Modeling the Clinical Implications of Andexanet Alfa in Factor Xa Inhibitor–Associated Intracerebral Hemorrhage

Background and Objectives:Andexanet alfa was recently approved as a reversal agent for the Factor Xa inhibitors (FXai) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. We aimed to explore potential clinical implications of andexanet alfa in FXai-associated ICH in this simulation study.Methods:We simulated potential downstream implications of andexanet alfa across a range of possible hemostatic effects using data from a single center that treats FXai-associated ICH with prothrombin complex concentrate (PCC). We determined baseline probabilities of inadequate hemostasis across FXai and non-FXai patients via multivariable regression models, then determined probabilities of unfavorable 3-month outcome (modified Rankin Scale 4-6) using models comprising established predictors and each patient’s calculated probability of inadequate hemostasis. We applied bootstrapping with model parameters from this derivation cohort to simulate a range of hemostatic improvements and corresponding outcomes, then calculated absolute risk reduction (relative to PCC) and projected number needed to treat (NNT) to prevent one unfavorable outcome.Results:Training models using real-world patients (n=603 total; 55 FXai) had good accuracy in predicting inadequate hemostasis (AUC 0.78) and unfavorable outcome (AUC 0.78). Inadequate hemostasis was strongly associated with unfavorable outcome (OR 4.5, 95% CI 2.0-9.9) and occurred in 11.4% of FXai patients. Across simulated FXai patients comparable to those in the ANNEXA-4 study, predicted absolute risk reduction of unfavorable outcome was 4.9% (95% CI 1.3%-7.8%) when the probability of inadequate hemostasis was reduced by 33%, and 7.4% (95% CI 2.0%-11.9%) at 50% reduction, translating to projected NNTs of 21 (cumulative cost $519,750) and 14 ($346,500), respectively.Discussion:Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered. Placebo-controlled randomized trials are needed before its use can definitively be recommended.

Pharmacological Activities of Sulfated Fucose-Rich Polysaccharides after Oral Administration: Perspectives for the Development of New Carbohydrate-Based Drugs

Marine organisms are a source of active biomolecules with immense therapeutic and nutraceutical potential. Sulfated fucose-rich polysaccharides are present in large quantities in these organisms with important pharmacological effects in several biological systems. These polysaccharides include sulfated fucan (as fucoidan) and fucosylated chondroitin sulfate. The development of these polysaccharides as new drugs involves several important steps, among them, demonstration of the effectiveness of these compounds after oral administration. The oral route is the more practical, comfortable and preferred by patients for long-term treatments. In the past 20 years, reports of various pharmacological effects of these polysaccharides orally administered in several animal experimental models and some trials in humans have sparked the possibility for the development of drugs based on sulfated polysaccharides and/or the use of these marine organisms as functional food. This review focuses on the main pharmacological effects of sulfated fucose-rich polysaccharides, with an emphasis on the antidislipidemic, immunomodulatory, antitumor, hypoglycemic and hemostatic effects.

Evaluation and Comparison of Structurally Different Cellulose-Based Hemostatic Agents in a Rat Kidney Model

Different topical hemostatic materials are used to achieve effective hemostasis. High hemostatic activity, biocompatibility, bioresorbability, and easy manipulation are to be expected in such a developed product. In the surgical world with these specific requirements, finding a proper hemostatic agent is very difficult. The study compared several materials of various construction properties, which were assessed for structural and related properties by morphological analyses and assessed in vivo for their efficiency and behaviour using a model of rat partial nephrectomy. New sodium salt of carboxymethyl cellulose (CMC) sponge with the lowest porosity and free swell absorptive capacity contained the highest amount of hydroxyl and carboxyl groups. Results revealed that this CMC material in the form of a bioresorbable sponge may ensure the necessary hemostatic effects, while also providing a positive influence on the reaction of the local tissue. The CMC material also needed significantly less time to achieve hemostasis (p < 0.001). Moreover, the sponge reached satisfactory results in the histopathological evaluation with the lowest destruction score and favorable healing reaction. This modified product proved itself to be a promising bioresorbable hemostat, which, according to its design, matches with its surgical applications. In general, the obtained data elucidated the dependency of the total effect on its structure and composition.

Abstract MP39: Modeling the Clinical Implications of Andexanet Alfa in Factor Xa Inhibitor-Associated Intracerebral Hemorrhage

Background: Andexanet alfa was recently approved as a reversal agent for the Factor Xa inhibitors (FXai) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. Methods: We performed a simulation study to determine the potential clinical implications of andexanet alfa across a range of possible hemostatic effects using data from a single-center cohort of ICH patients who did not receive the drug. We used this data to determine the baseline probability of insufficient hemostatic efficacy (IHE) across patients with and without FXai use via k-fold cross-validated multivariable regression models, which we aggregated into an IHE propensity score. We then determined the probability of unfavorable 3-month outcome (modified Rankin Scale 4-6) using a model comprised of established clinical predictors and IHE propensity. We applied model parameters from this derivation cohort to simulate a range of IHE reductions and corresponding outcomes, which we used to calculate absolute risk reduction (ARR) and projected number needed to treat (NNT) to prevent one unfavorable outcome. Results: Training models using a real-world ICH cohort (n=604 total; 55 FXai patients) had good accuracy in predicting IHE (AUC 0.78) and unfavorable outcome (AUC 0.82). IHE was strongly associated with unfavorable outcome (OR 6.7, 95% CI 3.8-11.8) and occurred in 11.4% of FXai patients. Predicted ARR of unfavorable outcome was 5% (95% CI 3-8%) at one-third reduction of IHE and 8% (95% CI = 4-13%) at 50% IHE reduction, translating to a projected NNT of 20 (cumulative treatment cost $495,000) and 13 ($321,750), respectively. Conclusion: Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered, and placebo-controlled randomized trials are needed before its use can definitively be recommended.

Thrombosis Complicating Non-Factor Therapy for Hemophilia

This is an exciting time in hemophilia treatment with the unprecedented development of novel non-factor therapies. These agents have re-balanced hemostasis in patients with hemophilia A and B, with and without inhibitors, tipping the balance toward hemostasis and improved thrombin generation. While there have been numerous publications about the beneficial hemostatic effects and significant bleed reduction possible with these novel non-factor agents, little has been written about the less well-recognized thrombotic complications. Yet, the latter underscores the fine balance between hemostasis and thrombosis and the fact these agents prevent but do not treat bleeds, requiring clotting factor requirement to treat acute bleeds. The purpose of this Commentary is to review thrombotic complications that have occurred with non-factor therapies, risk factors for thrombosis, potential mechanisms, and potential mitigation approaches.

A Review of Isolation, Chemical Properties, and Bioactivities of Polysaccharides from Bletilla striata

Recently, polysaccharides from Bletilla striata, a member of the orchidaceous family, aroused the wide interest of people, especially their isolation, chemical properties, and bioactivities. It is reported that these polysaccharides are the most important biologically active components of B. striata, exhibiting various biological activities, such as immunomodulatory, antioxidant, antifibrotic, and hemostatic effects. This review appraised the available literatures which described different aspects of B. striata polysaccharides, including the extraction, separation, purification, structural characterization, and biological activities. We expect to lay the foundation for further investigation of the application of B. striata polysaccharides in the field of functional foods and biomedicine.