Icolos: a workflow manager for structure-based post-processing of de novo generated small molecules.

SUMMARY: We present Icolos, a workflow manager written in Python as a tool for automating complex structure-based workflows for drug design. Icolos can be used as a standalone tool, for example in virtual screening campaigns, or can be used in conjunction with deep learning-based molecular generation facilitated for example by REINVENT, a previously published molecular de novo design package. In this publication, we focus on the internal structure and general capabilities of Icolos, using molecular docking experiments as an illustrative example. AVAILABILITY AND IMPLEMENTATION: The source code is freely available at https://github.com/MolecularAI/Icolos under the Apache 2.0 license. Tutorial notebooks containing minimal working examples can be found at https://github.com/MolecularAI/IcolosCommunity. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Trends in utilization, reimbursement, and price for DOACs and warfarin in the US Medicaid population from 2000 to 2020.

The use of direct oral anticoagulants (DOACs) is widely increasing in the United States (US). Warfarin has been the conventional anticoagulant used in the past few decades, but it has been gradually replaced by DOACs. The objective of the study was to analyze trends in utilization, reimbursement, and price for those anticoagulants in the US Medicaid population. Retrospective data analysis was conducted using the National Summary Files for the Medicaid State Drug Utilization Data. Study drugs included dabigatran, rivaroxaban, apixaban, edoxaban and warfarin. The study assessed secular trends of utilization, reimbursement, and per-prescription price. The data was collected from the first quarter of 2000 through to the second quarter of 2020 restricted for outpatient prescriptions only. During the 21-year study period, a substantial rise in total expenditures on warfarin and DOACs was observed from $144 million in 2000 to $694 million in 2020. Moreover, the utilization of DOACs has increased significantly since the first approval of Xarelto in 2010 from 1079 in 2011 to 1.5 million in 2019. The per-prescription price of DOACs increased from an average of $200 in 2011 to $407 in 2020. Conversely, the total number of prescriptions of Warfarin and branded Coumadin decreased from 2.4 million to 1.4 million and from 3.9 million to less than a million, respectively. The present study demonstrated a change in the trends of US expenditure and utilization for warfarin and DOACs with DOACs representing the majority of market share of both spending per prescription and reimbursement.

Bayesian Optimization for Chemical Reactions.

Reaction optimization is challenging and traditionally delegated to domain experts who iteratively propose increasingly optimal experiments. Problematically, the reaction landscape is complex and often requires hundreds of experiments to reach convergence, representing an enormous resource sink. Bayesian optimization (BO) is an optimization algorithm that recommends the next experiment based on previous observations and has recently gained considerable interest in the general chemistry community. The application of BO for chemical reactions has been demonstrated to increase efficiency in optimization campaigns and can recommend favorable reaction conditions amidst many possibilities. Moreover, its ability to jointly optimize desired objectives such as yield and stereoselectivity makes it an attractive alternative or at least complementary to domain expert-guided optimization. With the democratization of BO software, the barrier of entry to applying BO for chemical reactions has drastically lowered. The intersection between the paradigms will see advancements at an ever-rapid pace. In this review, we discuss how chemical reactions can be transformed into machine-readable formats which can be learned by machine learning (ML) models. We present a foundation for BO and how it has already been applied to optimize chemical reaction outcomes. The important message we convey is that realizing the full potential of ML-augmented reaction optimization will require close collaboration between experimentalists and computational scientists.

