. In an ex-vivo porcine arterio-venous fistula model, the ticagrelor-coated stents (TCS) were placed in alternating series adjacent to uncoated bare metal stents (BMS). Similarly, TCS and everolimus-eluting stents were placed in the porcine left circumflex arteries for acute (7 days) and chronic (35 days) studies. Results: ( Figure 1 ): Grossly, no thrombus was seen on the TCS compared to the BMS. Platelet and micro-thrombi adherence were significantly reduced on TCS. Notably, inflammation, measured by neutrophil and monocyte adherence, was also reduced by approximately 10-fold on the TCS vs the BMS. Angiography, optical coherence tomography (OCT), and histopathology results show the TCS widely patent without systemic DAPT. Conclusion: These findings show that TCS prevents stent thrombosis through focal anti-platelet action and may reduce the bleeding risk associated with prolonged use of systemic DAPT. Long-term safety and efficacy studies are underway.

Early antiplatelet therapy after intravenous thrombolysis for acute ischemic stroke: a systematic review and meta-analysis.

Early neurological deterioration (END) and recurrence of vessel blockage frequently complicate intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). Several studies have indicated the potential effectiveness of the early initiation (within < 24 h) of antiplatelet therapy (APT) after IVT. However, conflicting results have been reported by other studies. We aimed to offer a thorough overview of the current literature through a systematic review and meta-analysis. Our systematic review and meta-analysis were prospectively registered on PROSPERO (ID: CRD42023488173) following the PRISMA guidelines. We systematically searched Web of Science, SCOPUS, PubMed, and Cochrane Library until May 5, 2024. Rayyan. ai facilitated the screening process. The R statistical programming language was used to calculate the odds ratios and conduct a meta-analysis. Our primary outcomes were excellent functional recovery (modified Rankin Scale score 0-1), symptomatic intracranial hemorrhage (sICH), and mortality. Eight studies involving 2,134 participants were included in the meta-analysis. Early APT showed statistically significant increased odds of excellent functional recovery (mRS 0-1) compared to the standard APT group (OR, 1.81; [95% CI: 1.10, 2.98], p = 0.02). However, we found no differences between the early and standard APT groups regarding sICH (OR, 1.74; [95% CI: 0.91, 3.33], p = 0.10) and mortality (OR, 0.88; [95% CI: 0.62, 1.24]; p = 0.47). Early APT within 24 h of IVT in stroke patients is safe, with no increase in bleeding risk, and has a positive effect on excellent functional recovery. However, there was a statistically insignificant trend of increased sICH with early APT, and the current evidence is based on highly heterogeneous studies. Further large-scale RCTs are warranted.

Risk of death, thromboembolic events, and bleeding in elderly patients with Atrial Fibrillation and Clinical Complexity who are not taking oral anticoagulation

