Citations

Background: Procalcitonin (PCT) is recognized as an inflammatory biomarker, often elevated in COVID-19 pneumonia alongside other biomarkers. Understanding its association with severe outcomes and comparing its predictive ability with other biomarkers is crucial for clinical management. Objectives: This retrospective multicenter observational study aimed to investigate the association between PCT levels and adverse outcomes in hospitalized COVID-19 patients. Additionally, it sought to compare the predictive performance of various biomarkers. Design: The study analyzed data from the Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) registry, comprising COVID-19 patients hospitalized across multiple Mayo Clinic sites between March 2020 and June 2022. Methods: A total of 7851 adult COVID-19 patients were included. Patients were categorized into 6 groups based on the worst WHO ordinal scale. Multivariate models were constructed using peak biomarker levels within 72 hours of admission, adjusted for confounders. Results: Elevated PCT levels were independently associated with increased odds of adverse outcomes, including ICU admission (adjusted odds ratio [aOR] 1.32, 95%CI 1.27-1.38), IMV requirement (aOR 1.35, 95%CI: 1.28-1.42), and in-hospital mortality (aOR 1.30, 95%CI: 1.22-1.37). A 3.48-fold increase in IMV requirement and 3.55 times increase in in-hospital mortality were noted with peak PCT ⩾ 0.25 ng/ml. Similar associations were observed with other biomarkers like NLR (AUC 0.730), CRP, IL-6, LDH (AUC 0.800), and D-dimer (AUC 0.719). Models incorporating NLR, LDH, D-dimer, and PCT demonstrated the highest predictive accuracy, with a combined model exhibiting an area under the curve (AUC) of 0.826 (95%CI 0.803-0.849). Conclusions: Higher PCT levels were significantly linked to worse outcomes in COVID-19 patients, emphasizing its potential as a prognostic marker. Biomarker-based predictive models, particularly those including PCT, showed promising utility for risk assessment and clinical decision-making. Further prospective studies are warranted to validate these findings on a larger scale.

Abstract High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

Introduction: The prognosis for CLL/SLL has improved with the advent of novel therapeutic classes, including BTKis. While comparative data for several BTKis have been published, there are limited data on patient preferences in BTKi treatment selection. Understanding and integrating patient perspective in the BTKi treatment selection process is crucial to shared decision-making and attaining optimal treatment outcomes. To understand patients' priorities for different treatment attributes that impact their treatment decisions, a comprehensive quantitative analysis of patient preferences on BTKi treatment attributes was conducted. Methods: A patient survey with a discrete-choice experiment (DCE) design was conducted from March to June 2024 among USA adults (≥18 years) with confirmed diagnosis of CLL/SLL, recruited through online patient panels, physician referrals, and support groups. BTKi treatment attributes were selected based on results of a targeted literature review and clinical inputs. Patients responded to DCE questions on attributes related to efficacy, safety (eg, impacts of diarrhea, headache, atrial fibrillation, and hypertension on quality of life [QoL]), formulation type, and dosing frequency. The impact of adverse events (AEs) on QoL was defined as the extent to which AEs caused interruptions in patients' ability to engage in their usual day-to-day activities. A conditional logistic regression model was used to calculate the relative importance of each attribute, as well as patient willingness to trade off specified BTKi treatment attributes. Results: A total of 200 patients with CLL/SLL completed the survey (median age: 61 years; 78% White; 55% female; 60% commercially insured; 82% suburban/urban residence). Less than half (43%) were diagnosed ≥5 years ago, and 61% received ≥3 lines of therapy. Almost all (89%) patients reported having experienced ≥1 AE from treatment previously, with the most common AEs being fatigue (76%), diarrhea (51%), headache (51%), and nausea and/or vomiting (51%). When considering the importance of efficacy measures, most patients prioritized CLL/SLL treatments that extended life expectancy (93%), followed by those that increased the likelihood of remission or cure (84%) and those that paused the progression of disease (67%). Patients preferred treatments with higher efficacy, less impact of AEs on QoL, and lower dosing frequency (P<.001). The top 3 treatment attributes with the highest relative importance to patients were impact of atrial fibrillation on QoL (24%), progression-free survival (PFS; 19%), and impact of headache on QoL (18%), followed by impact of diarrhea (14%) and hypertension (14%) on QoL, dosing frequency (9%), and formulation type (3%). On average, patients were willing to accept a reduction of 2.6, 1.9, 1.4, and 1.4 years of PFS to receive a treatment with less (none or mild vs significant) impact of atrial fibrillation, headache, diarrhea, and hypertension on QoL, respectively. Patients were willing to accept a reduction of 1.0 year of PFS to receive once-daily vs twice-daily treatment. Conclusions: Findings from this patient preference survey suggested that impact of atrial fibrillation on QoL, PFS, and impact of headache on QoL were the most important attributes of BTKi treatment for patients with CLL/SLL in the USA. Shared decision-making in CLL/SLL treatment selection should include an informed discussion about AEs, as besides efficacy comparisons, patients may prefer treatments with less impact of AEs on their QoL. Future prospective studies evaluating the effects of shared treatment decision-making on treatment adherence and outcomes are needed to better understand their impact on CLL/SLL patient care and inform clinical practice.

