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[This corrects the article DOI: 10.1371/journal.pone.0291628.].

Current guidelines recommend a combination therapy with aspirin and a parenteral anticoagulant in patients with non-ST-elevation myocardial infarction (NSTEMI) prior to invasive assessment. However, these recommendations are based on clinical trials conducted at a time when NSTEMI patients were not routinely assessed invasively. Today, nearly all NSTEMI patients in Denmark undergo coronary angiography within 72 hours, and the necessity of routine anticoagulation remains uncertain. The FOXY trial aims to assess whether aspirin alone is noninferior to a combination therapy with aspirin and fondaparinux in preventing death, recurrent myocardial infarction, and refractory ischemia while lowering the risk of bleeding. The FOXY trial is a multicenter, open-label, noninferiority, randomized controlled trial enrolling 5,076 patients with NSTEMI. Participants will be randomized 1:1 to receive either aspirin alone or aspirin plus fondaparinux before invasive evaluation. The primary endpoint is a composite of 30-day mortality, recurrent MI, and refractory ischemia. Secondary outcomes include long-term ischemic events, cerebrovascular accidents, left ventricular function, hospital length of stay, and major bleeding. The study will be conducted across multiple cardiology centers, with the first patients enrolled in spring 2025. The FOXY trial is the first study to investigate parenteral anticoagulant use in NSTEMI patients undergoing routine invasive management. By comparing aspirin alone to combination therapy, the study seeks to challenge current guideline recommendations and potentially simplify NSTEMI treatment. If noninferiority is demonstrated, the trial may support a shift toward a safer and more cost-effective management of NSTEMI patients. This could lead to a revision of clinical guidelines, minimizing bleeding risk, improving patient safety, and reducing healthcare costs. EU Trial Number: 2024-517229-18-00; ClinicalTrials.gov identifier: NCT06710184. [Display omitted]

In intermediate- and high-risk non-ST elevated acute coronary syndrome (NSTE-ACS) patients, a routine invasive approach is recommended. The timing of coronary angiography remains controversial. To assess whether an immediate (<3 hours) invasive treatment strategy would reduce infarct size and is safe, compared with an early strategy (12-24 hours), for patients admitted with NSTE-ACS while preferably treated with ticagrelor. In this single-center, prospective, randomized trial an immediate or early invasive strategy was randomly assigned to patients with NSTE-ACS. At admission, the patients were preferably treated with a combination of aspirin, ticagrelor and fondaparinux. The primary endpoint was the infarct size as measured by area under the curve (AUC) of CK-MB in 48 hours. Secondary endpoints were bleeding outcomes and major adverse cardiac events (MACE): composite of all-cause death, MI and unplanned revascularization. Interim analysis showed futility regarding the primary endpoint and trial inclusion was terminated. In total 249 patients (71% of planned) were included. The primary endpoint of in-hospital infarct size was a median AUC of CK-MB 186.2 ng/mL in the immediate group (IQR 112-618) and 201.3 ng/mL in the early group (IQR 119-479). Clinical follow-up was 1-year. The MACE-rate was 10% in the immediate and 10% in the early group (hazard ratio [HR] 1.13, 95% CI: 0.52-2.49). In NSTE-ACS patients randomized to either an immediate or an early-invasive strategy the observed median difference in the primary endpoint was about half the magnitude of the expected difference. The trial was terminated early for futility after 71% of the projected enrollment had been randomized into the trial.

Background The prevalence of conditions necessitating anticoagulation therapy among pregnant women has been steadily increasing. Although low-molecular-weight heparin (LMWH) is commonly used, several studies have investigated the use of fondaparinux in pregnant women. However, the safety profile of fondaparinux in this population remains to be fully elucidated. Methods A comprehensive literature search across ten databases was conducted in September 2024. This meta-analysis was conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for systematic reviews of observational studies. Dichotomous data from eligible studies were combined using the Mantel‒Haenszel model. Standard mean differences with 95% confidence intervals were assessed. Heterogeneity was evaluated using I 2 statistics and the Cochran Q test, and the quality of evidence was appraised using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results Nine studies met the inclusion criteria. Based on the GRADE approach, the quality of evidence ranged from very low to low. Fondaparinux did not increase the incidence of bleeding-related adverse events (vaginal bleeding: OR = 0.99, 95% CI 0.43–2.30, P  = 0.98; postpartum haemorrhage: OR = 0.35, 95% CI 0.07–1.73, P  = 0.20). Fondaparinux was associated with reduced risks of hepatic transaminase elevation (OR = 0.20, 95% CI 0.08–0.49, P  < 0.01), gastrointestinal reactions, allergies, and injection site skin reactions (OR = 0.19, 95% CI 0.09–0.41, P  < 0.01). Conclusion The findings of this systematic review and meta-analysis suggest that the use of fondaparinux among pregnant women has certain advantages. However, these conclusions warrant further validation through high-quality, large-scale studies conducted in multiple countries. (PROSPERO–CRD42024591579).