Abstract Background Patients with Atrial Fibrillation (AF) often exhibit Clinical Complexity (CC), defined as ≥2 features, i.e. patients aged ≥75 years plus a body mass index (BMI) &amp;lt; 23/kg/m2 and/or bleeding history and/or chronic kidney disease. No data are available about the clinical course of patients with Atrial Fibrillation (AF) and CC who are not taking oral anticoagulation (OAC). Purpose To assess the risk of thrombotic and hemorrhagic events in patients with Atrial Fibrillation (AF) and CC who are not taking OAC. Methods Retrospective study with a health care research network (TriNetX). Based on the ICD-10-CM codes entered between 2011-2022 from 85 health care organizations mainly located in the United States, AF patients ≥75 years with CC were categorized into two groups based on the use of OAC during the last year before the study period. The primary outcomes were the one-year risk of death, major cardiovascular events ([MACE]: heart failure, stroke, and myocardial infarction), and major bleeding (central nervous system, gastrointestinal, internal bleeding, and hypovolemic shock). Secondary outcomes were each component of the primary outcome and catheter ablation. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% CIs following propensity score matching 1:1. Results Overall, we identified 271,402 AF CC patients not on OAC (80.1±6.8 years, 46.5% females) and 87,101 AF CC patients on OAC (79.8±6.5 years, 47.6% females). Before PSM, AF CC patients not on OAC showed no significant differences in cardiovascular and bleeding risk factors but were less treated with pharmacological treatment than AF CC patients on OAC. After PSM, no significant differences were found between the two groups, but AF CC not on OAC were at higher risk of all-cause death (HR 1.54, 95%CI 1.50-1.57), MACE (HR 1.13, 95%CI 1.11-1.16), and major bleeding (HR 1.34, 95%CI 1.31-1.38), when compared to AF CC on OAC. AF CC patients not on OAC were associated with a higher risk of each component of the primary outcome and with a lower use of catheter ablation procedures (HR 0.48, 95%CI 0.43-0.54) (Table 1). The risk of the composite outcomes was the highest in those with all the three CC components. A progressive increase in OAC prescription was observed during the follow-up period, with increasing of NOACs and lower use of warfarin being observed. There was a clear temporal relationship between increasing OAC prescription and incidence of bleeding in CC patients (Figure 1) Conclusions AF CC patients not on OAC have a high risk of all-cause death, thrombotic and hemorrhagic events. Over time, increasing NOAC use was associated with more bleeding in CC patients. New antithrombotic approaches aimed at reducing thrombotic risk without increasing bleeding risk are needed in these patients.Figure 1 OAC new prescriptions

Low rates of haemorrhagic stroke, not increased by age, renal/hepatic impairment, concomitant anti-platelet use and high CHA2DS2-VASc scores, in the 4-year follow-up of ETNA-AF-Europe

Abstract Background Balancing the risks of stroke and bleeding is necessary to optimise oral anticoagulation use in clinical practice. Concerns remain over the increased bleeding risk in patients receiving NOACs, and long-term safety data in this population are limited. Purpose To report annualised rates of haemorrhagic stroke in various sub-populations of patients with atrial fibrillation (AF) treated with edoxaban during the 4-year follow-up of ETNA-AF-Europe. Methods ETNA-AF-Europe, a post-authorisation, observational study conducted across 776 sites from 10 European countries, assessed the risks and benefits of edoxaban use in patients with AF. Here, we present the annualised event rates of haemorrhagic stroke during the 4-year follow-up, that occurred overall (on-/off-edoxaban) and on-edoxaban, including sub-populations stratified by age, renal impairment, hepatic impairment, chronic concomitant antiplatelet use and CHA2DS2-VASc score. Patient characteristics were collected at baseline and annualised event rates were reported for outcomes. Results A total of 13,164 patients were included in the full analysis set. Baseline characteristics are reported in Table 1. The overall and on-edoxaban annualised haemorrhagic stroke rates were low (number of events, % [95% confidence interval]: 36, 0.1 [0.05;0.11] and 31, 0.1 [0.05;0.10] respectively). The overall haemorrhagic stroke rates remained low in subgroups stratified by age (&amp;lt;65 years: 4, 0.1 [0.00;0.11]; ≥65–75 years: 13, 0.1 [0.04;0.13]; ≥75 years: 19, 0.1 [0.05;0.12]), renal impairment (yes: 23, 0.1 [0.05;0.13]; no: 12, 0.1 [0.03;0.11]), hepatic impairment (yes: 0, 0.0 [0.00;0.00]; no: 35, 0.1 [0.06;0.11]), concomitant antiplatelet use (yes: 2, 0.1 [0.00;0.16]; no: 34, 0.1 [0.05;0.11]) and CHA2DS2-VASc score (low [0–1]: 0, 0.0 [0.00;0.00]; moderate [2–4]: 28, 0.1 [0.06;0.12]; high [&amp;gt;4]: 7, 0.1 [0.03;0.18]) (Figure). Likewise, on-edoxaban haemorrhagic stroke rates were low irrespective of age (&amp;lt;65 years: 3, &amp;lt;0.1 [0.00;0.010; ≥65–75 years: 12, 0.1 [0.04;0.13]; ≥75 years: 16, 0.1 [0.04;0.12]); renal impairment (yes: 20, 0.1 [0.05;0.12]; no: 10, 0.1 [0.02;0.10]); hepatic impairment (yes: 0, 0.0 [0.00;0.00]; no: 30, 0.1 [0.05;0.11]); chronic concomitant antiplatelet use (yes: 2, 0.1 [0.00;0.18; no: 29, 0.1[0.05;0.10]) or CHA2DS2-VASc score (low [0–1]: 0, 0.0 [0.00;0.00]; moderate [2–4]: 25, 0.1 [0.05;0.12]; High [&amp;gt;4]: 6, 0.1 [0.02;0.17]) (Figure). Conclusions The overall and on-edoxaban annualised rates of haemorrhagic stroke were low and were not increased by non-modifiable risk factors such as age, renal/hepatic impairment, concomitant antiplatelet use and high CHA2DS2-VASc scores during the 4-year follow-up. The overall annualised rates on-edoxaban in ETNA-AF-Europe registry are quite comparable with incidence rates reported in the literature in age-stratified populations (incidence/100 person-years: 55-64 years: 0.06 [0.04-0.07]; 65-74 years: 0.1 [0.09-0.1]; 75-84 years 0.2 [0.1-0.2]).Baseline Characteristics

