Risk of volume depletion events with concomitant use of sodium glucose co-transporter 2 inhibitors and loop diuretics: A self-controlled case series study.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2is) are used to prevent cardiovascular complications in type 2 diabetes mellitus (T2DM) and newly indicated to treat heart failure (HF). Loop diuretics are commonly prescribed to manage volume overload in HF and may increase the risk of volume depletion in real-world practice. This study evaluated the risk of volume depletion following concomitant use of SGLT2is and loop diuretics in veterans. METHODS: Veterans with T2DM were included if they received concomitant loop diuretics and SGLT2is and experienced at least one volume depletion event between December 2012 and December 2019, utilizing a self-controlled case series design. Concomitant prescribing periods were divided into focal windows of 1 to 14 days, 14 to 28 days, and greater than 28 days. Incidence rate ratios (IRR) were estimated using multivariable Poisson regressions adjusted for age and renal function. RESULTS: 3352 patients experienced at least one volume depletion event and were concomitantly prescribed SGLT2is and loop diuretics at least once. The risk of volume depletion increased in the treatment versus control windows during the 1 to 14-day window (IRR = 1.82, 95% CI 1.63-2.02) the 15-to-28-day window (IRR = 1.46, 95% CI 1.28-1.67), and the greater than 28-day window (IRR = 1.22, 95% CI 1.21-1.34). CONCLUSIONS: Concomitant prescribing of SGLT2is and loop diuretics is associated with an increased risk of volume depletion, an effect that attenuates with longer therapy durations. Prescribers need to closely monitor fluid status in patients receiving concomitant therapy, especially those with advancing age or with eGFR below 60.

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program.

INTRODUCTION: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. PATIENTS AND METHODS: Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. RESULTS: In total, 52 patients were included [median age 57 years (range 32-81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1-4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. CONCLUSIONS: Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.

Working smarter, not harder: evaluating a population health approach to anticoagulation therapy management.

Inappropriate direct acting oral anti-coagulants (DOAC) prescribing increases the risk of adverse events. Population health management tools (PMTs) could help reduce adverse events through the early, efficient identification of questionable prescribing practices, but the impact of such a tool remains unknown. We evaluated the effect of PMT use on questionable DOAC dosing rates within 40 VHA medical centers and whether this effect differed by DOAC indication or agent. Medical centers were divided into PMT user or standard of care (SOC) groups based upon high or low tool access in the prior year. Questionable DOAC dosing rate was defined as the proportion of patients prescribed DOACs who were also flagged by the tool. Chi-square tests were used to determine if PMT user versus SOC groups differed with high (above 15.3%) versus low (below 15.3%) questionable dosing rates. T-tests were used to determine if mean questionable dosing rates significantly differed between the PMT user and SOC groups. DOAC PMT users were classified less frequently as being 'High" questionable dosage rate compared to SOCs (25% PMT vs. 75% SOC, respectively, p = 0.002). DOAC PMT utilization within the overall cohort was associated with a 4.3% absolute reduction in questionable DOAC dosing rates (13.2% PMT vs 17.5% SOC; p = 0.01). Tool use within the atrial fibrillation (AF) subgroup was associated with a 5.1% absolute reduction in questionable dosing rates (10.4% SOC vs. 5.3% PMT, p < 0.001). Tool use was also associated with lower questionable dosing rates in the apixaban (p < 0.001), dabigatran (p = 0.03) and AF plus venous thromboembolism (p < 0.001) subgroups. In our study, PMT use was associated with reduced questionable DOAC dosing, a difference most pronounced within AF patients. A population health approach has the potential to reduce adverse events among patients prescribed DOACs.

Comorbidity Matters: Social Visual Attention in a Comparative Study of Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder and Their Comorbidity.

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) represent two common neurodevelopmental disorders with considerable co-occurrence. Their comorbidity (ASD + ADHD) has been included in the latest diagnostic guidelines (DSM-V, 2013). The present study focuses on social visual attention that i) is a main aspect of social attention reflecting social cognition and ii) its atypicalities have been suggested as a potential biomarker for ASD. Considering the possible shared background of both disorders and their comorbidity, it is important to compare such traits directly. Here, 73 children and adolescents paired for age and IQ diagnosed with ASD (N = 12), ADHD (N = 21), comorbid ASD + ADHD (N = 15), and "typically developing" (TD) controls (N = 25), were shown static real-life social scenes while their gaze movements were recorded with eye-tracking. Scenes with two levels of social complexity were presented: low complexity (one person depicted) and high (four interacting individuals). Gaze fixation variables were investigated. Fixation duration on faces was significantly reduced only in ASD + ADHD which also required longer time to fixate all faces at least once. Fixation duration on faces in ASD was reduced, compared to TD, only when looking at scenes with high versus low social complexity. ADHD individuals did not differ from TD. Concluding, the observed alterations of social visual attention support the existence of possible dysfunctional particularities differentiating ASD, ADHD, and ASD + ADHD, which can be revealed with the new method of eye-tracking technique. The objective gaze measurements provided contribute to the development of biomarkers enabling early diagnosis, amelioration of care and further interventions specified for each group.

