Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.

Use of defibrotide in COVID-19 pneumonia: comparison of a phase II study and a matched real-world cohort control.

The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by 31st December 2023. The DEFI-VID19 study (ClinicalTrials.gov NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg/d intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was Respiratory Failure Free Survival (RFFS); Overall Survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (HR=0.71[0.95CI: 0.34 to 1.29, P= .138]) and OS (HR=0.78[0.95CI: 0.33 to 1.53, P= .248]) and showed a significantly increased number of post-recovery days (difference in means: 3.61[ 0.95CI: 0.97 to 6.26, P= .0037]). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.

Chronic Pain and Pain Management in Older Adults: Protocol and Pilot Results.

BACKGROUND: Chronic pain occurs in 30% of older adults. This prevalence rate is expected to increase, given the growth in the older adult population and the associated growth of chronic conditions contributing to pain. No population-based studies have provided detailed, longitudinal information on the experience of chronic pain in older adults; the pharmacological and nonpharmacological strategies that older adults use to manage their chronic pain; and the effect of chronic pain on patient-reported outcomes. OBJECTIVES: This article aims to describe the protocol for a population-based, longitudinal study focused on understanding the experience of chronic pain in older adults. The objectives are to determine the prevalence and characteristics of chronic pain; identify the pharmacological and nonpharmacological pain treatments used; evaluate for longitudinal differences in biopsychosocial factors; and examine how pain types and pain trajectories affect important patient-reported outcomes. Also included are the results of a pilot study. METHODS: A population-based sample of approximately 1,888 older adults will be recruited from the National Opinion Research Center at the University of Chicago's AmeriSpeak Panel to complete surveys at three waves: enrollment (Wave 1), 6 months (Wave 2), and 12 months (Wave 3). To determine the feasibility, a pilot test of the enrollment survey was conducted among 123 older adults. RESULTS: In the pilot study, older adults with chronic pain reported a range of pain conditions, with osteoarthritis being the most common. Participants reported an array of pharmacological and nonpharmacological pain strategies. Compared to participants without chronic pain, those with chronic pain reported lower physical and cognitive function and poorer quality of life. Data collection for the primary, longitudinal study is ongoing. DISCUSSION: This project will be the first longitudinal population-based study to examine the experience and overall effect of chronic pain in older adults. Pilot study results provide evidence of the feasibility of study methods. Ultimately, this work will inform the development of tailored interventions for older patients targeted to decrease pain and improve function and quality of life.

Balancing Benefit and Harm of Intensive Blood Pressure Lowering Based on Individual Outcome Profile Analysis.

BACKGROUND: Intensive blood pressure lowering prevents major adverse cardiovascular events, but some patients experience serious adverse events. Examining benefit-harm profiles may be more informative than analyzing major adverse cardiovascular events and serious adverse events separately. METHODS: We analyzed data from the Systolic Blood Pressure Intervention Trial (n = 9361), comparing intensive treatment (systolic blood pressure target <120 mm Hg) to standard treatment (<140 mm Hg). A 4-year hierarchical outcome profile was defined for each participant: 1) alive with neither major adverse cardiovascular events nor serious adverse events (most desirable); 2) alive with serious adverse events only; 3) alive with major adverse cardiovascular events only; 4) alive with both events; and 5) deceased (least desirable). We compared 4-year outcome profiles between the treatment groups in the entire population and by frailty subgroups defined using physical frailty phenotype (non-frail, pre-frail, and frail). RESULTS: The proportion who died were lower with intensive treatment than standard treatment (5% vs 6%). A higher proportion of the intensive treatment group was alive with serious adverse events and no major adverse cardiovascular events (36% vs 33%), and a lower proportion were alive with both events (6% vs 5%) than the standard treatment group. The outcome profiles were more favorable among those with physical frailty phenotype who were treated with intensive treatment vs standard treatment, but outcome profiles were similar between the treatment groups among non-frail or pre-frail participants. CONCLUSIONS: This post hoc proof-of-concept analysis demonstrates the utility of the outcome profile analysis that simultaneously examines the benefit and harm of the treatment.

Using a Clinically Interpretable End Point Composed of Multiple Outcomes to Evaluate Totality of Treatment Effect in Comparative Oncology Studies.

