A meta-analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor-related major bleeding.

BACKGROUND: Andexanet alfa (andexanet) and prothrombin complex concentrate (PCC) are both reversal agents for major bleeding in patients using factor Xa inhibitors (FXaIs). Our aim was to evaluate the current evidence for the effectiveness and safety of andexanet and PCC in a systematic review and meta-analysis. OBJECTIVES: Primary objective was hemostatic effectiveness. Secondary objectives were thromboembolic event rate and mortality. METHODS: A systematic review was performed in PubMed and Embase. Studies describing the effectiveness and/or safety of PCC or andexanet in patients with major bleeding using FXaIs were included. Meta-analysis was performed using a random-effects model. RESULTS: Seventeen PCC studies, 3 andexanet studies, and 1 study describing PCC and andexanet were included, comprising 1428 PCC-treated and 396 andexanet-treated patients. None of the included studies had control groups, hampering a pooled meta-analysis to compare the two reversal agents. Separate analyses for andexanet and PCC were performed. In subgroup analysis, the pooled proportion of patients with effective hemostasis in studies that used Annexa-4 criteria demonstrated a hemostatic effectiveness of 0.85 (95% confidence interval [CI], 0.80-0.90) in PCC and 0.82 (95% CI, 0.78-0.87) in andexanet studies. The pooled proportion of patients with thromboembolic events was 0.03 (95% CI, 0.02-0.04) in PCC and 0.11 (95% CI, 0.04-0.18) in andexanet studies. CONCLUSION: Based on the available evidence with low certainty from observational studies, PCC and andexanet demonstrated a similar, effective hemostasis in the treatment of major bleeding in patients using FXaIs. Compared to PCC, the thromboembolic event rate appeared higher in andexanet-treated patients.

Quantification of total and unbound cefuroxime in plasma by ultra-performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure.

BACKGROUND: Pharmacokinetic studies of cefuroxime by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) have been limited to measurements of total concentrations. Here, we developed a robust method for quantifying total and unbound cefuroxime concentrations using UPLC-MS/MS and ultrafiltration in critically ill patients with hypoalbuminemia and renal failure. METHODS: Method validation included accuracy, linearity, precision, repeatability, recovery, and limit of quantification (LOQ). Feasibility of the method was performed on samples obtained from randomly selected intensive care unit (ICU) patients. Total and unbound cefuroxime concentrations were quantified using UPLC-MS/MS. Sampling times were categorized as trough (180-1 min prior to administration), peak (10-30 min after administration), mid (30-360 min after administration), and continuous (sampling during administration). Pharmacokinetic/pharmacodynamic (PK/PD) targets were unbound cefuroxime concentrations above 4 times the minimum inhibitory concentration (32 mg/L). RESULTS: Intra-assay and inter-assay precision was <3%. Recovery was 99.7%-100.3%, and LOQ was 0.1 mg/L. We included 11 patients (median age 72 years (range 54-77). Median albumin serum concentrations and eGFR were 19 g/L (range 11-40 g/L) and 48 mL/min/1.73 m2 (range 7-115 mL/min/1.73 m2 ), respectively. Median trough and mid concentrations of total cefuroxime were 22.27 mg/L (range 5.42-54.03 mg/L) and 71.49 mg/L (range 53.87-73.86 mg/L), and median unbound fraction was 75.42% (range 27.36%-99.75%). Median unbound cefuroxime concentrations were 11.94 mg/L (range 3.85-32.39 mg/L) (trough) and 55.62 mg/L (range 10.03-62.62 mg/L) (mid). CONCLUSION: The method is precise and accurate according to ISO 15189 and within the clinical range of cefuroxime (0.5-100 mg/L). The method was applied in ICU patients and is suitable for TDM on unbound cefuroxime concentrations.

Use of high-dose intermittent systemic glucocorticoids and the risk of fracture in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow obstruction and respiratory symptoms. While short course systemic GCs are prescribed in patients with acute COPD exacerbations, little is known of the risk of fractures with intermittent exposure to high-dose GC and the effect of proxies of disease severity. METHODS: A case-control study was conducted using the Danish National Hospital Discharge Registry (NHDR) between January 1996 to December 2011. Conditional logistics regression models were used to derive adjusted odds ratios (OR) risk of fractures in subjects with COPD stratified by intermittent high-dose, and proxies of disease severity. RESULT: A total of 635,536 cases and the same number of controls were identified (mean age 67.5±13.8, 65% female). COPD patients with intermittent use of high average daily dose oral glucocorticoids did not have an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fracture compared to non-COPD patients (adj. OR 0.65; 95% CI: 0.50-0.86, 0.70; 95% CI: 0.70-0.99, 1.17; 95% CI: 0.59-2.32, 1.98; 95% CI: 0.59-6.65 respectively). We identified an elevated risk of osteoporotic fracture among patients who visited the emergency unit (adj. OR 1.47; 95% CI 1.20-1.79) or were hospitalised in the past year for COPD (adj. OR 1.76; 95% CI 1.66-1.85). Current GC use among COPD patients was associated with an increased risk of osteoporotic, hip and clinically symptomatic vertebral fractures compared to patients without COPD. CONCLUSION: Intermittent high-dose GCs was not associated with an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fractures in patients with COPD. Current GC use was however associated with an increased risk of hip and clinically symptomatic vertebral fractures. Therefore, emphasis on prophylactic treatment of fractures may not be essential in patients with COPD receiving intermittent dose of GCs, whereas this should be considered for high-dose long-term users with advanced COPD disease stage, postmenopausal women and men over 40years.