The effect of polypharmacy on quality of life in adult patients with nonalcoholic fatty liver disease in the United States.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a significant epidemiological problem with rising prevalence. Due to limited literature, the objective of this study is to examine the association between polypharmacy and health-related quality of life (QoL) in NAFLD adult patients. METHODS: A retrospective observational study design was conducted to analyze health data collected by Steatohepatitis Clinical Research Network (NASH CRN). Patients were classified as receiving a polypharmacy therapy with five or more medications in their first screening visit. QoL was measured using the Short Form 36 (SF-36) instrument. Each patient self-reported the SF-36 form during the screening visit was compared between polypharmacy and non-polypharmacy groups using Wilcoxon Rank Sum test. Multivariable generalized linear models and multinomial logistic regression were performed to examine each predictor and its effect on QoL. RESULTS: Data included 1067 NAFLD adult patients; 834 patients used polypharmacy. The mean age was 48.64 years, and most patients were female (62%). Comparing NAFLD patients without steatohepatitis, borderline NASH, and definite NASH, the non-polypharmacy group had a significantly higher QoL than the polypharmacy group in Physical Component Summary (PCS) (86.25 vs 66.88, 85 vs 67.5, and 79.375 vs 63.12, respectively, all p < 0.01) and Mental Component Summary (MCS) (83.5 vs 73.38, 78.75 vs 67.62, and 78.75 vs 70.65, respectively, all p < 0.01). DISCUSSION AND CONCLUSION: Adults with NAFLD and polypharmacy have lower QoL than adults with NAFLD and non-polypharmacy. Number of medications had a significant negative impact on PCS, MCS, and all SF-36 domains except mental health, role physical limitation and role emotional limitation domains. Other factors that affect QoL negatively in NAFLD adult patients are female gender, obesity, diabetes, depression, and unemployment. Higher income had favorable effect on QoL.

Comparative effectiveness and persistence of TNFi and non-TNFi in juvenile idiopathic arthritis: a large paediatric rheumatology centre in the USA.

OBJECTIVE: To evaluate the persistence and effectiveness of TNF inhibitors (TNFi) vs non-TNFi among newly diagnosed JIA patients after initiation of biologic DMARD (bDMARD). METHODS: Using longitudinal patient-level data extracted from electronic medical records in a large Midwestern paediatric hospital from 2009 to 2018, we identified JIA patients initiating TNFi and non-TNFi treatment. Treatment effectiveness was assessed based on disease activity. Inverse probability of treatment weighting of propensity score was used to estimate the treatment effectiveness and Kaplan-Meier analyses were conducted to assess persistence. RESULTS: Of 667 JIA patients, most (92.0%) were prescribed one of the class of TNFi as their initial biologic treatment. Etanercept was the most frequently prescribed (67.1%) treatment, followed by adalimumab (27.5%). Only around 5% of patients were prescribed off-label bDMARDs as their first-course treatment; however, >20% were prescribed off-label biologics as their second-course therapy. Some 7.2% of patients received four or more bDMARDs. The median persistence of the first-course bDMARD is 320 days, with TNFi being significantly longer than the non-TNFi (395 vs 320 days, P = 0.010). The clinical Juvenile Disease Activity Score (cJADAS) reduction of TNFi users (6.6, 95% CI 5.7, 7.5) was significant greater compared with non-TNFi users (3.0, 95% CI 1.5, 4.6, P < 0.0001) at 6-month follow-up visit. CONCLUSION: Persistence was significantly longer among patients initiating TNFi as their first biologic therapy than those receiving non-TNFi. Patients receiving TNF therapy had significant greater reduction of cJADAS at the 6-month follow-up visit compared with patients in the non-TNF cohort.

Drug Expenditure, Price, and Utilization in the U.S. Medicaid: A Trend Analysis for SSRI and SNRI Antidepressants from 1991 to 2018.