Preclinical characterisation and first-in-human results on the tolerability and pharmacodynamic effect of REGN9933, a monoclonal antibody targeting the factor XI/activated factor XI apple 2 domain

Abstract Background/Introduction Standard-of-care anticoagulants are associated with increased bleeding risk. Genetic/pharmacological data suggest coagulation factor XI (FXI) inhibition can prevent thrombosis with minimal increased bleeding risk. We present preclinical and first-in-human (FIH) data on REGN9933, a FXI-binding monoclonal Ab. Purpose To characterise REGN9933 epitope binding sites, affinities for FXI and activated FXI (FXIa), and effect on high molecular weight kininogen (HMWK)’s interaction with FXI. Also, to assess safety, tolerability and pharmacodynamics in healthy human participants (pts). Methods Epitope binding sites mapped with cryogenic electron microscopy, binding affinities determined with plasmon resonance techniques, effect on thrombin generation assessed with a thrombin generation assay, and impact on HMWK:FXI interaction analysed using ELISAs. In the FIH, Ph 1, randomised, double-blind, single-centre study, pts received a single dose of REGN9933 intravenously (IV; 3–300 mg) or subcutaneously (SC; 100 mg &amp; 300 mg), or placebo (PBO). Primary endpoint: incidence and severity of treatment-emergent AEs (TEAEs). Other endpoints: effect of REGN9933 on activated partial thromboplastin time (aPTT) and prothrombin time (PT) to assess intrinsic and extrinsic pathway-triggered coagulation, respectively; and FXI activity. Results REGN9933 was found to bind the FXI apple 2 domain, with subnanomolar binding affinities for FXI and FXIa at 37°C, resulting in reduced thrombin generation from the intrinsic (not extrinsic) pathway. REGN9933 competed with HMWK for FXI binding in a dose-related manner. In the Ph 1 study, 56 pts received REGN9933 (IV, n=30; SC, n=12) or PBO (n=14); 42.9% and 21.4% had ≥1 TEAE, respectively (most common with REGN9933: headache, 12%; oropharyngeal pain, 5%). No serious/severe TEAEs, or TEAEs of special interest (inc. moderate/severe bleeding) reported. Laboratory tests revealed no clinically meaningful differences in the number/type of treatment-emergent potentially clinically significant values with REGN9933 vs PBO. REGN9933 resulted in dose-dependent prolongation of aPTT; aPTT mean fold change from baseline was highest with IV 300 mg after 8 hrs (2.7) and remained &amp;gt;2 for 36 days (Fig 1). There was no detectable effect on PT or clinically meaningful effect on bleeding time. REGN9933 supressed FXI activity in a dose-dependent manner, with suppression to approx. the lower limit of assay quantification (5%) with IV ≥30 mg (Fig 2). Conclusion(s) REGN9933 binds the FXI apple 2 domain and inhibits HMWK:FXI interaction, preventing intrinsic pathway-triggered FXI activation. FIH data showed dose-dependent inhibition of the intrinsic coagulation pathway by REGN9933, without affecting the extrinsic or common pathways. Pharmacodynamic and safety findings support continued development of REGN9933 as an anticoagulant that may carry less bleeding risk than currently approved agents.

