Annals of Pharmacotherapy最新文献

Objective: The objective of the study is to critically review the literature about clinical evidence on the efficacy and safety of fitusiran among patients with hemophilia A or B.

Data sources: A targeted search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov was performed from inception through November 2025 using the terms fitusiran, antithrombin, RNA interference, siRNA, and hemophilia A or B.

Study selection and data extraction: Eligible studies were randomized controlled trials across all phases enrolling patients with hemophilia A or B. The review incorporated 2 phase 1 studies, 1 phase 2 study, and 4 phase 3 trials.

Data synthesis: Fitusiran prophylaxis reduced annualized bleeding rates by about 70% to 90% compared with on-demand therapy or previous prophylaxis using bypassing agents, and by up to 50% compared with prior prophylaxis with clotting factor concentrates. Between 50% and 65% of participants experienced no bleeds requiring treatment. Health-related quality of life improved, with mean reductions in Hemophilia-specific Quality of Life Questionnaire for Adults (Haem-A-QoL) scores ranging from -4.6 to -12.3. Safety evaluations showed aminotransferase elevations in 19% to 25%, gallbladder events in 13% to 15%, and thrombotic events in ≤5% of patients, primarily associated with low antithrombin levels or excessive factor use. Long-term extension studies confirmed sustained bleed protection and safety with antithrombin-guided dosing.Relevance to patient care and clinical practice in comparison to existing drugs:Fitusiran is a subcutaneous nonfactor prophylactic treatment that lowers antithrombin to rebalance coagulation with or without inhibitors in patients with hemophilia A and B. It is administered every 2 months, and associated with fewer bleeds, and improved quality of life compared with standard of care.

Conclusions: Fitusiran expands prophylactic options for hemophilia A and B, providing sustained bleed protection with infrequent dosing. Integration into practice requires monitoring of antithrombin activity to mitigate thrombotic or bleeding risk, and liver and gallbladder functions for safety.

Background: Current guidelines advise against use of aspirin for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients with increased bleeding risk, including use of anticoagulation. However, limited data exist regarding safety and efficacy of low-dose aspirin (75 to 100 mg daily) for primary prevention of ASCVD in patients with atrial fibrillation (AF) receiving a direct oral anticoagulant (DOAC) for thromboembolism prevention.

Objective: This study aimed to evaluate the safety and effectiveness of low-dose aspirin for primary ASCVD prevention in patients with AF who are receiving DOAC therapy.

Methods: This multicenter, retrospective cohort study evaluated apixaban or rivaroxaban plus low-dose aspirin for primary prevention of ASCVD (combination therapy group) compared with those receiving DOAC monotherapy in patients 18 to 79 years of age with AF and no history of ASCVD. The primary safety endpoint was incidence of major bleeding per 100 patient-years, defined by the International Society on Thrombosis and Hemostasis criteria. Secondary endpoints included incidence of clinically relevant non-major bleeding (CRNMB), hospitalization for an ASCVD event, and death.

Results: A total of 611 patients were included (411 DOAC monotherapy and 200 combination therapy), contributing 973 patient-years of follow-up. Incidence of major bleeding was significantly lower in the DOAC monotherapy group (1.37 vs 5.74 per 100 patient-years; relative risk [RR] = 0.35, 95% confidence interval [CI] = 0.16-0.77, P = 0.006). On multivariable analysis, combination therapy remained independently associated with major bleeding (odds ratio= 3.15, 95% CI = 1.32-7.79, P = 0.010). The combination group also experienced a significantly higher incidence of CRNMB. No difference in ischemic events was observed between groups.

Conclusion and relevance: In patients with AF and no history of ASCVD, the addition of low-dose aspirin to DOAC therapy significantly increased risk of major bleeding and CRNMB without reducing ischemic events. These findings support deprescribing aspirin for primary prevention in this population to minimize bleeding risk while maintaining thromboembolic prevention.