Social Visual Perception Under the Eye of Bayesian Theories in Autism Spectrum Disorder Using Advanced Modeling of Spatial and Temporal Parameters.

Social interaction in individuals with Autism Spectrum Disorder (ASD) is characterized by qualitative impairments that highly impact quality of life. Bayesian theories in ASD frame an understanding of underlying mechanisms suggesting atypicalities in the evaluation of probabilistic links within the perceptual environment of the affected individual. To address these theories, the present study explores the applicability of an innovative Bayesian framework on social visual perception in ASD and demonstrates the use of gaze transitions between different parts of social scenes. We applied advanced analyses with Bayesian Hidden Markov Modeling (BHMM) to track gaze movements while presenting real-life scenes to typically developing (TD) children and adolescents (N = 25) and participants with ASD and Attention-Deficit/Hyperactivity Disorder (ASD+ADHD, N = 15) and ASD without comorbidity (ASD, N = 12). Regions of interest (ROIs) were generated by BHMM based both on spatial and temporal gaze behavior. Social visual perception was compared between groups using transition and fixation variables for social (faces, bodies) and non-social ROIs. Transition variables between faces, namely gaze transitions between faces and likelihood of linking faces, were reduced in the ASD+ADHD compared to TD participants. Fixation count to faces was also reduced in this group. The ASD group showed similar performance to TD in the studied variables. There was no difference between groups for non-social ROIs. Our study provides an innovative, interpretable example of applying Bayesian theories of social visual perception in ASD. BHMM analyses and gaze transitions have the potential to reveal fundamental social perception components in ASD, contributing thus to amelioration of social-skill interventions.

Optimizing Nutrition Assessment to Create Better Outcomes in Lung Transplant Recipients: A Review of Current Practices.

Lung transplantation offers patients with end-stage lung disease an opportunity for a better quality of life, but with limited organ availability it is paramount that selected patients have the best opportunity for successful outcomes. Nutrition plays a central role in post-surgical outcomes and, historically, body mass index (BMI) has been used as the de facto method of assessing a lung transplant candidate's nutritional status. Here, we review the historical origins of BMI in lung transplantation, summarize the current BMI literature, and review studies of alternative/complementary body composition assessment tools, including lean psoas area, creatinine-height index, leptin, and dual x-ray absorptiometry. These body composition measures quantify lean body mass versus fat mass and may provide a more comprehensive analysis of a patient's nutritional state than BMI alone.

Estimated GFR Decline Following Sodium Phosphate Enemas Versus Polyethylene Glycol for Screening Colonoscopy: A Retrospective Cohort Study.

BACKGROUND: Associations between sodium phosphate enemas and nephropathy have raised concerns about the safety of use as part of a bowel-cleansing regimen administered prior to colonoscopies. The objectives of this analysis are to evaluate the impact of sodium phosphate enema versus polyethylene glycol powder for oral solution (PEG) use prior to colonoscopy screening on estimated glomerular filtration rate (eGFR) decline in Veterans Affairs (VA) patients and identify other risk factors contributing to eGFR decline. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 70,499 VA patients receiving sodium phosphate enemas (with or without PEG) or PEG alone prior to colonoscopy screenings. PREDICTOR: Use of either sodium phosphate or PEG. OUTCOMES: A 50% increase in serum creatinine level over a 15-month, over a 6-week, and between a 9- and 15-month period was used to define any, acute, or long-term eGFR decline, respectively. MEASUREMENTS: Multivariable logistic regressions estimated the likelihood of eGFR decline conditional on the use of sodium phosphate enemas versus PEG alone, controlling for potential confounders. RESULTS: A greater proportion of patients using sodium phosphate enemas versus PEG had any (P<0.001) or long-term (P=0.003) eGFR declines, whereas similar proportions had acute eGFR declines (P=0.9). In the adjusted analyses, use of sodium phosphate enemas (± PEG was associated with an increased likelihood of having any (OR, 1.3; 95% CI, 1.2-1.5) or long-term (OR, 1.4; 95% CI, 1.1-1.8) eGFR decline, but not acute eGFR decline (OR, 1.0; 95% CI, 0.6-1.7). Other risk factors for eGFR decline included diabetes and non-iron deficient anemia. LIMITATIONS: Unobserved heterogeneity due to volume depletion and potential selection bias due to higher-risk patients preferentially prescribed sodium phosphate enemas. CONCLUSIONS: Use of sodium phosphate enemas versus PEG alone prior to colonoscopy screening increases the risk for VA patients having long-term eGFR decline. Patients with non-iron deficient anemia are at particularly high risk for eGFR decline. These findings motivate the need to re-examine prescribing practices for sodium phosphate enemas as part of a bowel-cleansing regimen.

Clostridium difficile-positive stools: a retrospective identification of risk factors.

In an attempt to determine the association of potential risk factors and an increase in the rate of Clostridium difficile-associated diarrhea (CDAD) at a tertiary teaching institution in the Midwest United States, all CDAD cases among admissions from a period of 20 consecutive months were analyzed. A retrospective chart review was performed on 4992 admissions from this period. Logistic regression analysis suggested a correlation between CDAD and multiple factors.

