Brad Woodward

A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: comparison with a controlled clinical trial.

Objective:To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (DrotAA) in clinical practice to those treated in a phase III randomized controlled trial (PROWESS). Design:Observational data were collected retrospectively from patients who received DrotAA as part of physician-directed treatment. Setting:Intensive care units of five teaching institutions. Patients:Patients were ≥18 yrs old, had severe sepsis (confirmed/suspected infection with one or more sepsis-induced organ dysfunctions), and received DrotAA. Interventions:None. Measurements and Main Results:Baseline demographics, severity of illness, time from organ dysfunction onset to DrotAA treatment, daily assessment of organ dysfunction, serious bleeding events, and in-hospital mortality were reported. Timing from severe sepsis documentation to start of DrotAA infusion was categorized: day 0 (same calendar day); day 1 (next calendar day); and day ≥2 (second calendar day or later). Clinical practice patients (n = 274) were younger, had more comorbidities, had higher severity of illness (as measured by organ dysfunction or greater vasopressor/ventilator use), and received DrotAA later than PROWESS patients (all p < .05). Overall hospital mortality for clinical practice patients was 42%, compared with 37% for DrotAA-treated PROWESS patients with Acute Physiology and Chronic Health Evaluation II score ≥25. Mortality for day 0, day 1, and day ≥2 groups was 33%, 40%, and 52%, respectively. In PROWESS, the vast majority were treated on day 0 or day 1. Serious bleeding events during infusion were noted in 4.0% of clinical practice patients compared with 2.2% of PROWESS DrotAA-treated patients with Acute Physiology and Chronic Health Evaluation II score ≥25. Conclusions:Patients treated in clinical practice differed from those in PROWESS. Patients were younger, had more comorbidities, had greater severity of illness, and had longer mean time from severe sepsis onset to the start of DrotAA. Hospital mortality for patients treated within 1 day of severe sepsis onset was similar to DrotAA-treated PROWESS patients. While the low number of serious bleeding events precludes a definitive assessment, the observed incidence of serious bleeding events in clinical practice patients was numerically higher than in DrotAA-treated PROWESS patients.

CURB-65, PSI, and APACHE II to assess mortality risk in patients with severe sepsis and community acquired pneumonia in PROWESS.

Background: Patients with community-acquired pneumonia (CAP) comprised 35.6% of the overall phase 3 Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study and 33.1% of the placebo arm. We investigated the use of CURB-65, the Pneumonia Severity Index (PSI), and Acute Physiology and Chronic Health Evaluation II (APACHE II) prediction scores to identify the CAP population from the PROWESS placebo arm at the greatest mortality risk. Methods: Patients were classified as having CAP if the lung was the primary infection site and the patient originated from home. The abilities of CURB-65, PSI, and APACHE II scores to determine the 28-day and in-hospital mortality were compared using receiver operator characteristic (ROC) curves and the associated areas under the curve. Results: PROWESS enrolled 278 patients with CAP in the placebo arm. The areas under the ROC curves for PSI = 5, CURB-65 ≥3, and APACHE II ≥25 for predicting 28-day (c = 0.65, 0.66, and 0.64, respectively) and in-hospital mortality (c = 0.65, 0.65, and 0.64, respectively) were not statistically different from each other. The 28-day mortality of patients with a PSI score of 5, CURB-65 ≥3, and APACHE II ≥25 was 41.6%, 37.9%, and 43.5%, respectively. Conclusions: Despite early diagnosis and appropriate antibiotic therapy, conventionally treated CAP with PSI = 5, CURB-65 ≥3, or APACHE II ≥25 has an unacceptably high mortality. In this study, PSI, CURB-65, and APACHE II scoring systems perform similarly in predicting the 28-day and in-hospital mortality; however, differences in the categorization of severe CAP were observed and there was a significant mortality in patients with a CURB-65 <3 and PSI <5.

Safety of drotrecogin alfa (activated) in severe sepsis: Data from adult clinical trials and observational studies

Drotrecogin alfa (activated) (DrotAA), or recombinant human activated protein C, represents the only Food and Drug Administration-approved therapy for mortality reduction in adult patients with severe sepsis. Drotrecogin alfa (activated) has properties that address microvascular injury in severe sepsis through its direct effects on endothelial cells and leukocytes while also having antithrombotic and indirect profibrinolytic properties. Sepsis bundle and guideline implementation has been associated with improved survival and includes DrotAA administration in appropriate patients. Several DrotAA postapproval clinical studies have yielded additional outcome and safety data, better defining its benefit/risk profile. Bleeding is more common in DrotAA-treated patients; therefore, a careful assessment of bleeding risk and an understanding of the safety profile is required. This summary provides a detailed review of safety data and outcomes of patients treated with DrotAA in recent clinical studies enrolling more than 7000 adult patients.