An analysis of the virtual cardio-oncology research initiative (VICORI) resource: bleeding risk among cancer patients beyond 1-year post-myocardial infarction

Abstract Introduction Cardiovascular disease (CVD) and cancer are common causes of morbidity and mortality. Advancements in treatment strategies for both diseases have resulted in a growing population who live with both conditions. Myocardial infarction (MI) represents approximately 20% of all CVD admissions in cancer patients and 10% of patients who present with an acute MI have cancer. Managing MI patients with cancer require careful balancing of their ischaemic and bleeding risks. While dual antiplatelet therapy (DAPT) increases a patient’s bleeding risk, cancer patients are at further increased risk due to a range of direct and indirect cancer effects. While our recent studies demonstrated an increased bleeding risk in cancer patients in the 1st year after MI (the period of intensive APT), it is currently not known if this risk is sustained beyond this period. VICORI is the world’s first whole-country cardio-oncology research platform, linking data from the National Cancer Registration and Analysis Service, National Institute for Cardiovascular Outcomes Research and Hospital Episode Statistics [1]. We investigated the risk of bleeding among MI patients in the 2nd year post-MI, where a large majority of patients would have completed a course of DAPT, stratified by the presence or absence of cancer. Methods In this retrospective observational study, we investigated the risk of bleeding following an MI between 2006-2019, in patients with and without cancer. Cancer was defined as a diagnosis of cancer in the 1-year preceding MI. Patients who lived past the 1st year after MI were followed-up from 12 to 24 months after their MI. We used inverse probability weighting based on propensity scores to produce a balanced cohort of patients with and without cancer. Cox proportional hazard and flexible parametric modelling were used to investigate cancer as a predictor of bleeding. Subgroup analyses were performed on stent status, MI and cancer type. Results Of 506280 patients presenting with MI, 5666 (1.1%) had cancer while 500614 (98.9%) did not. Prostate (n=1377), colorectal (n=1024), lung (n=490), breast (n=448) and bladder (n=334) cancers were among the most common types of cancers. The rate (hazard) of bleeding in MI was higher in patients with cancer in the 2nd year post-MI (HR:1.42, 95%CI 1.29-1.56) compared to those without. From the flexible parametric survival analysis, the risk of bleeding in cancer patients in the 2nd year post-MI was lower compared to the 1st year but remained statistically significant compared to non-cancer patients. Conclusion In this large real-world study, cancer patients have a persistent, increased bleeding risk beyond the 1-year post-MI period, compared to those without cancer, and this risk differed by type of cancer. Further work is needed to identify specific patient characteristics in each patient sub-group which alters one’s ischaemic or bleeding risk so they can be balanced favourably with personalised strategies.

Polygenic risk, aspirin and primary prevention of coronary artery disease.