Assessing the cost-effectiveness of COX-2 specific inhibitors for arthritis in the Veterans Health Administration.

OBJECTIVE: This study was designed to assess the cost-effectiveness of cyclooxygenase-2 specific (COX-2) inhibitors (rofecoxib and celecoxib) over nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk arthritis patients from the perspective of the Veterans Health Administration (VA). METHODS: This literature-based economic analysis (with data summarized from MEDLINE-indexed and other published sources, FDA reports, and data on file at VA San Diego Healthcare System) compared rofecoxib and celecoxib to NSAIDS in two arthritis patient populations considered at higher risk of developing clinically significant upper gastrointestinal events (CSUGIEs): (1) patients of any age with previous medical history of perforation/ulcer/bleed (PUB); and (2) patients 65 years and older (regardless of history of PUB). Two outcome measures were reported: (1) incremental cost per CSUGIE averted over 1 year; and (2) incremental cost per quality-adjusted life-year (QALY) gained, considering both the mortality and morbidity associated with gastrointestinal (including CSUGIEs) and cardiovascular-related adverse events. When possible, costs were modeled to reflect the VA perspective. Sensitivity analyses were conducted to test the robustness of the analysis. RESULTS: Compared to NSAIDS, rofecoxib and celecoxib increased costs but reduced the incidence of CSUGIE. Cost per CSUGIE avoided were $7476 and $16,379 (in patients with a PUB history) and $14,294 and $18,376 (in patients aged > or = 65 years) for celecoxib and rofecoxib, respectively. In both populations, celecoxib was associated with a cost per QALY less than $50,000. In contrast, rofecoxib was found to cost more and result in a net QALY loss, due in particular to the increase in the risk of cardiovascular complications, and was therefore considered cost-ineffective. Results were most dependent on assumptions about the incidence of cardiovascular events and CSUGIE and the COX-2 inhibitors' acquisition price. CONCLUSIONS: This analysis suggests that COX-2 inhibitors may be cost-effective from the perspective of the VA. However, cost-effectiveness appears to depend less on the specific characteristics of the high-risk target population considered but more on the agent evaluated. Celecoxib appears to be an alternative to traditional NSAIDs in the patient populations studied.

Clinical and economic comparison of epoetin alfa and darbepoetin alfa.

BACKGROUND: The pharmacoeconomics of erythropoietic therapy for the treatment of anemia is receiving renewed attention due to the current availability of two agents. Epoetin alfa has been the standard of therapy for patients with renal disease and cancer-related anemia for more than a decade. Darbepoetin alfa, an alternative agent, is now approved for anemia resulting from renal disease and cancer chemotherapy. METHODOLOGY: Although direct comparative trials have not been performed with these agents, information published in the last several years regarding their clinical efficacy, safety, and dosing is sufficient, in most cases, to compare costs. With the disclaimer that any efficacy comparison of competing products using published reports has certain limitations, a cost-minimization approach from a provider's perspective was conducted. RESULTS: To provide background for the economic evaluation, pharmacokinetic and pharmacodynamic data for these two agents are discussed. Recent clinical trials in the nephrology and oncology therapeutic areas are summarized, highlighting study designs, dosing regimens, patient entry criteria, study endpoints, and published results. Cost data, based on average wholesale prices (AWP) in 2003, are compared and calculated from available clinical data with an emphasis on efficacy. CONCLUSION: These evaluations largely conclude that epoetin alfa is the better pharmacoeconomic value of the two currently available erythropoietic agents.

Interaction of rofecoxib and celecoxib with warfarin.

The interaction of celecoxib and rofecoxib with warfarin was studied. Patients stable on warfarin therapy and concurrently taking a cyclooxygenase-2 (COX-2) inhibitor comparator (traditional nonsteroidal antiinflammatory medications, salsalate, or acetaminophen) randomly received celecoxib 200 mg/day or rofecoxib 25 mg/day for three weeks. After a one-week washout period, the patients were crossed over to treatment with the opposite COX-2 inhibitor for three more weeks. The International Normalized Ratio (INR) was measured at baseline and at weeks 1, 2, and 3 of therapy with each COX-2 inhibitor by testing blood samples obtained by finger stick. Data for 16 patients were analyzed. The INR increased by 13%, 6%, and 5% on average in patients taking celecoxib at weeks 1, 2, and 3, respectively, and by 5%, 9%, and 5% in patients taking rofecoxib. Changes in the INR were statistically significant at week 1 for celecoxib and at week 2 for rofecoxib. Of the 12 subjects who had a clinically significant > or = 15% change in the INR while receiving either COX-2 inhibitor, 4 showed this change for both agents. Adverse drug reactions were similar for each COX-2 inhibitor, but the rate of edema requiring medical intervention was higher in the rofecoxib group. Significant increases in the INR were observed in patients who were stable on warfarin therapy after the addition of therapy with rofecoxib or celecoxib.