Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

THE INFLUENCE OF HUMAN LEUKEMIA DIFFERENTIATION FACTOR ON ABILITY OF BLOOD CELLS TO PRODUCE IL-1β, IL-1ra AND IL-8 IN CHRONIC ATROPHIC GASTRITIS, ADENOMAS AND ADENOCARCINOMAS OF THE STOMACH

We studied biological effects of Human Leukemia Differentiation Factor (HLDF), first derived from the cultural media of human myelogenous HL-60 leukemia cells, on the production of IL-1β, IL-1ra and IL-8 by immune cells from the patients with chronic atrophic gastritis, adenomas and adenocarcinomas of the stomach. To evaluate the influence of HLDF on cytokine-producing function of the whole blood cells, the latter were incubated with this factor or without it. The levels of IL-1β, IL-1ra and IL-8 were determined in supernates of these cells. The stimulation indices of HLDF upon cytokine production were estimated as a cytokine production ratio of stimulated versus resting cells. Histological analysis of gastric mucous tissue samples and removed tumors was also performed. It was revealed that, in chronic atrophic gastritis, HLDF significantly increased IL-1ra and IL-8production. In patients with stomach adenomas and adenocarcinomas, HLDF increased IL-1ra, IL-8 and IL-1β production. In cases of stomach adenomas, the indices of HLDF stimulation upon blood cells cytokine production are significant higher than in patients with chronic atrophic gastritis. Interdependence study between the stimulation indices of HLDF and histological parameters of gastric mucosa and tumor samples have shown a negative correlations between the stimulation index of HLDF upon IL-1ra production and the grade of intestinal metaplasia and dysplasia of the adenoma epithelium, and a positive correlation between the stimulation index of HLDF on IL-8 production and the intensity of lymphoid infiltration of the adenomas. In patients with gastric adenocarcinomas, a positive correlation between the stimulation index of HLDF on IL-8 production and number of blood vessels with tumor embolus was revealed. One may presume that immune cells activation caused by HLDF may exert following actions: (1) triggering some processes of chronic inflammation that underly malignancy development, and (2) the mechanisms restricting the disturbances of epithelial regeneration. Finally, the results of HLDF effects depend on balance between proand antioncogenic cytokines produced by immune cells

Anticoagulant-related bleeding in patients with heart failure in combination with chronic obstructive pulmonary disease and atrial fibrillation. Experience with Idarucizumab

Aim. To study the characteristics of direct oral anticoagulant-related bleeding in patients with heart failure in combination with chronic obstructive pulmonary disease (COPD) and atrial fibrillation. To show the efficacy of idarucizumab in complex therapy of severe gastrointestinal bleeding caused by dabigatran.Material and methods. The single-center prospective observational study included 150 patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants. Of these patients, 75 had heart failure in combination with COPD (experimental group) and 75 — HF without comorbidities (comparison group). Groups were formed by propensity score matching. Sex, age, bleeding risk by HAS-BLED score were covariates. HF was diagnosed in accordance with the criteria applied by Russian Federal clinical guidelines. COPD was diagnosed according to GOLD 2011-2020 criteria. Frequency of all bleeding, major bleeding, bleeding into critical organs were evaluated. Follow-up period was 14 (12; 16) months. Cox regression method was used to determine relationships.Results. Annual rate of major bleeding in group of HF and COPD was higher (Hazard ratio (HR) 3,0, 95% confidence interval (CI) 1,1-6,2, р=0,02), regardless of which anticoagulant was used. Gastrointestinal bleeding occurs in 7 (9,3%) and 2 (2,7%) patients (HR 3,5, 95% CI 1,1-7,3, р=0,05). In subjects with comorbidity, major and gastrointestinal bleeding were associated with partial pressure of arterial oxygen (HR 0,89, 95% CI 0,55-0,95 and HR 0,88, 95% CI 0,50-0,98 respectively), serum NT-pro-BNP (HR 1,10, 95% CI 1,05-2,14 and HR 1,14, 95% CI 0,07-4,28, respectively) and chemokine ligand 18 (HR 1,15, 95% CI 1,11-5,75 and HR 1,13, 95% CI 1,09-4,50). A case of successful use of idarucizumab for reversal of dabigatran anticoagulant effect in the patient with severe bleeding from esophageal erosion, nonvalvular AF, HF and COPD was reported. Coagulation was restored within 4 hours, which allowed to stop bleeding conservatively and antishock measures were effective.Conclusion. Anticoagulation therapy in patients with AF and comorbidity of HF and COPD is associated with additional risk of major bleeding, especially gastrointestinal. Possibility to reverse the anticoagulant effect is an important argument when choosing an anticoagulant for these patients

Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely Ill medical patients: An APEX trial substudy

Background-Extended-duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm. Methods and Results-This was a post hoc analysis of the APEX trial-a multicenter, double-blind, randomized controlled trial comparing extended-duration betrixaban versus standard-of-care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time-to-first event analysis. In patients with positive D-dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [P=0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [P=0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [P=0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [P=0.002]). Conclusions-Among hospitalized medically ill patients, extended-duration betrixaban demonstrated an 48 30% reduction in fatal or irreversible ischemic or bleeding events compared with standard-duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin