Inhalable FN-binding liposomes or liposome-exosome hybrid bionic vesicles encapsulated microparticles for enhanced pulmonary fibrosis therapy.

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease that seriously threatens human life and health. Our previous study demonstrated the unique superiority of traditional Chinese medicine cryptotanshinone (CTS) combined with sustained pulmonary drug delivery for treating PF. In this study, we aimed to enhance the selectivity, targeting efficiency and sustained-release capability based on this delivery system. To this end, we developed and evaluated CTS-loaded modified liposomes-chitosan (CS) microspheres SM(CT-lipo) and liposome-exosome hybrid bionic vesicles-CS microspheres SM(LE). The prepared nano-in-micro particles system integrates the advantages of the carriers and complements each other. SM(CT-lipo) and SM(LE) achieved lung myofibroblast-specific targeting through CREKA peptide binding specifically to fibronectin (FN) and the homing effect of exosomes on parent cells, respectively, facilitating efficient delivery of anti-fibrosis drugs to lung lesions. Furthermore, compared with daily administration of conventional microspheres SM(NC) and positive control drug pirfenidone (PFD), inhaled administration of SM(CT-lipo) and SM(LE) every two days still attained similar efficacy, exhibiting excellent sustained drug release ability. In summary, our findings suggest that the developed SM(CT-lipo) and SM(LE) delivery strategies could achieve more accurate, efficient and safe therapy, providing novel insights into the treatment of chronic PF.

Shengxian decoction improves lung function in rats with bleomycin-induced idiopathic pulmonary fibrosis through the inhibition of PANoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Shengxian decoction (SXD) is a classic Chinese medicinal formula that can effectively improve clinical symptoms and quality of life and delay disease progression in idiopathic pulmonary fibrosis (IPF) patients; however, the underlying mechanisms remain unclear. AIM OF THE STUDY: This study aimed to observe PANoptosis in bleomycin-induced IPF and to assess the efficacy and mechanism of action of SXD in the treatment of IPF. MATERIALS AND METHODS: Fifty SD rats were randomly divided into the sham, IPF, IPF + pirfenidone (PFD), IPF + SXD-medium dose (SXD-M), and IPF + SXD-low dose (SXD-L) groups. Lung function analysis and microcomputed tomography imaging of the rats with IPF treated with oral pirfenidone or oral SXD for 28 days were performed. Hematoxylin and eosin (HE) staining and Masson's trichrome staining were used to observe pathological lung damage. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum levels of IL-1ß, IL-18, TNF-α, and IFN-γ. Pyroptosis, apoptosis, and necroptosis were assessed using TUNEL, TUNEL/caspase-1, and PI fluorescence staining, respectively. GSDMD, caspase-3, and MLKL were examined by immunohistochemistry. The expression of fibrin-, ZBP1-, pyroptosis-, apoptosis-, and necroptosis-related proteins in the lung tissue was determined by western blotting. RESULTS: SXD normalized lung function in rats with bleomycin-induced IPF and reduced serum inflammatory factor levels and lung tissue fibrosis. The underlying mechanism of action involves the inhibition of pyroptosis pathway proteins, such as NLRP3, caspase-1, cleaved caspase-1, and GSDMD; apoptotic pathway proteins, such as Bax, Bcl-2, cleaved caspase-3, and caspase-3; and necroptosis pathway proteins, such as RIPK1, RIPK3, p-MLKL and MLKL. These pathways are modulated by the PANoptosis initiator ZBP1. Notably, the efficacy of SXD is concentration dependent, with a medium dose exhibiting superior effectiveness compared to a low dose. CONCLUSION: Bleomycin induced PANoptosis in the lung tissue of rats with IPF. Additionally, SXD effectively delayed or reversed the early pathological changes in bleomycin-induced pulmonary fibrosis by inhibiting PANoptosis.

Clot time ratio (CTR) and treatment outcomes in Apixaban-treated atrial fibrillation patients.

There are clinical situations where information about the anticoagulant effects of Apixaban could be useful. Specialised methods for measuring Apixaban concentrations are not available at all medical laboratories while methods for measuring the functional effects of Apixaban, using clot time ratio (CTR), can be performed in most medical laboratories around the clock using well-established measurement procedures. The aim of this study was to investigate CTR in trough and peak samples during Apixaban treatment of atrial fibrillation and to correlate the findings to bleeds and thrombotic events. Three trough- and three peak samples from 61 patients (31 on Apixaban 5 mg twice daily and 30 on Apixaban 2.5 mg twice daily) were analysed with MRX PT DOAC. Patients were followed for 30 + /-15 months, and bleeds and thrombotic events were documented. The effect of Apixaban could be measured with MRX PT DOAC and there was a statistically significant difference between CTR in trough samples compared to peak samples (p < 0.001). A total of 21 patients suffered bleeds during follow-up; two patients suffered major bleeds, and 19 suffered minor bleeds. Patients with major bleeds had both mean peak- and mean trough CTR above the respective first to third quartile (Q1-Q3) range. Four patients suffered thromboembolic events. Generally, the peak CTRs were below or in the lower end of the peak Q1-Q3 for these patients. The new test MRX PT DOAC can be used to measure the effect of Apixaban during the treatment of atrial fibrillation. High mean peak- and mean trough CTR were seen in 2 patients with major bleeds, and low peak CTR was seen in 4 patients with thromboembolic events.

The impact of chelation compliance in health outcome and health related quality of life in thalassaemia patients: a systematic review.

Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.

Efficacy, safety, and feasibility of Apixaban for postoperative venous thromboembolism prophylaxis following open gynecologic cancer surgery at a comprehensive cancer center.

OBJECTIVES: To evaluate safety, efficacy, and feasibility of apixaban for postoperative venous thromboembolism (VTE) prophylaxis following open gynecologic cancer surgery at a comprehensive cancer center. METHODS: This retrospective, cohort study included patients with gynecologic cancer who underwent open surgery between 3/2021 and 3/2023 and received 28-day postoperative VTE prophylaxis. Patients on therapeutic anticoagulation preoperatively were excluded. Predictors of 90- and 30-day VTE and 30-day bleeding events were determined using multivariable logistic regression, adjusting for known confounders. RESULTS: 452 patients were included in the cohort: 348 received apixaban and 104 received enoxaparin. Those who received enoxaparin were more likely to be American Society of Anesthesiologists class III/IV (compared to I/II) (p = 0.033), current or former smokers (p = 0.012) and have a higher BMI (p < 0.001), Charlson Comorbidity Index (p = 0.005), and age (p = 0.046). 30-day VTE rate was significantly lower in the apixaban group (0.6%) compared to the enoxaparin group (6.2%) (adjusted OR 0.13, 95% CI 0.03-0.56; p = 0.006). 90-day VTE rate was 2.7% and 6.2% in the apixaban and enoxaparin groups, respectively (adjusted OR 0.85, 95% CI 0.38-1.92; p = 0.704). Major bleeding complications (2.4% vs. 2.0%) and minor bleeding complications (0.9% vs. 3.0%) were similar in the apixaban and enoxaparin groups, respectively, on multivariate analyses. The median patient out of pocket cost was $10 (IQR 0.0-40.0) for apixaban and $20 (IQR 3.7-67.7) for enoxaparin (p = 0.001). CONCLUSIONS: Our findings along with previously published data suggest that apixaban should be considered the standard of care for VTE prophylaxis in patients undergoing open surgery for gynecologic malignancies.

Clinical Observational Study on the Therapeutic Efficacy of Pirfenidone in Sjögren's Syndrome Complicated with Nonspecific Interstitial Pneumonia.

Objective: This study aimed to evaluate the therapeutic impact of pirfenidone in patients with nonspecific interstitial pneumonia (NSIP) secondary to Sjögren's syndrome, comparing its effectiveness against conventional treatments. Methods: A controlled clinical trial was conducted on a cohort of patients diagnosed with primary Sjögren's syndrome complicated by interstitial lung disease. The study included a total of 120 patients, divided equally into two groups: a control group comprising 60 patients and an observation group with another 60 patients. Random assignment placed patients in either a control group receiving hydroxychloroquine and prednisone or an observation group supplemented with pirfenidone. Pulmonary function parameters, Warrick scores from high-resolution CT scans, and Leicester Cough Quality of Life Questionnaire (LCQ) scores were assessed before and after treatment. Adverse reactions were monitored for treatment safety. Results: Before treatment, no statistically significant differences in pulmonary function indicators (FVC%, FEV1%, DLco%) were observed between the groups (P > .05). Post-treatment, both groups showed significant improvements in these parameters (P < .05). Importantly, the observation group demonstrated superior improvements in pulmonary function compared to the control group (P < .05). Warrick's scores improved significantly in both groups after treatment, with the observation group achieving a more substantial reduction in scores compared to the control group (P < .05). LCQ scores showed no significant differences between the groups before treatment (P > .05). However, after treatment, both groups exhibited significant improvements, with the observation group consistently scoring higher (P < .05). Safety assessments revealed a slightly higher incidence of adverse reactions, including neurosensory abnormality and drowsiness, in the observation group compared to the control group. Conclusions: This study suggests that adding pirfenidone to the treatment regimen for NSIP secondary to Sjögren's syndrome leads to significant improvements in pulmonary function, high-resolution CT scores, and quality of life compared to conventional treatments.