BACKGROUND: SSRIs and SNRIs are antidepressants that have largely substituted old antidepressants like Monoamine Oxidase Inhibitors (MAOIs) and Tricyclic Antidepressants (TCAs). They have been widely used since 1987 when the FDA approved the first SSRI Fluoxetine and the first SNRI Venlafaxine in 1993. Since then, several new SSRIs and SNRIs have been approved and entered the market. Utilization, pricing, and spending trends of SSRIs and SNRIs have not been analyzed yet in Medicaid. AIM: To assess the trends of drug expenditure, utilization, and price of SSRI and SNRI antidepressants in the US Medicaid program, and to highlight the market share of SSRIs and SNRIs and the effect of generic drug entry on Medicaid drug expenditure. METHODS: A retrospective descriptive data analysis was conducted for this study. National pharmacy summary data for study brand and generic drugs were retrieved from the Medicaid State Outpatient Drug Utilization Data. These data were collected by the US Centers for Medicare and Medicaid Services (CMS). The study period was between 1991 and 2018. Study drugs include 12 different SSRI and SNRI brands and their generics available in the market, such as citalopram, escitalopram, paroxetine, fluoxetine, sertraline, venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran. Data were analyzed annually and categorized by total prescriptions (utilization), total reimbursement (spending), and cost per prescription as the proxy of the price for each drug. RESULTS: From 1991 to 2018, total prescriptions of SSRI and SNRI drugs rose by 3001%. Total Medicaid spending on SSRIs and SNRIs increased from USD 64.5 million to USD 2 billion in 2004, then decreased steadily until it reached USD 755 million in 2018. The SSRIs average utilization market share was 87% compared to 13% of the SNRIs utilization market share. About 72% of total Medicaid spending on the two groups goes to SSRIs, while the remaining 28% goes to SNRIs. Brand SSRIs and SNRIs prices increased over time. On the contrary, generic drugs prices steadily decreased over time. DISCUSSION: An increase in utilization and spending for both SSRI and SNRI drugs was observed. After each generic drug entered the market, utilization shifted from the brand name to the respective generic due to their lower price. These generic substitutions demonstrate a meaningful cost-containment policy for Medicaid programs. IMPLICATIONS FOR HEALTH POLICIES: Our findings show the overall view of Medicaid expenditure on one of the most commonly prescribed drug classes in the US. They also provide an important insight toward the antidepressant market and the importance of monitoring different drugs and their alternatives.

Healthcare services expenditures among prostate cancer patients with and without mood disorders in the United States: A propensity score-matched cross-sectional study.

OBJECTIVES: To compare the averages of healthcare services utilization and of expenditures for men with prostate cancer with and without diagnoses of mood disorders applying propensity score matching (PSM), and to identify the potential predictors associated with increased healthcare expenditures. DESIGN: Cross-sectional study. SAMPLE AND METHODS: A total of 308,602 weighted patients with prostate cancer were identified after applying PSM. The datasets for men with prostate cancer were extracted from the Medical Expenditure Panel Survey (MEPS) from 2010 to 2015. For cohort formation, 1:1 PSM was applied. Healthcare utilization and expenditures analyzed included emergency room visits, length of stay for hospital inpatients, outpatient visits, office-based visits, and prescriptions. Generalized linear model with gamma distribution and log link was used to determine which covariates are associated with the increase in healthcare expenditures for each healthcare service. FINDINGS: The mean expenditures for emergency room visits between men with prostate cancer and mood disorders was $3,092.34, and it was $1,330.64 for patients without mood disorders (p = 0.038). The weighted total expenditures for emergency room visits in prostate cancer patients with mood disorders is 57% higher (p = 0.0109). Moreover, the weighted total expenditures for outpatient visits in prostate cancer patients with mood disorders is 93% higher (p = 0.0001). The potential predictor in total healthcare expenditures is perceived health status (fair/poor) (p = 0.0066). CONCLUSIONS AND IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS OR POLICY: Individuals with a diagnosis of mood disorders were found to have higher average healthcare expenditures in emergency room visits than those without mood disorders. Therefore, the implications of this study are to inform the patient care team that the assessment and management of mood disorders is a priority. Moreover, screening of mood- disorder symptoms should occur early to optimize care. Finally, policymakers should provide accessible care to minimize emergency room visits.

Cost-Effectiveness of Simvastatin Plus Ezetimibe for Cardiovascular Prevention in Patients With a History of Acute Coronary Syndrome: Analysis of Results of the IMPROVE-IT Trial.