Critically ill patients often need continuous renal replacement therapy (CRRT). This process can remove particles as large as 10 kDa, including medications such as fondaparinux. In this study, we investigated whether patients who received prophylactic doses of fondaparinux and are treated with continuous veno-venous hemodiafiltration (CVVHDF) would achieve prophylactic levels of anti-Xa factor activity. In this observational study, we compared two groups of patients: 20 individuals who underwent CVVHDF and 20 individuals who did not undergo CVVHDF. Each patient received a prophylactic subcutaneous dose of 2.5 mg daily of fondaparinux. Anti-Xa factor activity was measured on the third day of treatment with fondaparinux. Blood samples were collected at four time points: immediately before the administration of fondaparinux and then 3, 6, and 9 h later. Anti-Xa factor activity levels were below the recommended range in the control group and in most CVVHDF patients but significantly increased after fondaparinux administration. Interestingly, individuals who underwent CVVHDF had greater anti-Xa factor activity than control patients did at several time points. In critically ill patients treated with prophylactic fondaparinux, CVVHDF appears to have a statistically significant but small effect on Xa factor activity. However, the clinical significance of this finding is unknown. Clinical Trial Registration: The study was prospectively registered at ClinialTrials.gov (NCT04671160).

Glycosaminoglycans (GAGs) are key ligands for proteins involved in physiological and pathological processes. Specific GAG-binding patterns are rarely identified, with the heparin pentasaccharide as an Antithrombin-III ligand being the best characterized. Generating glycan-specific antibodies is difficult due to their size, pattern dispersion, and flexibility. Single-domain variable new antigen receptors (VNAR nanobodies) from nurse sharks are highly soluble, stable, and versatile. Their unique properties suggest advantages over conventional antibodies, particularly for challenging biotherapeutic targets. Here we have used VNAR semi-synthetic phage libraries to select high-affinity fondaparinux-binding VNARs that did not show cross-reactivity with other GAG species. Competition ELISA and surface plasmon resonance identified a single fondaparinux-selective VNAR clone. This VNAR exhibited an extraordinarily stable protein fold: the beta-strands are stabilized by a robust hydrophobic network, as revealed by heteronuclear NMR. Docking fondaparinux to the VNAR structure revealed a large contact surface area between the CDR3 loop of the antibody and the glycan. Fusing the VNAR with a human Fc domain resulted in a stable product with a high affinity for fondaparinux (Kd = 9.3 × 10−8 M) that could efficiently discriminate between fondaparinux and other glycosaminoglycans. This novel glycan-targeting screening technology represents a promising therapeutic strategy for addressing GAG-related diseases.

AimThere is no specific evidence on the antithrombotic management of survivors of out-of-hospital cardiac arrest (OHCA) due to acute myocardial infarction (AMI). We sought to compare the short-term outcome of unfractioned heparin (UFH) vs fondaparinux in OHCA survivors due to AMI admitted in our Institution in the last decade.MethodsWe performed a retrospective cohort study on survivors of OHCA due to AMI managed with UFH or fondaparinux during the hospitalization. The primary outcome was the occurrence of any bleeding, all-cause mortality, cerebrovascular accidents, re-MI, and unplanned revascularization at 1 month. A propensity-score matching was performed to compare the outcome between UFH and fondaparinux.ResultsOut of 2083 AMI patients undergoing successful PCI, OHCA was present in 94 (4.5%): 41 (43.6%) treated with UFH and 53 (56.4%) with fondaparinux. At clinical follow-up, the incidence of the primary outcome was 65.9% in UFH and 35.8% in fondaparinux group (p = 0.007). More than half of the events included in the primary outcome were related to bleeding complications. In the matched cohort of 56 patients, the primary outcome occurred in 46.4% and 25.0% (p = 0.16), while bleeding was present in 32.1% and 7.1% (p = 0.04), in the UFH and fondaparinux group, respectively.ConclusionsThe present analysis suggests that fondaparinux is safer than UFH in the management of OHCA due to AMI by reducing early bleeding complications at one month.

Venous thromboembolism (VTE) remains a significant global health burden, particularly in older adults. While fondaparinux sodium, enoxaparin sodium, and dalteparin sodium are commonly used anticoagulants, their safety profiles require further evaluation. This study analyzes their adverse drug events (ADEs) using data from the FDA Adverse Event Reporting System (FAERS). A retrospective pharmacovigilance study was conducted using FAERS data from Q1 2004 to Q2 2024. Reports identifying fondaparinux sodium, enoxaparin sodium, or dalteparin sodium as the primary suspect drug were extracted. ADEs were classified using MedDRA 23.0 at the System Organ Class (SOC) and Preferred Term (PT) levels. Disproportionality analysis was performed with Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). FAERS contained 470 reports for fondaparinux sodium, 1,375 for enoxaparin sodium, and 344 for dalteparin sodium. Most cases involved patients aged ≥ 60, with a female predominance. Hospitalization was the most frequent outcome. Fondaparinux showed the strongest signals for intra-abdominal haematoma (ROR = 374.14, PRR = 371.14), muscle haemorrhage (ROR = 354.91, PRR = 347.04), and retroperitoneal haematoma (ROR = 214.97, PRR = 213.25). Enoxaparin demonstrated notable signals for heparin-induced thrombocytopenia (HIT) (ROR = 149.42, PRR = 147.53) and retroperitoneal haemorrhage (ROR = 287.68, PRR = 284.03). Dalteparin showed notable signals for HIT (ROR = 127.88, PRR = 126.49) and retroperitoneal haemorrhage (ROR = 103.23, PRR = 102.75). Distinct ADE profiles were identified among the three anticoagulants, underscoring the need for individualized risk assessment. These findings highlight the importance of close monitoring, particularly in high-risk patients, to optimize anticoagulation safety.