Effects on hearing after long-term use of iron chelators in beta-thalassemia: Over twenty years of longitudinal follow-up.

OBJECTIVE: The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. METHODS: We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. RESULTS: A total of 42 adult TDT patients (18 male, 24 female; age range: 41-55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. CONCLUSION: This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.

Dolutegravir-induced neural tube defects in mice are folate responsive.

OBJECTIVES: In 2018, the Botswana Tsepamo Study reported a nine-fold increased risk of neural tube defects in infants whose mothers were treated with dolutegravir (DTG) from the time of conception. As maternal folate supplementation and status is a well known modifier of neural tube defect (NTD) risk, we sought to evaluate birth outcomes in mice fed normal and low folic acid diets treated with DTG during pregnancy. DESIGN: DTG was evaluated for developmental toxicity using pregnant mice fed normal or low folic acid diet. METHODS: CD-1 mice were provided diet with normal (3 mg/kg) or low (0.3 mg/kg) folic acid. They were treated with water, a human therapeutic-equivalent dose, or supratherapeutic dose of DTG from mouse embryonic day E6.5 to E12.5. Pregnant dams were sacrificed at term (E18.5) and fetuses were inspected for gross, internal, and skeletal defects. RESULTS: Fetuses with exencephaly, an NTD, were present in both therapeutic human equivalent and supratherapeutic exposures in dams fed low folic acid diet. Cleft palates were also found under both folate conditions. CONCLUSIONS: Recommended dietary folic acid levels during mouse pregnancy ameliorate developmental defects that arise from DTG exposure. Since low folate status in mice exposed to DTG increases the risk for NTDs, it is possible that DTG exposures in people living with HIV with low folate status during pregnancy may explain, at least in part, the elevated NTD risk signal observed in Botswana. Based on these results, future studies should consider folate status as a modifier for DTG-associated NTD risk.

The Effect of Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes: A Study by the Israeli MDS Working Group.

BACKGROUND: Most patients with lower risk myelodysplastic neoplasms or syndromes (MDSs) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron-overloaded RBC transfusion-dependent patients with lower risk MDSs. METHODS: Adult lower risk MDS patients with a cumulative transfusion burden of >20 red blood cell units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin, and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side effects were recorded as well. A paired t test was applied for statistical analyses. RESULTS: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p < 0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p < 0.01 for all). The iron-overload marker and cellular labile iron pool decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p < 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1-2. CONCLUSIONS: Herein, we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs.

The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.

Successful chelation in beta-thalassemia major in the 21st century.

This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209 patients, independent of the chelation regimen, ferritin, cardiac T2* and liver iron concentration changes were evaluated. We defined chelation success (ChS) as no iron load in the heart and acceptable levels in the liver. Over 3 early magnetic resonance imagings, the same parameters were assessed in 2 subgroups, the only 2 that had sufficient patients continuing on 1 regimen and for a significant period of time, 1 on deferrioxamine (low iron load patients n = 41, Group A) and 1 on deferoxamine-deferiprone (iron overloaded n = 60, Group B). Finally, 28 deaths and causes were compared to those of an earlier period. The 209 patients significantly optimized those indices, while the number of patients with chelation success, increased from 6% to 51% (P < .0001). In group A, ChS after about 8 years increased from 21 to 46% (P = .006), while in Group B, from 0% to 60% (P < .001) after about 7 years. Deaths over the 2 periods showed significant reduction. Combined clearance of cardiac and liver iron (ChS) is feasible and should become the new target for all patients. This requires, serial magnetic resonance imagings and often prolonged intensified chelation for patients.

Association of type of oral anticoagulation with risk of bleeding in 45,114 patients with venous thromboembolism during initial and extended treatment-A nationwide register-based study.