BACKGROUND: Simvastatin plus ezetimibe reduced the risk of cardiovascular events in the IMProved Reduction of Outcomes: Vytorin Efficacy International (IMPROVE-IT) study. The aim of this study is to investigate the cost-effectiveness of adding ezetimibe to simvastatin treatment for patients with ACS based on the recently completed IMPROVE-IT trial. METHODS: We constructed a Markov state-transition model to evaluate the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness (ICER) associated with co-therapy compared with simvastatin alone from a health care perspective. We ran separate base-case analyses assuming a trial-length and longer term follow-up. One-way sensitivity analyses were used to explore uncertainty in model parameters. RESULTS: In the trial-length model, the ICERs compared with simvastatin alone were $114,400 per QALY for the combination therapy. In 5- and 10-year time horizons, the ICERs remained above the cost-effectiveness threshold of $50,000 per QALY. In the lifetime horizon model, The ICER was $45,046 per QALY for combination treatment compared with simvastatin alone. The combination therapy is cost-effective at an 80% decrease in the current branded simvastatin and ezetimibe cost. Probabilistic sensitivity analysis suggested simvastatin and ezetimibe co-therapy would be a cost-effective alternative to simvastatin monotherapy 60.7% of the time. CONCLUSIONS: In our trial-length, 5-year, and 10-year models, the co-therapy was not a cost-effective alternative; however, as follow-up was extended to lifetime, the co-therapy became a cost-effective treatment compared with the simvastatin monotherapy in patients with histories of ACS.

Twenty years of triptans in the United States Medicaid programs: Utilization and reimbursement trends from 1993 to 2013.

OBJECTIVE: After sumatriptan was approved by the Food and Drug Administration in 1992, triptans became first-line anti-migraine therapies. Rapidly rising triptan expenditures, however, led payers, including Medicaid, to implement cost-containment policies. We describe triptan utilization and reimbursement trends in Medicaid. METHODS: Using national summary files for outpatient drug utilization, utilization and expenditure data from 1993 to 2013 were extracted and summed for all triptan national drug codes reimbursed by Medicaid. Data were collected separately for tablets, injections and sprays. RESULTS: The number of triptan prescriptions increased from 87,348 in 1993 to 0.9 million in 2004; fell to 0.4 million in 2009; rose to 1 million in 2011; and rose 1.2 million in 2013. In 2013, Medicaid spent $96.8 million on triptans: 74.4%, 18.4% and 7.2% for tablets, injections and sprays, respectively. Average reimbursement per prescription was $54 for tablets, $351 for injections and $235 for sprays in 2013. From 1993 to 2013, sumatriptan was the most widely prescribed among the triptans. CONCLUSIONS: The substantial increase in triptan prescriptions from 2009 to 2011, without being convincingly explained by either rising migraine prevalence or rising Medicaid enrollment, is suggestive of reduced access to these medications prior to 2009. Cost-containment policies may have inadvertently prevented Medicaid migraineurs from obtaining appropriate pharmacotherapy. PRIOR PRESENTATIONS: An earlier version of this paper was presented as a poster at the Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research, Philadelphia, PA, May 2015, where it received a finalist award.

Off-label use of oral fluoroquinolone antibiotics in outpatient settings in the United States, 2006 to 2012.

PURPOSE: The aim of this study was to evaluate the practice pattern of off-label use of fluoroquinolones (FQs) in ambulatory settings and to identify the related risk factors. METHODS: The National Ambulatory Medical Care Surveys from 2006 through 2012 was used to identify subjects who received FQ off-label prescriptions. We defined off-label use as the use of FQs for indications other than those in the FDA-approved drug label. Descriptive statistics were calculated by using a series of weighted chi-squared statistics. Multivariate logistic regression was conducted to identify factors associated with off-label FQ drug use. RESULTS: There were 93 million ambulatory visits in which an FQ was prescribed, and 53.16% of these visits involved the prescribing of FQs in an off-label manner. The percentage of off-label prescriptions was the highest among individuals ≥80 years old (61.6%) and male patients (60.9%). The FQ drug prescribed most for an off-label indication in our study was ciprofloxacin (29.5% of the total visits). The multivariate analysis showed that age of ≥80 years and male patient was significantly associated with off-label use of FQs (adjusted odds ratio (OR) 3.66, 1.72-7.80 and OR 3.26, 2.32-4.56, respectively). Medicaid or private insurance versus Medicare were associated with significantly higher off-label prescribing of FQs (OR 2.53, 1.28-5.01 and 1.77, 1.03-3.03, respectively). CONCLUSION: The percentage of visits involving off-label FQs in US ambulatory settings is substantial. Efforts are needed consolidate and evaluate what high-quality scientific evidence is available and what is needed to support the safety and effectiveness of such off-label uses. Copyright © 2016 John Wiley & Sons, Ltd.