Recent aspirin primary prevention trials failed to identify a net benefit of aspirin for preventing cardiovascular disease versus the harms of bleeding. This study aimed to investigate whether a high-risk subgroup, individuals with elevated genetic predisposition to coronary artery disease (CAD), might derive more benefit than harm with aspirin, compared to those with lower genetic risk. We performed genetic risk stratification of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial using a CAD polygenic risk score (GPSMult). For 12,031 genotyped participants (5,974 aspirin, 6,057 placebo) overall, we stratified them by GPSMult quintiles (q1-5), then examined risk of CAD (composite of myocardial infarction and coronary heart disease death) and bleeding events using Cox models. During a median 4.6 years of follow-up with randomization to 100 mg/day aspirin versus placebo, 234 (1.9%) participants had CAD and 373 (3.1%) had bleeding events. In the overall cohort, aspirin resulted in higher bleeding risk (adjusted Hazard Ratio [aHR]=1.30 [1.06-1.61], P=0.01) but no significant CAD reduction (aHR=0.84 [0.64-1.09], P=0.19). However, among the highest quintile of polygenic risk (q5, top 20% of the GPSMult distribution), there was a 47% reduction in risk of CAD events with aspirin (aHR=0.53 [0.31-0.90], P=0.02) without increased bleeding risk (aHR=1.05 [0.60-1.82], P=0.88). Interaction between the GPSMult and aspirin was significant for CAD (q5 versus q1, P=0.02) but not bleeding (P=0.80). The balance between net benefit and harm on aspirin in the primary prevention setting shifts favourably in individuals with an elevated genetic predisposition.

Optimal antithrombotic therapy in ischemic stroke patients with non-valvular atrial fibrillation and atherothrombosis: study protocol for a randomized controlled trial.

The addition of antiplatelet therapy to anticoagulant therapy in patients with stroke with non-valvular atrial fibrillation (NVAF) and atherothrombotic disease may increase bleeding risk without reducing recurrent stroke risk. To evaluate the clinical benefits of anticoagulant monotherapy compared to combination therapy with anticoagulants and antiplatelet agents. This is an investigator-initiated prospective multicenter, randomized, open-label, parallel-group clinical trial. Patients with NVAF and atherothrombotic disease who have had a recent ischemic stroke or transient ischemic attack will be eligible to participate in this trial. The primary outcome is a composite of ischemic cardiovascular events, including cardiovascular death, ischemic stroke, myocardial infarction, systemic embolism, ischemic events requiring urgent revascularization, and major bleeding events within 2 years after randomization. This study will enroll 400 patients, 200 receiving anticoagulant monotherapy and 200 receiving combination therapy. This sample size will provide 90% power (one-sided p = 0.025) to detect a risk reduction in outcome events within 2 years, assuming event rates of 13 and 27% for each group, respectively, and a 10% loss to follow-up at a 2.5% significance level with one-sided log-rank tests at an interim analysis and a final analysis. This will be the first study to assess the net clinical benefit of oral anticoagulant monotherapy in ischemic stroke patients with NVAF and atherothrombosis. https://clinicaltrials.gov/study/NCT03062319, NCT03062319; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000029222, UMIN000025392; https://jrct.niph.go.jp/latest-detail/jRCTs051180202, jRCTs051180202.

Effect of mild hypothermia vs normothermia cardiopulmonary bypass on postoperative bleeding in patients undergoing coronary artery bypass grafting: protocol of a multi-center, randomized, controlled trial

BackgroundCoronary artery bypass grafting (CABG) is often performed with hypothermic cardiopulmonary bypass (CPB) to reduce metabolic demands and protect the myocardium. However, hypothermia can increase bleeding risks and other complications.MethodsThis is a prospective, multi-center, randomized controlled trial. From September 2023 to December 2024, a total of 336 eligible patients planning to undergo on-pump CABG will be enrolled. All participants will be randomly divided into mild hypothermia CPB group (target oxygenator arterial outlet blood temperature at 32–33℃) or normothermia CPB group (target oxygenator arterial outlet blood temperature at 35–36℃). The primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2–4. Secondary endpoints are class of UDPB, levels of coagulation and inflammatory factors, in-hospital mortality, perioperative related complications, ICU length of stay, and hospital length of stay.DiscussionThis clinical trial aims to compare the effects of different target temperature during CPB on postoperative bleeding and to explore optimal temperature strategy to provide new clinical evidence.Trial registrationChictr.org.cn: ChiCTR2300075405. The trial was prospectively registered on 4 September 2023.