This cohort study demonstrates how to use cumulative event count curves to create a clinically meaningful end point by simultaneously considering recurrence, progression, and survival times from the individual patient.

Effect of Dapagliflozin on Total Heart Failure Events in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Trial.

Importance: In the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, dapagliflozin reduced the risk of time to first worsening heart failure (HF) event or cardiovascular death in patients with HF with mildly reduced or preserved ejection fraction (EF). Objective: To evaluate the effect of dapagliflozin on total (ie, first and recurrent) HF events and cardiovascular death in this population. Design, Setting, and Participants: In this prespecified analysis of the DELIVER trial, the proportional rates approach of Lin, Wei, Yang, and Ying (LWYY) and a joint frailty model were used to examine the effect of dapagliflozin on total HF events and cardiovascular death. Several subgroups were examined to test for heterogeneity in the effect of dapagliflozin, including left ventricular EF. Participants were enrolled from August 2018 to December 2020, and data were analyzed from August to October 2022. Interventions: Dapagliflozin, 10 mg, once daily or matching placebo. Main Outcomes and Measures: The outcome was total episodes of worsening HF (hospitalization for HF or urgent HF visit requiring intravenous HF therapies) and cardiovascular death. Results: Of 6263 included patients, 2747 (43.9%) were women, and the mean (SD) age was 71.7 (9.6) years. There were 1057 HF events and cardiovascular deaths in the placebo group compared with 815 in the dapagliflozin group. Patients with more HF events had features of more severe HF, such as higher N-terminal pro-B-type natriuretic peptide level, worse kidney function, more prior HF hospitalizations, and longer duration of HF, although EF was similar to those with no HF events. In the LWYY model, the rate ratio for total HF events and cardiovascular death for dapagliflozin compared with placebo was 0.77 (95% CI, 0.67-0.89; P < .001) compared with a hazard ratio of 0.82 (95% CI, 0.73-0.92; P < .001) in a traditional time to first event analysis. In the joint frailty model, the rate ratio was 0.72 (95% CI, 0.65-0.81; P < .001) for total HF events and 0.87 (95% CI, 0.72-1.05; P = .14) for cardiovascular death. The results were similar for total HF hospitalizations (without urgent HF visits) and cardiovascular death and in all subgroups, including those defined by EF. Conclusions and Relevance: In the DELIVER trial, dapagliflozin reduced the rate of total HF events (first and subsequent HF hospitalizations and urgent HF visits) and cardiovascular death regardless of patient characteristics, including EF. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Quantifying and Interpreting the Prediction Accuracy of Models for the Time of a Cardiovascular Event-Moving Beyond C Statistic: A Review.

Importance: For personalized or stratified medicine, it is critical to establish a reliable and efficient prediction model for a clinical outcome of interest. The goal is to develop a parsimonious model with fewer predictors for broad future application without compromising predictability. A general approach is to construct various empirical models via individual patients' specific baseline characteristics/biomarkers and then evaluate their relative merits. When the outcome of interest is the timing of a cardiovascular event, a commonly used metric to assess the adequacy of the fitted models is based on C statistics. These measures quantify a model's ability to separate those who develop events earlier from those who develop them later or not at all (discrimination), but they do not measure how closely model estimates match observed outcomes (prediction accuracy). Metrics that provide clinically interpretable measures to quantify prediction accuracy are needed. Observations: C statistics measure the concordance between the risk scores derived from the model and the observed event time observations. However, C statistics do not quantify the model prediction accuracy. The integrated Brier Score, which calculates the mean squared distance between the empirical cumulative event-free curve and its individual patient's counterparts, estimates the prediction accuracy, but it is not clinically intuitive. A simple alternative measure is the average distance between the observed and predicted event times over the entire study population. This metric directly quantifies the model prediction accuracy and has often been used to evaluate the goodness of fit of the assumed models in settings other than survival data. This time-scale measure is easier to interpret than the C statistics or the Brier score. Conclusions and Relevance: This article enhances our understanding of the model selection/evaluation process with respect to prediction accuracy. A simple, intuitive measure for quantifying such accuracy beyond C statistics can improve the reliability and efficiency of the selected model for personalized and stratified medicine.