Background: Two National Cancer Institute-funded pharmacovigilance programs have identified 49 serious hematology-related ADRs since 1998. The programs, called RADAR (Research on Adverse Drug events and Reports) and then SONAR (Southern Network on Adverse Reactions) involve > 50 institutions and > 75 co-investigators worldwide. The work builds on three prior studies evaluating “Davids and Goliaths” in medical oncology and in cardiology (PLOS One, eClinicalMedicine, and Journal of Scientific and Professional Integrity). Here we review the hematology focused safety investigations of RADAR/SONAR. Methods: Data were based on initial safety signals being identified by a RADAR/SONAR co-investigator. Then, case-series were derived. Collaborations with basic scientists allowed for basic science correlative studies. Results were disseminated primarily as Brief Report in the literature and Black Box warnings on the related drug. In some instances, studies identified hematologic toxicities that prevent FDA from approving a submitted drug application. Results: sADRs were frequently identified based on very small case series, including ticlopidine-and clopidogrel associated thrombotic thrombocytopenic purpura (22 and 10 patients, respectively), thalidomide- and lenalidomide-associated venous thromboembolism (9 and 5 patients, respectively), rituximab-associated progressive multi-focal leukoencephalopathy (22 patients), peginesatide-associated fatal anaphylaxis (5 patients), and COVID-19 vaccine associated immune thrombocytopenia (1 patient). Meta-analyses provided data for epoetin- and darbepoetin-associated mortality among cancer patients and lenalidomide- and thalidomide-associated venous thromboembolism. Following the onset of the COVID-19 pandemic, RADAR/SONAR investigated social media and pre-prints (COVID-19 vaccine associated cerebral vein thrombosis and immune thrombocytopenia). Time from FDA approval to sADR discovery was a median of 5 years (range, 0 months (thalidomide-associated venous thromboembolism) to 34 years (ciprofloxacin-associated neuropsychiatric toxicity). Basic science correlative studies identified ADAMTS13 autoantibodies (ticlopidine), leachates that developed in a multi-dose vial (peginesatide), anti-red blood cell antibodies (epoetin-associated pure red cell aplasia), and high-risk genes (fluoroquinolones and rituximab). Overall, RADAR/SONAR studies are estimated to have saved over 1 million lives and also resulted in overall payments to the Department of Justice of $1.5 billion (related to marketing of unsafe drugs). Discussion: RADAR/SONAR has proven to be a very important adjunct to FDA and pharmaceutical manufacturer-led safety investigations for hematology, paralleling the success in medical oncology and in cardiology. Going forward, independent centers of excellence for safety-focused investigations such as the CERSI network and the SENTINEL network (both are NIH funded) should be broadened to include a hematology-focused safety center.

Objective Extracorporeal cardiopulmonary resuscitation (ECPR) utilizes veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in cardiac arrest patients to reduce the risk of mortality and multiorgan dysfunction from systemic hypoperfusion. We aimed to compare clinical outcomes of patients receiving ECPR versus conventional cardiopulmonary resuscitation (CCPR) for refractory cardiac arrest. Data Sources This was a systematic review and meta-analysis. A librarian searched the main databases, Ovid MEDLINE (including epub ahead of print, in-process & other non-indexed citations), Ovid EMBASE and Ovid Cochrane Central Register of Controlled Trials from inception through July 2024. Study Selection We included randomized controlled trials and observational studies that compared the outcomes of ECPR to CCPR in cardiac arrest patients. Primary outcomes were neurological sequelae and survival. Data Extraction We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two reviewers independently screened articles, extracted data on selected articles and performed risk of bias assessments using ROBINS-I for non-randomized controlled trials and the revised Cochrane risk of bias tool for randomized controlled trials with disagreements settled by a third independent reviewer. Data Synthesis Out of 3458 studies identified and screened, 28 studies including 304,360 cardiac arrest patients met eligibility criteria and were included. Survival at hospital discharge was 20% for ECPR versus 3.3% for CCPR (OR 0.48 [CI 0.27, 0.84]). Favorable neurological outcome at hospital discharge was 11.8% for ECPR versus 1.9% for CCPR (OR 0.41 [CI 0.17, 1.01]). Complications from bleeding were ten times higher in the ECPR group (35.3% vs 3.7%; OR 0.08 [0.03, 0.24]). Conclusions ECPR appeared to be superior to CCPR for improved neurological outcome and survival in cardiac arrest patients, although bleeding was increased. There was large heterogeneity in the included studies and outcomes reported. Future prospective studies may improve the identification of subgroups of patients that will benefit most from ECPR. Systematic review and meta-analysis registration: PROSPERO - CRD42023394128.