Impact of thrombocytopenia on bleeding and thrombotic outcomes in adults with cancer-associated splanchnic vein thrombosis

AbstractMalignancy is a risk factor for splanchnic vein thrombosis (SpVT). Data on the natural history of cancer-associated SpVT are limited. This was a single-center, retrospective cohort study of 581 adult patients with cancer and SpVT. We aimed to characterize the impact of thrombocytopenia on major bleeding and progression or recurrence of SpVT within 1 year of an initial cancer-associated SpVT diagnosis. Baseline thrombocytopenia (platelet <100 × 103/μL within 15 days of SpVT diagnosis) was present in 39.5% of patients. A total of 39.2% of patients received therapeutic anticoagulation within 2 weeks of an SpVT diagnosis. The cumulative 1-year incidence of major bleeding was 10.7% (95% confidence interval [CI], 8.2-13.2) and 16.2% (95% CI, 13.2-19.2) for SpVT recurrence/progression. In the multivariable regression analysis, therapeutic anticoagulation was associated with increased major bleeding (adjusted risk ratio [aRR], 1.74; 95% CI, 1.08-2.81) and decreased progression/recurrence of SpVT (aRR, 0.55; 95% CI, 0.35-0.86). Baseline thrombocytopenia was not independently associated with either major bleeding (aRR, 0.76; 95% CI, 0.43-1.34) or progression/recurrence of SpVT (aRR, 1.14; 95% CI, 0.73-1.78). A secondary analysis using inverse probability of treatment weighting with propensity scores for baseline thrombocytopenia corroborated that patients with thrombocytopenia did not have an increased bleeding risk (adjusted hazard ratio [aHR], 0.81; 95% CI, 0.48-1.39). The multivariable analysis in which platelets were treated as a time varying covariate also did not reveal an association with major bleeding (aHR, 0.89; 95% CI, 0.55-1.45). Bleeding and thrombosis progression were frequent in patients with cancer-associated SpVT. Anticoagulation was associated with increased major bleeding and decreased thrombotic progression; thrombocytopenia did not impact the outcomes.

Drug-drug-interactions in patients with atrial fibrillation admitted to the emergency department.

Polypharmacy is a growing concern in healthcare systems. While available data on potential drug-drug interactions (pDDI) from emergency department (ED) patients is derived from heterogenous populations, this study specifically focused on patients with atrial fibrillation (AF). We hypothesized that patients with AF have similar comorbidities, receive similar drugs, and have similar pDDIs. The overarching aim was to highlight frequent pDDIs, providing practical guidance for treating healthcare professionals and consequently reduce the risk of adverse drug reactions. Two hundred patients ≥18years with AF, who received rate- or rhythm-controlling medication at the ED of the University Hospital Vienna, and who were on long-term medication before admission, were eligible. Long-term medication alone, as well as in combination with medication administered at the ED were analyzed for pDDIs using the Lexicomp® Drug interactions database. Within the long-term medication of patients', we identified 664 pDDIs. Drugs administered at the ED increased pDDIs more than 3-fold to 2085. Approximately, every fifth patient received a contraindicated drug combination (on average 0.24 per patient), while 70% received drug combinations for which therapy modifications are recommended (on average 1.59 per patient). The most frequently involved drugs included amiodarone, propofol, bisoprolol, enoxaparin, and acetylsalicylic acid. Increased risk of bleeding, QTc prolongation, and myopathy were among the most relevant potential consequences of these interactions. In conclusion, an optimization of medication would be advisable in almost every AF patient. Treating healthcare professionals should be cautious of drugs that increase bleeding risk, prolong QTc, or bear a risk for myopathy.

Anticoagulation therapy for complex patient populations

Managing anticoagulant therapy in patients with comorbidities such as kidney disease, liver disease, obesity, thrombophilia and increased bleeding risk with thrombocytopenia presents unique challenges. Renal impairment affects drug clearance. Liver disease alters coagulation and drug metabolism. Obesity affects drug distribution and dosing. Increased bleeding risk with thrombocytopenia often requires different dosing. This review finds that tailored therapeutic strategies are essential to balance the risks and benefits in these complex patient populations.