Alessandra Bura-Riviere

Background: A recent U.S. study of initial anticoagulation in adults with acute pulmonary embolism (PE) requiring hospitalization found intravenous unfractionated heparin (UFH) use exceeded 50%. Guidelines, however, recommend low molecular weight heparin (LMWH) over UFH for most patients requiring parenteral anticoagulation. Use patterns in other geographic regions are unclear. Methods: We analyzed data from RIETE, a prospective multinational registry of consecutive patients with venous thromboembolism. We included adults hospitalized for acute PE from 2013 through 2024 in 273 hospitals across 31 countries. We assessed temporal trend and regional variation in initial anticoagulation. Using multivariable regression, we identified variables independently associated with UFH. Results: Among 36,210 adults, 83.2% received subcutaneous LMWH, 7.1% UFH, and 6.8% direct oral anticoagulants. LMWH use decreased slightly from 2013 to 2024 (85.8% to 79.2%; unadjusted), while UFH increased (8.9% to 10.4%). Wide geographic variation was observed in overall use of LMWH (37%--95%) and UFH (2%--39%). When adjusted for demographic and clinical covariates, increased weight, recent surgery, recent major bleeding, severe anemia, thrombocytopenia, severe renal dysfunction, abnormal vital signs, and early reperfusion therapy were positively associated, whereas age >80 years, active cancer, chronic lung disease, prior ischemic stroke, and year were negatively associated with UFH. Compared with Spanish hospitals, hospitals in other European countries, the United States, and Asia were independently associated with UFH use. Conclusions: Results highlight opportunities for some geographic regions to align anticoagulation practices more closely with evidence-based guidelines recommending LMWH as the preferred parenteral agent in most patients with PE requiring hospitalization.

Objective: The present study was performed to investigate putative sex differences in the reporting of acetyl salicylic acid (ASA)–related bleeding in the global pharmacovigilance database. Methods: Using Vigibase, the global pharmacovigilance database, all bleeding reports with ASA between January 1, 2008, and December 31, 2021, in adults were included. The main bleeding locations with ASA were compared in men versus women. A secondary objective was to analyze possible age differences. Results are presented as reporting odds ratios (RORs) with their 95% confidence interval. Results: Among 29 034 bleeding with ASA, the most frequent were gastrointestinal (41.2%), neurological (21.3%), and nasal (13.6%). Higher ROR values were found in men for all bleeding in general (ROR = 1.56 [1.51–1.61]) but also for gastrointestinal, neurological, nasal, and renal locations. Similar trends were found for “serious” reports (except for gastrointestinal bleeding). Neurological fatal reports were more frequently reported in men. These sex differences were also found in all the age categories. Higher ROR values were found in patients from 65 years. Conclusion: The risk of total, “serious,” and fatal bleeding reporting with ASA was higher in men than in women and after 65 years. Similar conclusions can be made for the most frequent locations of ASA‐associated bleeding: gastrointestinal followed by neurological and nasal ones.

Chronic limb-threatening ischaemia (CLTI) is defined as ischaemic rest pain, or non-healing ulceration, requiring endovascular or surgical lower limb revascularization (LLR). Lower limb revascularization in CLTI entails a high risk of major adverse limb events (MALE) and major adverse cardiovascular events (MACE). This scientific statement addresses this risk based on a systematic review. A structured literature search was performed, and articles were independently evaluated by two investigators. In total, 1678 articles were identified, of which 34 were included in the final analysis. Only three randomized controlled trials (RCTs) addressed antithrombotic therapy in CLTI following LLR. None of these demonstrated superiority of any antithrombotic regimen over the other. Eight RCTs investigated antithrombotic therapy following LLR in populations with peripheral arterial disease including CLTI subgroups and suggest a benefit of dual antiplatelet therapy on limb events. One large RCT demonstrated that dual pathway inhibition with aspirin and vascular-dose rivaroxaban reduced the risk of MALE, MACE, and unplanned target limb revascularization. Data from 22 observational studies suggest a benefit of dual antiplatelet therapy on overall survival and amputation-free survival after LLR as compared with single antiplatelet therapy. Intensified antithrombotic treatment should be proposed in patients with CLTI following LLR to reduce the risk of MALE and MACE. Randomized controlled trials on antithrombotic therapy in patients with CLTI following LLR are scarce. Dual pathway inhibition is the only regimen for which an RCT demonstrated a reduction of MALE and MACE following LLR. Dual antiplatelet therapy appears to be associated with a reduced risk of MALE in CLTI following LLR.

BACKGROUND: Vascular Ehlers-Danlos syndrome is a rare genetic disorder characterized by defective type III collagen and a high risk of arterial morbidity and mortality. Several cardiovascular drugs are used for treatment, including celiprolol, but no controlled trial in this condition has been conducted to date. We hypothesized the benefit of the addition of an angiotensin II receptor blocker. METHODS: A multicenter, randomized, placebo-controlled trial was conducted to assess the efficacy and safety of the angiotensin II receptor blocker irbesartan in adults with vascular Ehlers-Danlos syndrome on stable background celiprolol therapy. Patients were randomized 1:1 to receive irbesartan (150 mg/day titrated to 300 mg/day) or placebo for 2 years. The composite primary outcome was defined as any vascular Ehlers-Danlos syndrome–related fatal or nonfatal arterial event or any new or worsening arterial lesions detected by systematic head-to-pelvis computed tomography angiography or peripheral arterial duplex ultrasound at different time points, using a time-to-first-event analysis. RESULTS: Twenty-nine participants (62% female; 40.3±11.3 years of age) were randomized to irbesartan, and 28 (64% female; 40.7±11.0 years of age) were randomized to placebo. The composite primary outcome occurred in 8 of 29 patients (27.6%) receiving irbesartan versus 15 of 28 patients (53.6%) receiving placebo (hazard ratio, 0.42 [95% CI, 0.17, 0.99]; P P =0.002). A reduction of progression of arterial lesions was observed at all sites. Irbesartan significantly reduced systolic blood pressure compared with placebo (baseline-adjusted difference of 5.4 mm Hg [ P <0.001]), but no relation was observed with the reduction of the primary composite outcome. Eleven episodes of irbesartan-related hypotension were recorded, leading to a downtitration in 4 patients. CONCLUSIONS: Compared with placebo, irbesartan reduced the risk of severe symptomatic and asymptomatic arterial events in patients with vascular Ehlers-Danlos syndrome on background celiprolol therapy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02597361.

Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.

Aim The present study investigated the risk of bleeding when antidepressants are added to antithrombotics. Methods Using data registered in VigiBase^®, the WHO pharmacovigilance database, between 01/01/2000 and 31/12/2022, we compared the risk of reporting “serious” bleeding (Reporting Odds Ratio, ROR) with antidepressants + antithrombotics versus antithrombotics alone. Results Increased values of ROR were found for the association Serotonin Reuptake Inhibitors (SRIs) + Direct Oral Anticoagulants (DOACs) versus DOACs alone (ROR=1.49(1.17-1.89)). Similar results were found for Factor Xa inhibitors or Thrombin inhibitors. This association was also found for other antithrombotics: Vitamin K Antagonists (ROR=1.37(1.12-1.68)), Platelet Aggregation Inhibitors PAIs (ROR=1.38(1.21-1.57)) and Heparins (2.04(1.59-2.62)) but not with other antidepressants (Non-Selective Monoamine Reuptake Inhibitors, NSMRIs). Conclusion The present study suggests an increased risk of “serious” bleeding when SRIs (but not NSMRIs) are associated with antithrombotics (all antithrombotics and not only DOACs).