Comparative persistence on ß-blockers versus calcium channel blockers for ventricular rate control in nonelderly patients with atrial fibrillation.

BACKGROUND: For patients with atrial fibrillation (AF), early treatment is essential to prevent serious complications such as stroke. Several randomized clinical trials have shown that rate-control may be as effective as rhythm-control medications, whereas the latter have serious side effects. Little evidence exists, however, about which class of rate-control medication-ß-blockers (BBs) or calcium channel blockers (CCBs)-may be superior. OBJECTIVE: The objective was to compare the long-term persistence on BBs versus CCBs in nonelderly adult patients with AF. METHODS: A longitudinal retrospective cohort study for patients 40 to 60 years old with newly diagnosed AF (identified by ICD-9 code 427.31) was performed using data from Ohio Medicaid physician, institutional, and pharmacy claims from January 2006 through June 2011. A Cox proportional hazard regression, with time to change out of rate-control therapy as the dependent variable, was estimated to compare persistence on (proxy for effectiveness of) rate-control medication across drug classes. A propensity-score analysis was used to control for selection bias. Additional covariates included age, development of heart failure, and medication adherence. RESULTS: Out of 1239 patients included in the cohort, 1016 received a BB; 223 received a CCB. Over time, patients on CCBs were significantly more likely to switch out of rate-control therapy (hazard ratio = 1.89; 95% CI = 1.14-3.09) than patients on BBs. CONCLUSIONS: Evidence suggests that nonelderly AF patients, when prescribed rate-control therapy, persist longer on BBs than CCBs. Because this is the first long-term study comparing the 2 drug classes in the nonelderly population, further research is suggested.

Risk of childhood overweight or obesity associated with excessive weight gain during pregnancy: a meta-analysis.

PURPOSE: Several investigations have shown that the risk of childhood overweight and obesity may be associated with excessive gestational weight gain (GWG), but the study samples were limited and results were mixed; hence we conducted this meta-analysis to assess the explicit association between them and present evidence. METHODS: We searched PubMed, EMbase, Ovid, Web of knowledge and Cochrane library for relevant studies. Bibliographies from retrieved articles were also manually searched. Cohort studies that presented results by OR or RR with 95 % CI for the association of maternal excessive GWG and child overweight/obesity were included. The pooled estimates were calculated by fixed-effect model or random-effect model according to the heterogeneity. RESULTS: Twelve cohort studies were identified, and the combined OR of excessive GWG and childhood overweight/obesity was 1.33 (95 % CI 1.18-1.50) with evidence of heterogeneity (P = 0.000, I (2) = 71.1 %). Adjustment of maternal BMI, investigation area, age of children, research type, and omission of any single study had little effect on the pooled estimate. After eliminating the effect of publication bias by trim and fill analyses, the result still remained statistically significant (OR 1.21, 95 % CI 1.05-1.40). CONCLUSIONS: This meta-analysis suggests that the risk of childhood overweight/obesity is significantly associated with excessive gestational weight gain.

Augmented Memory: Sample-Efficient Generative Molecular Design with Reinforcement Learning.