e19049 Background: Acala and zanu are 2nd generation Bruton tyrosine kinase inhibitors (BTKis) that have demonstrated improved safety profiles vs 1st generation BTKi ibrutinib in clinical trials. While head-to-head comparison of zanu vs acala is lacking, a recent meta-analysis of clinical trials provided a comprehensive, indirect comparison of the AE profiles in B-cell malignancies (Hwang, Hemasphere. 2023;7(S3):1134). This study aims to evaluate costs and impacts on quality of life (QoL) for zanu vs acala using their AE profiles. Methods: A health economic model was developed to determine cost and QoL associated with AE management for zanu and acala. The incidence rates ( IRs) of all grade and grade ≥3 AEs of interest (n=21, including bleeding events, hypertension, atrial fibrillation, cytopenias, infections, headache, arthralgia, diarrhea) were taken from the meta-analysis. Additional model inputs, such as disutility, average duration of AE, and unit cost of each AE were sourced from published literature and publicly available cost databases in consultation with clinical experts. The model was developed from the US perspective, considering Medicare costs, inflated to 2023 USD. Model outcomes were AE management cost (= IR * unit cost) and quality-adjusted life years (QALYs) lost due to AE (= IR * Disutility * Duration/365.25). Results: In the base-case scenario (considering all AEs), treating a hypothetical cohort of 1000 patients (pts) with zanu instead of acala yielded cost savings of $124K and 3.7 QALY gains (i.e., 3.7 years extra in full health). Subgroup analysis for severe (grade ≥3) and non-severe AEs (grade 1-2) demonstrated similar trends. A sensitivity analysis limited to AEs significantly different between zanu and acala (n=13) yielded consistent results. Additionally, a probabilistic sensitivity analysis, conducted with 1000 iterations to account for uncertainty in model parameters, confirmed robustness of the model, indicating stable conclusions across a wide range of parameter uncertainties. Conclusions: This analysis suggested that zanu is cost-saving and associated with added health benefits compared to acala in terms of AE management in pts with B-cell malignancies. Should these results derived from meta-analysis of clinical trial data be applicable to real-world pt populations across different indications, the potential cost savings could be considerable. These results could be further improved if the differences in efficacy of zanu vs acala are also incorporated. [Table: see text]

Abstract Aims Diagnosing myocardial infarction (MI) in patients with chronic kidney disease (CKD) is difficult as they often have increased high-sensitivity cardiac troponin T (hs-cTnT) concentrations. Methods and results Observational US cohort study of emergency department patients undergoing hs-cTnT measurement. Cases with ≥1 hs-cTnT increase > 99th percentile were adjudicated following the Fourth Universal Definition of MI. Diagnostic performance of baseline and serial 2 h hs-cTnT thresholds for ruling-in acute MI was compared between those without and with CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2). The study cohort included 1992 patients, amongst whom 501 (25%) had CKD. There were 75 (15%) and 350 (70%) patients with CKD and 80 (5%) and 351 (24%) without CKD who had acute MI and myocardial injury. In CKD patients with baseline hs-cTnT thresholds of ≥52, >100, >200, or >300 ng/L, positive predictive values (PPVs) for MI were 36% (95% CI 28–45), 53% (95% CI 39–67), 73% (95% CI 50–89), and 80% (95% CI 44–98), and in those without CKD, 61% (95% CI 47–73), 69% (95% CI 49–85), 59% (95% CI 33–82), and 54% (95% CI 25–81). In CKD patients with a 2 h hs-cTnT delta of ≥10, >20, or >30 ng/L, PPVs were 66% (95% CI 51–79), 86% (95% CI 68–96), and 88% (95% CI 68–97), and in those without CKD, 64% (95% CI 50–76), 73% (95% CI 57–86), and 75% (95% CI 58–88). Conclusion Diagnostic performance of standard baseline and serial 2 h hs-cTnT thresholds to rule-in MI is suboptimal in CKD patients. It significantly improves when using higher baseline thresholds and delta values.