BACKGROUND: Safety data for different anticoagulant medications in venous thromboembolism (VTE) are scarce, in particular for extended treatment. OBJECTIVES: To compare major bleeding rates depending on the choice of anticoagulation during initial (first 6 months) and extended treatment (6 months up to 5 years). METHODS: A nationwide register-based study including cancer-free patients with a first-time VTE between 2014 and 2020. Cox proportional hazards models were used to compare bleeding rates. RESULTS: We included 6558 patients on warfarin, 18,196 on rivaroxaban, and 19,498 on apixaban. At 6 months, 4750 (72.4%) remained on warfarin, 11,366 (62.5%) on rivaroxaban, and 11,940 (61.2%) on apixaban. During initial treatment, major bleeding rates were 3.86 (95% CI 3.14-4.58), 2.93 (2.55-3.31), and 1.95 (1.65-2.25) per 100 patient-years for warfarin, rivaroxaban, and apixaban, respectively, yielding adjusted hazard ratios (aHRs) of 0.89 (95% CI 0.71-1.12) for rivaroxaban versus warfarin, 0.55 (0.43-0.71) for apixaban versus warfarin, and 0.62 (0.50-0.76) for apixaban versus rivaroxaban. During extended treatment, major bleeding rates were 1.55 (1.19-1.91), 1.05 (0.85-1.26), and 0.96 (0.78-1.15) per 100 patient-years for warfarin, rivaroxaban, and apixaban, respectively, with aHRs of 0.72 (0.53-0.99) for rivaroxaban versus warfarin, 0.60 (0.44-0.82) for apixaban versus warfarin, and 0.85 (0.64-1.12) for apixaban versus rivaroxaban. Previous bleeding and increasing age were risk factors for bleeding both during initial and extended treatment. CONCLUSION: Apixaban had a lower bleeding risk than warfarin or rivaroxaban during initial treatment. During extended treatment, bleeding risk was similar for apixaban and rivaroxaban, and higher with warfarin.

Comparison of bleeding and ischemic events with apixaban vs. rivaroxaban in triple antithrombotic therapy regimens.

OBJECTIVE: To compare the risk of readmissions for major bleeding within one year between apixaban and rivaroxaban as a component of triple antithrombotic therapy. METHODS: This study was a multicenter, retrospective cohort study conducted at two academic medical centers in the Western New York and New York City region between July 1, 2011 and September 25, 2019. Adult patients were included if they were diagnosed with atrial fibrillation or venous thromboembolism and discharged on new triple antithrombotic therapy. The primary outcome compared the rates of 1-year readmission for major bleeding between apixaban and rivaroxaban groups. Secondary outcomes included rate of ischemic outcomes. Time to event analysis was determined with a Kaplan-Meier plot and Cox proportional hazard ratios (HR). RESULTS: A total of 378 patients were included in the study, 212 in the apixaban group and 166 in the rivaroxaban group. Within 1 year, readmission for major bleeding events occurred in six (2.8%) patients in the apixaban group and four (2.4%) patients in the rivaroxaban group ( P  = 1.000). After adjustment, the major bleeding event rate was not statistically significantly different between apixaban and rivaroxaban [adjusted hazard ratio (aHR) 0.68, 95% confidence interval (CI) 0.12-3.77; P  = 0.6624]. Higher albumin levels were identified to be protective against major bleeding related readmission events (aHR 0.18, 95% CI 0.05-0.63; P  = 0.0072). The ischemic outcome occurred in seven (3.3%) patients in the apixaban group and three (1.8%) in the rivaroxaban group ( P  = 0.7368). CONCLUSION: Use of apixaban or rivaroxaban in a triple antithrombotic regimen was not associated with bleeding or ischemic outcomes.

Combination chelation therapy.

Combination chelation therapies are considered in transfusion-dependent thalassemia patients for whom monotherapy regimens have failed to achieve iron balance or intensification of iron chelation therapy is required for the rapid reduction of excess iron to avoid permanent organ damage. Combination chelation may provide a more flexible approach for individualizing chelation therapy, thereby improving tolerability, adherence, and quality of life. In principle, iron chelators can be combined with an infinite number of dosing regimens; these involve simultaneous or sequential exposure to the chelators on the same day or alternating the drugs on different days. Clinical studies have established the safety and efficacy of chelation combinations. However, real-life data with combination therapies indicate the significance of compliance for a meaningful reduction in iron overload compared to monotherapies.

Efficacy and safety of early-start deferiprone in infants and young children with transfusion-dependent beta thalassemia: Evidence for iron shuttling to transferrin in a randomized, double-blind, placebo-controlled, clinical trial (START).