Sample efficiency is a fundamental challenge in de novo molecular design. Ideally, molecular generative models should learn to satisfy a desired objective under minimal calls to oracles (computational property predictors). This problem becomes more apparent when using oracles that can provide increased predictive accuracy but impose significant computational cost. Consequently, designing molecules that are optimized for such oracles cannot be achieved under a practical computational budget. Molecular generative models based on simplified molecular-input line-entry system (SMILES) have shown remarkable sample efficiency when coupled with reinforcement learning, as demonstrated in the practical molecular optimization (PMO) benchmark. Here, we first show that experience replay drastically improves the performance of multiple previously proposed algorithms. Next, we propose a novel algorithm called Augmented Memory that combines data augmentation with experience replay. We show that scores obtained from oracle calls can be reused to update the model multiple times. We compare Augmented Memory to previously proposed algorithms and show significantly enhanced sample efficiency in an exploitation task, a drug discovery case study requiring both exploration and exploitation, and a materials design case study optimizing explicitly for quantum-mechanical properties. Our method achieves a new state-of-the-art in sample-efficient de novo molecular design, outperforming all of the previously reported methods. The code is available at https://github.com/schwallergroup/augmented_memory.

Racial/Ethnic and Socioeconomic Disparities and Self-reported Work Productivity in Urinary Incontinence Females Using the National Institute of Diabetes and Digestive and Kidney Diseases Data.

OBJECTIVE: To explore the relationship between racial/ethnic and socioeconomic disparities and self-reported work productivity in urinary incontinence females. METHODS: This was a retrospective observational and secondary analysis of the National Institute of Diabetes and Digestive and Kidney Diseases database trials. We included females with stress urinary incontinence and ≥21 years old. The primary outcome was self-reported work productivity evaluated using a proportional-odds regression model. A backward elimination method was utilized to create a final reduced model. The socioeconomic predictors were age, race/ethnicity, education, marital status, personal income, and language. RESULTS: We included 1252 participants with a median age of 52 years old. Whites accounted for 76.2% of total participants, while Hispanics constituted 11.4% only. Work productivity of Hispanic or non-Hispanic other group was greatly affected compared to Whites (OR: 1.771, P value: .0008 and OR: 1.592, P value=.0231, respectively). Work productivity of patients with higher education was less affected compared to less educated patients. Married females were less likely to report being greatly affected in work productivity than nonmarried females (OR 0.663, P-value .0005). Age, income, and language were not predictive of the outcome variable in the final model. CONCLUSION: Our finding showed that racial/ethnic and socioeconomic disparities play an important role in individuals' work productivity. Future research is needed to the influence of social determinants of health not captured by racial and socioeconomic factors.

Sample efficient reinforcement learning with active learning for molecular design.

Reinforcement learning (RL) is a powerful and flexible paradigm for searching for solutions in high-dimensional action spaces. However, bridging the gap between playing computer games with thousands of simulated episodes and solving real scientific problems with complex and involved environments (up to actual laboratory experiments) requires improvements in terms of sample efficiency to make the most of expensive information. The discovery of new drugs is a major commercial application of RL, motivated by the very large nature of the chemical space and the need to perform multiparameter optimization (MPO) across different properties. In silico methods, such as virtual library screening (VS) and de novo molecular generation with RL, show great promise in accelerating this search. However, incorporation of increasingly complex computational models in these workflows requires increasing sample efficiency. Here, we introduce an active learning system linked with an RL model (RL-AL) for molecular design, which aims to improve the sample-efficiency of the optimization process. We identity and characterize unique challenges combining RL and AL, investigate the interplay between the systems, and develop a novel AL approach to solve the MPO problem. Our approach greatly expedites the search for novel solutions relative to baseline-RL for simple ligand- and structure-based oracle functions, with a 5-66-fold increase in hits generated for a fixed oracle budget and a 4-64-fold reduction in computational time to find a specific number of hits. Furthermore, compounds discovered through RL-AL display substantial enrichment of a multi-parameter scoring objective, indicating superior efficacy in curating high-scoring compounds, without a reduction in output diversity. This significant acceleration improves the feasibility of oracle functions that have largely been overlooked in RL due to high computational costs, for example free energy perturbation methods, and in principle is applicable to any RL domain.

Factors Associated with Statin Discontinuation Following Metabolic and Bariatric Surgery: A Retrospective Analysis of 2012-2021 Electronic Medical Records Network Data.