Background: Lebrikizumab is a monoclonal antibody targeting interleukin 13 (IL-13), a key cytokine in the pathogenesis of atopic dermatitis (AD). It was approved by the Food and Drug Administration (FDA) in 2024 for the treatment of moderate-to-severe AD in patients aged ≥12 years.

Data sources: A literature search was conducted through October 2025 using PubMed and ClinicalTrials.gov with the terms "lebrikizumab," "Ebglyss," "lebrikizumab clinical trials," and "lebrikizumab atopic dermatitis." Phase I to III clinical trials, post-approval studies, and FDA package insert were reviewed.

Study selection and data extraction: Trials evaluating lebrikizumab in patients with AD were included. Data were extracted on study design, pharmacology, efficacy outcomes, and safety events. One phase I, 2 phase II, and 6 phase III studies were summarized along with real-world evidence.

Data synthesis: Lebrikizumab had dose-dependent reductions in AD severity and pruritus, with improvements observed as early as day 2. Across phase III trials, 33% to 43% of lebrikizumab-treated patients achieved an Investigator's Global Assessment Score (IGA) 0/1 compared with 11% or less with placebo. Adverse events were mild; conjunctivitis occurred less frequently than with agents targeting both IL-4 and IL-13.Relevance to patient care and clinical practice in comparison to existing drugs:As a selective IL-13 inhibitor, lebrikizumab offers comparable efficacy with reduced ocular adverse events relative to dupilumab. Its pharmacologic distinctions from tralokinumab may carry clinical implications.

Conclusion: Lebrikizumab is an effective and well-tolerated biologic with rapid onset of action and favorable safety for treatment of moderate-to-severe AD.

Background: In 2019, the Food and Drug Administration issued a warning regarding the risk of respiratory depression with gabapentin use, especially when combined with opioids or other central nervous system depressants. While prior inpatient studies have observed increased respiratory risks in postoperative patients, data are limited in hospitalized patients with renal dysfunction.

Objective: The objective of the study is to evaluate the association between gabapentinoid use and respiratory depression in hospitalized patients with chronic kidney disease (CKD).

Methods: This single-center retrospective cohort study included adult inpatients receiving a multimodal pain regimen with or without gabapentinoid and CKD stage III, IV, or V. Patients were excluded if they had a history of epilepsy, generalized anxiety disorder, restless leg syndrome, acute respiratory conditions, hepatic disease, or were initially admitted to the intensive care unit. The primary outcome was a composite measure of respiratory depression, including use of high-flow nasal cannula, bilevel positive airway pressure, mechanical ventilation, oxygen escalation, naloxone or flumazenil administration, or rapid response/code activation. Secondary outcomes included altered mental status, falls, and individual components of the primary outcome.

Results: A total of 320 patients were included. In the unadjusted analysis, respiratory depression occurred in 35.6% of gabapentinoid users versus 24.1% of nonusers (P = 0.10). After controlling for confounders, gabapentinoid use was associated with a significantly higher risk of respiratory depression (odds ratio: 1.71; 95% confidence interval: 1.02-2.89). A dose-dependent relationship was observed with respiratory depression: gabapentin >1400 mg/d (83.3%), 800 to 1400 mg/d (42.3 %), and 100 to 700 mg/d (29.7%); pregabalin >150 mg/d (66.7%) and ≤150 mg (26.3%). Secondary outcomes were not significantly different between groups.

Conclusion and relevance: Gabapentinoid use in hospitalized CKD patients was associated with respiratory depression. These findings support the need for careful dosing and monitoring of gabapentinoids in this high-risk population.