Children with transfusion-dependent thalassemia (TDT) require regular blood transfusions that, without iron-chelation therapy, lead to iron-overload toxicities. Current practice delays chelation therapy (late-start) until reaching iron overload (serum ferritin ≥1000 µg/L) to minimize risks of iron-depletion. Deferiprone's distinct pharmacological properties, including iron-shuttling to transferrin, may reduce risks of iron depletion during mild-to-moderate iron loads and iron overload/toxicity in children with TDT. The early-start deferiprone (START) study evaluated the efficacy/safety of early-start deferiprone in infants/young children with TDT. Sixty-four infants/children recently diagnosed with beta-thalassemia and serum ferritin (SF) between 200 and 600 µg/L were randomly assigned 1:1 to receive deferiprone or placebo for 12 months or until reaching SF-threshold (≥1000 µg/L at two consecutive visits). Deferiprone was initiated at 25 mg/kg/day and increased to 50 mg/kg/day; some recipients' dosages increased to 75 mg/kg/day based on iron levels. The primary endpoint was the proportion of patients ≥SF-threshold by month 12. Monthly transferrin saturation (TSAT) assessment evaluated iron-shuttling. At baseline, there was no significant difference in mean age (deferiprone: 3.03 years, placebo: 2.63 years), SF (deferiprone: 513.8 µg/L, placebo: 451.7 µg/L), or TSAT (deferiprone: 47.98%, placebo: 43.43%) between groups. At month 12, there was no significant difference in growth or adverse event (AE) rates between groups. No deferiprone-treated patients were iron-depleted. At month 12, 66% of patients receiving deferiprone remained below SF threshold versus 39% of placebo (p = .045). Deferiprone-treated patients showed higher TSAT levels and reached ≥60% TSAT threshold faster. Early-start deferiprone was well-tolerated, not associated with iron depletion, and efficacious in reducing iron overload in infants/children with TDT. TSAT results provide the first clinical evidence of deferiprone shuttling iron to transferrin.

The efficacy of direct oral anticoagulants in patients on concomitant treatment with levetiracetam.

Guidelines do not support the combination of direct oral anticoagulants (DOACs) and the antiepileptic drug levetiracetam, due to potential relevant P-glycoprotein (P-gp) mediated interaction that might result in decreased DOACs concentrations and increased thromboembolic risk. However, there is no systematic data on the safety of this combination. The aim of this study was to find patients concurrently treated with levetiracetam and DOAC, assess their plasma concentrations of DOAC, and the incidence of thromboembolic events. From our registry of patients on anticoagulation drugs we identified 21 patients concomitantly treated with levetiracetam and DOAC, 19 patients with atrial fibrillation and two patients with venous thromboembolism. Eight patients received dabigatran, 9 apixaban and 4 rivaroxaban. For each subject blood samples were collected for determination of trough DOAC and trough levetiracetam concentrations. The average age was 75 ± 9 years, 84% were males, HAS-BLED score was 1.8 ± 0.8, and in patients with atrial fibrillation CHA2DS2-VASc score was 4.6 ± 2.0. The average trough concentration level of levetiracetam was 31.0 ± 34.5 mg/L. Median trough concentrations of DOACs were for dabigatran 72 (range 25-386) ng/mL, for rivaroxaban 47 (range 19-75) ng/mL, and for apixaban 139 (range 36-302) ng/mL. During the observation period of 1388 ± 994 days none of the patients suffered a thromboembolic event. Our results did not demonstrate a reduction in DOACs plasma levels during levetiracetam treatment, suggesting that levetiracetam could not be an important P-gp inducer in humans. DOAC in combination with levetiracetam remained effective therapy to protect against thromboembolic events.

Real-World Evaluation of Anticoagulant Treatment Patterns in Patients with Atrial Fibrillation: Data from Multicenter ROTA Study.