BACKGROUND: Bariatric surgery has been shown to improve hyperlipidemia, decreasing the need for statin medications. Although maintaining statin therapy post-surgery for those with a history of atherosclerotic cardiovascular disease (ASCVD) is advised, it is uncertain if discontinuation risks differ between those with and without ASCVD history. AIM: The study aims to analyze the rate and reasons for statin cessation post-bariatric surgery in the US using real-world data. METHODS: Using the TriNetX electronic medical records network from 2012 to 2021, the study involved patients aged 18 or older on statins at the time of bariatric surgery. They were categorized into primary and secondary prevention groups based on prior ASCVD. Statin discontinuation was defined as a 90-day gap post the last statin dosage. The Cox model assessed factors influencing statin cessation. RESULTS: Seven hundred and thirty-three statin users undergoing bariatric surgery were identified, with 564 (77%) in primary prevention. Six months post-surgery, 48% of primary prevention patients and 34.5% of secondary ones stopped statins. Primary prevention patients had a 30% higher likelihood of cessation compared to secondary prevention (hazard ratio, 1.30; 95% CI, 1.06-1.60) as shown by multivariable analysis. CONCLUSIONS: Post-bariatric surgery, primary prevention patients are more likely to discontinue statins than secondary prevention patients.

A risk stratification analysis of ASCVD events post-statin discontinuation in patients who underwent sleeve gastrectomy or Roux-en-Y gastric bypass bariatric/metabolic surgeries.

BACKGROUND: Cardiovascular disease remains a leading cause of mortality globally, and its prevalence is notably elevated in individuals with obesity. Bariatric surgery is an effective intervention to reduce obesity-related health risks. However, the implications of discontinuing statin therapy, particularly post-bariatric surgery, among those with a history of atherosclerotic cardiovascular disease have yet to be clarified. We aimed to ascertain the risk of atherosclerotic cardiovascular disease events following statin cessation after bariatric surgery and to delineate the variance in outcomes between primary and secondary prevention cohorts. METHODS: The TriNetX database, encompassing electronic medical records from 69 United States healthcare institutions, spanning 2012 to 2021. Using a retrospective cohort design, patients aged ≥18 years who underwent bariatric surgery and were concurrently on statin therapy were selected. Discontinuation was defined as a 90-day lapse after the last statin prescription. Patients were categorized as "primary" or "secondary" prevention based on their atherosclerotic cardiovascular disease history. The primary outcome was the occurrence of an atherosclerotic cardiovascular disease event post-statin cessation. Multivariable Cox proportional hazards models discerned factors influencing this outcome. RESULTS: Of the 453 statin users who underwent bariatric surgery, 332 (73.1%) were in the primary prevention group and 121 (26.7%) in the secondary prevention group. At 1-year post-surgery, atherosclerotic cardiovascular disease event-free rates were 93% for primary and 68% for secondary prevention groups. Primary prevention patients showed an 82% reduced risk of post-statin cessation atherosclerotic cardiovascular disease events than secondary prevention patients (hazard ratio, 0.181; 95% confidence interval, 0.119-0.274). Additionally, Hispanic/Latino patients had heightened post-statin cessation atherosclerotic cardiovascular disease risks compared to non-Hispanic/Latino peers. CONCLUSION: Post-bariatric surgery statin discontinuation can pose significant risks, especially for those with atherosclerotic cardiovascular disease history and certain demographic groups, such as those over age 40 with diabetes. Ethnic disparities in outcomes necessitate individualized, equitable healthcare strategies. Optimal decisions about statin cessation necessitate comprehensive evaluations of cardiovascular determinants, with future research crucial to refine therapeutic approaches based on these insights.

Drug Expenditure, Price, and Utilization in US Medicaid: A Trend Analysis for New Multiple Myeloma Medications from 2016 to 2022.