A prospective, observational study of Xigris Use in the United States (XEUS) ☆,☆☆

BACKGROUND Use of pharmacologic agents in clinical practice may differ from the manner in which they were studied in rigorous randomized clinical trials. This was a prospective, observational, noninterventional study to determine the profile of patients receiving drotrecogin alfa (activated) in clinical practice, provide additional outcome and safety data, and allow for a comparison to patients studied in the phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. METHODS A total of 548 adult patients with severe sepsis were enrolled from 61 nonteaching or academically affiliated hospitals in the United States. Patients received drotrecogin alfa (activated) as part of physician-directed therapy for severe sepsis. RESULTS The Xigris Use in the United States (XEUS) patients were younger (58 vs 63 years of age), had more comorbidities, and more sepsis-induced organ dysfunction at baseline compared to high-risk (Acute Physiology and Chronic Health Evaluation II score ≥ 25) PROWESS patients who received drotrecogin alfa (activated), (cardiovascular, 85.0% vs 79.7%; hematologic, 22.3% vs 16.4%; and renal, 57.9% vs 50.7%) (all P < .05). The XEUS patients had a higher mortality rate compared to high-risk PROWESS patients receiving drotrecogin alfa (activated) (36.7% vs 30.9%; P = .062) but a similar safety profile (infusion period serious bleeding, 2.7% vs 2.2%; P = .579; 28-day serious bleeding, 3.1% vs 3.9%; P = .520). The rate of intracranial hemorrhage in XEUS was 0.2%. CONCLUSIONS Patients receiving drotrecogin alfa (activated) in clinical practice were more acutely ill, had a higher mortality rate, but a similar safety profile with respect to serious bleeding events compared to the PROWESS trial.

Effects of Dulaglutide and Insulin Glargine on Estimated Glomerular Filtration Rate in a Real-World Setting

Dulaglutide (Trulicity) treatment of patients with type 2 diabetes (T2D) and moderate to severe chronic kidney disease was associated with lesser estimated glomerular filtration rate (eGFR) decline compared to insulin glargine (glargine) in a clinical trial. This study examined the relationship between dulaglutide or glargine use and eGFR for adults with T2D using real-world data from a U.S. electronic health records from 10/25/2013 to 6/18/2017. There were 13,869 glargine and 1,222 dulaglutide patients included in the descriptive analyses. Patients with initial eGFR Disclosure K. Boye: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. J. Wu: None. M.J. Lage: Consultant; Self; Eli Lilly and Company. Consultant; Spouse/Partner; Eli Lilly and Company. F.T. Botros: Employee; Self; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company.

Effects of Dulaglutide and Insulin Glargine on Estimated Glomerular Filtration Rate in a Real-world Setting

PURPOSE The aims of this study were to use real-world treatment results to compare changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA1c) among patients with type 2 diabetes who initiated treatment with dulaglutide or insulin glargine and to determine the proportions of patients with renal impairment who initiate each treatment. METHODS The study used data from the Practice Fusion electronic health records database from October 2013 through June 2017. Adults with type 2 diabetes who initiated dulaglutide or insulin glargine therapy and had multiple recorded serum creatinine and/or HbA1c laboratory test results were included in the study. The dulaglutide cohort (n = 1222) was matched to the insulin glargine cohort (n = 13,869) using Mahalanobis distance matching with propensity score calipers. Multivariable analyses of the matched cohorts of individuals with serum creatinine results (n = 1183 dulaglutide and 1183 insulin glargine) examined the association between intent-to-treat therapy and changes in eGFR. In addition, multivariable analyses were also conducted on a subset of these patients who also had recorded HbA1c tests (n = 1088 dulaglutide and 1088 insulin glargine) to examine the association between changes in HbA1c during the 1 year postperiod. FINDINGS Among patients who initiated dulaglutide therapy, only 0.9% of patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 0.1% had an index eGFR <15 mL/min/1.73 m2. In contrast, 4.1% of insulin glargine-treated patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 1.2% had an index eGFR <15 mL/min/1.73 m2. Compared with patients who initiated therapy with insulin glargine, initiation of dulaglutide therapy was associated with a significantly smaller decrease in eGFR (-0.4 vs -0.9 mL/min/1.73 m2; P = 0.0024), a significantly smaller likelihood of having a 30% or greater reduction in eGFR (3.3% vs 4.1%; P < 0.0001), and a significantly larger reduction in HbA1c (-0.5% vs -0.2%; P < 0.0001). IMPLICATIONS In clinical practice, the use of dulaglutide was relatively more limited in patients with a higher degree of renal impairment compared with use of insulin glargine. However, initiation of dulaglutide therapy, compared with insulin glargine therapy, was associated with a significantly smaller decrease in eGFR and a larger reduction in HbA1c during the 1 year postperiod.