OBJECTIVE: Oral anticoagulant therapy is the cornerstone of atrial fibrillation management to prevent stroke and systemic embolism. However, there is limited real-world information regarding stroke and systemic embolism prevention strategies in patients with atrial fibrillation. The aim of the ROTA study is to obtain the real-world data of anticoagulant treatment patterns in patients with atrial fibrillation. METHODS: The ROTA study is a prospective, multicenter, and observational study that included 2597 patients with atrial fibrillation. The study population was recruited from 41 cardiology outpatient clinics between January 2021 and May 2021. RESULTS: The median age of the study population was 72 years (range: 22-98 years) and 57.4% were female. The median CHA2DS2-VASc and HAS-BLED scores were 4 (range: 0-9) and 1 (range: 0-6), respectively. Vitamin K antagonists and direct oral anticoagulants were used in 15.9% and 79.4% of patients, respectively. The mean time in therapeutic range was 52.9% for patients receiving vitamin K antagonists, and 76% of those patients had an inadequate time in therapeutic range with <70%. The most common prescribed direct oral anticoagulants were rivaroxaban (38.1%), apixaban (25.5%), and edoxaban (11.2%). The rate of overuse of vitamin K antagonists and direct oral anticoagulants was high (76.1%) in patients with low stroke risk, and more than one-fourth of patients on direct oral anticoagulant therapy were receiving a reduced dose of direct oral anticoagulants. Among patients who were on direct oral anticoagulant treatment, patients with apixaban treatment were older, had higher CHA2DS2-VASc and HAS-BLED scores, and had lower creatinine clearance than the patients receiving other direct oral anticoagulants. CONCLUSIONS: The ROTA study provides important real-world information about anticoagulant treatment patterns in patients with atrial fibrillation.time in therapeutic range with <70%.

[Treatment of a severely injured with active bleeding under apixaban and residual anticoagulatory activity]. / Schwerstverletztenversorgung mit aktiver Blutung unter Apixaban und gerinnungsrelevanter Restaktivität.

Direct oral anticoagulants (DOAC) are increasingly being prescribed for prophylaxis of thromboembolic events. Their use, particularly in emergency settings is difficult as blood level measurements are often not immediately available and until recently there was no possibility for reversal. This article presents the case of a severely injured patient with life-threatening traumatic bleeding under long-term treatment with the factor Xa inhibitor apixaban, viscoelasticity-based detection of residual systemic anticoagulatory activity and targeted reversal.

Identifying treatment heterogeneity in atrial fibrillation using a novel causal machine learning method.

BACKGROUND: Lifelong oral anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent stroke. Over the last decade, multiple new oral anticoagulants (OACs) have expanded the number of treatment options for these patients. While population-level effectiveness of OACs has been compared, it is unclear if there is variability in benefit and risk across patient subgroups. METHODS: We analyzed claims and medical data for 34,569 patients who initiated a nonvitamin K antagonist oral anticoagulant (non-vitamin K antagonist oral anticoagulant (NOAC); apixaban, dabigatran, and rivaroxaban) or warfarin for nonvalvular AF between 08/01/2010 and 11/29/2017 from the OptumLabs Data Warehouse. A machine learning (ML) method was applied to match different OAC groups on several baseline variables including, age, sex, race, renal function, and CHA2DS2 -VASC score. A causal ML method was then used to discover patient subgroups characterizing the head-to-head treatment effects of the OACs on a primary composite outcome of ischemic stroke, intracranial hemorrhage, and all-cause mortality. RESULTS: The mean age, number of females and white race in the entire cohort of 34,569 patients were 71.2 (SD, 10.7) years, 14,916 (43.1%), and 25,051 (72.5%) respectively. During a mean follow-up of 8.3 (SD, 9.0) months, 2,110 (6.1%) of patients experienced the composite outcome, of whom 1,675 (4.8%) died. The causal ML method identified 5 subgroups with variables favoring apixaban over dabigatran; 2 subgroups favoring apixaban over rivaroxaban; 1 subgroup favoring dabigatran over rivaroxaban; and 1 subgroup favoring rivaroxaban over dabigatran in terms of risk reduction of the primary endpoint. No subgroup favored warfarin and most dabigatran vs warfarin users favored neither drug. The variables that most influenced favoring one subgroup over another included Age, history of ischemic stroke, thromboembolism, estimated glomerular filtration rate, Race, and myocardial infarction. CONCLUSIONS: Among patients with AF treated with a NOAC or warfarin, a causal ML method identified patient subgroups with differences in outcomes associated with OAC use. The findings suggest that the effects of OACs are heterogeneous across subgroups of AF patients, which could help personalize the choice of OAC. Future prospective studies are needed to better understand the clinical impact of the subgroups with respect to OAC selection.

Clinical Challenges with Iron Chelation in Beta Thalassemia.

Conventional therapy for severe thalassemia includes regular red cell transfusions and iron chelation therapy to prevent and treat complications of iron overload. Iron chelation is very effective when appropriately used, but inadequate iron chelation therapy continues to contribute to preventable morbidity and mortality in transfusion-dependent thalassemia. Factors that contribute to suboptimal iron chelation include poor adherence, variable pharmacokinetics, chelator adverse effects, and difficulties with precise monitoring of response. The regular assessment of adherence, adverse effects, and iron burden with appropriate treatment adjustments is necessary to optimize patient outcomes.