Adverse events and medication-related errors are common with anticoagulants. Heparin infusions are frequently associated with administration errors or challenges potentially leading to undesired events. Solving these challenges is multi-faceted given related complexities associated with the process, numerous variabilities related to heparin itself, heparin resistance, factors impacting assays to measure the intensity of anticoagulation, ineffective education processes, and limited data even on describing optimal target ranges to hard outcomes of thrombosis and bleeding. To overcome this, health care professionals have looked to technology as a potential solution. Some components of technology, such as smart pumps, and timing lab slips for ordering assays at a selected time to avoid incorrect information, have been means of improving management; however, gaps are still recognized. One component of treatment post a venous thromboembolism is achieving target goals within 24 hours. However, incorrect timing of assay draws related to the bolus and the related changes in order of elimination can work against achieving it unless the situation is understood and adapted during management. Machine learning is being explored to do this; however, it is not yet ready for prime time. Moving forward, clinicians need to stay engaged and be aware of the variables present. This includes an understanding of all assumptions, limitations and verification of what is intended does occur. The process should include validation of hard outcomes with the management approach.

Background: Rasburicase is used to prevent and treat tumor lysis syndrome (TLS) by breaking down uric acid. Administration methods vary, including fixed, weight-based (0.15-0.2 mg/kg), single and multiple doses. Our primary objective is to describe rasburicase use in both adults and children for TLS prevention and treatment. Secondary objectives are to describe the efficacy and safety of different regimens inventoried. Exploratory objective is to estimate savings associated with use of a single fixed dose.

Methods: Retrospective descriptive study conducted among patients who received rasburicase for TLS prevention or treatment between January 2014 and April 2024 in 3 oncology services of the Hospital Center.

Results: A total of 133 adults and 60 children were included, of which 42.9% and 5.0%, respectively, presented biochemical TLS pre-rasburicase. A single 6 mg dose was administered in 86.5% of adults and 21.7% of children. Multiple daily doses were used in 24.8% of adults and 76.7% of children. Few adults (1.5%) received weight-based doses, contrary to children (76.7%). Normalized uric acid (< 476 μmol/L) was observed in 97.9% of patients 24 hours after a first dose, with no serious adverse events. Estimated savings were 86 542.92 CA$ if all patients included (n = 193) received a single 0.15 mg/kg dose, capped at 6 mg.

Conclusion and relevance: In the adult and pediatric population, a single rasburicase dose of 0.15 to 0.2 mg/kg, capped at 6 mg, represents an effective, safe, and more cost-effective option for both the prevention and treatment of TLS. Further studies are warranted to compare single versus multiple dosing in pediatric populations and to identify potential risk factors for nonresponders.

Background: There is a lack of information regarding the combination therapy of phenobarbital (PB) and benzodiazepine (BZD) for the symptomatic management of patients in or at risk of severe alcohol withdrawal syndrome (AWS).

Objective: The objective of this study was to assess the safety and efficacy of a PB loading dose in addition to symptom-triggered BZD treatment for patients in or at risk of severe AWS.

Methods: Between January 2024 and May 2025, patients treated for AWS were screened for inclusion. Criteria for inclusion were age of at least 18 years old, a Prediction of Alcohol Withdrawal Severity Scale (PAWSS) score of 4 or higher, and a record of receiving treatment for AWS. Patients were excluded from the study if they were directly admitted to the intensive care unit (ICU) or psychiatric service, transferred to the ICU within 12 hours of admission, or with a length of stay less than 24 hours. The primary endpoint was the difference in cumulative BZD requirements. Secondary endpoints included the need for adjunct therapies, incidence of adverse events, and escalation of care.

Results: The final analysis included 75 patients in the BZD group and 63 patients in the PB group. There was a statistically significant decrease in the cumulative BZD utilization in the PB loading group. Patients who exclusively received BZD therapy for AWS used an average of 148 mg of diazepam equivalents versus 112 mg in the PB group (P = 0.002). The PB group was also associated with a statistically significant reduction in the incidence of hypotension, respiratory depression, and the need for adjunct therapies.

Conclusions and relevance: The addition of a weight-based PB loading dose showed a significant reduction in BZD utilization for patients in or at risk of severe AWS and was associated with fewer adverse events. Application of this information may aid in enhancing treatment for patients in or at risk of severe AWS.