INTRODUCTION: Multiple myeloma (MM) is the most common plasma cell tumor type. In late 2015, the FDA approved three new medications for MM. These medications were ixazomib, daratumumab, and elotuzumab. However, their utilization, reimbursement, and price in the Medicaid program have not been analyzed before. METHODS: A retrospective drug utilization study using the national Medicaid pharmacy claims data from 2016 to 2022 in the US. The primary metrics of analysis were utilization (number of prescriptions), reimbursement (total spending), and price (reimbursement per prescription). RESULTS: The overall Medicaid utilization of MM medications increased from 1671 prescriptions in 2016 to 34,583 prescriptions in 2022 (1970% increase). Moreover, the overall Medicaid reimbursement for the new MM medications increased from USD 9,250,000 in 2016 to over USD 214,449,000 in 2022 (2218% increase). Daratumumab had much higher utilization, reimbursement, and market shares than its competitors. Ixazomib was the most expensive medication compared to daratumumab and elotuzumab. CONCLUSION: The results of this study demonstrate that CMS utilization and spending on MM medications have significantly grown since 2016. Daratumumab has by far the highest utilization, spending, and market share. The utilization of and spending on specific pharmaceuticals are clearly impacted by policy and clinical guideline recommendations.

Spending, Utilization, and Price Trends for Immune Checkpoint Inhibitors in US Medicaid Programs: An Empirical Analysis from 2011 to 2021.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs) have become a cornerstone in cancer treatment. With high treatment costs and an increasing number of young and low-income patients with cancer, there is a need to determine the current spending and utilization of ICIs in a real-world population. The objective of this study was to outline the drug spending, utilization, and price trends of ICIs for US Medicaid programs from 2011 to 2021. METHODS: A retrospective descriptive analysis was conducted using the Medicaid State Drug Utilization pharmacy summary files managed by the Centers for Medicare and Medicaid Services. Six ICIs for this study include ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and cemiplimab. Yearly reimbursement and prescription numbers were calculated for six ICIs billed through Medicaid between 2011 and 2021. The average spending per prescription was calculated as a proxy for drug prices. RESULTS: Overall spending and utilization on ICIs have risen exponentially over the past decade. Between 2011 and 2021, expenditures increased from $2.8 million to $4.1 billion. Utilization increased from 94 prescriptions to 462,049 prescriptions in 2021 with six ICIs. The average spending per prescription, or average drug price, decreased 70%, from $29,795.88 in 2011 to $8914.69 in 2021. CONCLUSIONS: Spending on and utilization of ICIs have increased dramatically over the past decade. These findings shed new light on the impact of ICIs on state Medicaid programs and may provide insight into potential cost drivers that need to be addressed through policy.

The Utilization, Expenditure, and Price of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in the US Medicaid Programs: Trends Over a 31 Year Period.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are used for several indications including hypertension. Our aim is to evaluate the utilization, expenditure, and drug price of ACEIs and ARBs in the US Medicaid population. METHODS: A retrospective descriptive trend analysis was conducted using Medicaid State Drug Utilization outpatient pharmacy summary files managed by the Centers for Medicare and Medicaid Services from 1991 to 2021. Study drugs included ACEIs (e.g., captopril) and ARBs (e.g., losartan). Annual reimbursement and utilization were calculated for both classes. The average reimbursement per prescription was calculated as a proxy for drug prices. Market share competition between ACEIs and ARBs was analyzed over time. RESULTS: ACEI and ARB utilization rose by 25% from 1991 to 2021. Brand ACEIs utilization peaked in 2002 with 28 million prescriptions while brand ARBs utilization continued to increase until 2005 with over 23 million prescriptions. However, generic products took the lead and exceeded brand ACEI and ARB utilization in 2006 and 2012 respectively. Medicaid spent over $ 33.7 billion on ACEIs and ARBs over 31-year. Brand ACEIs and ARBs average prices increased sharply to $8,104 and $6,908 respectively in 2021. The total prescription market share for ACEIs was 68% compared to 32% of ARBs over the entire study. CONCLUSION: ACEIs and ARBs utilization increased over the last 31 years. Brand utilization switched over to generic resulting in less reimbursement. The average prices of brand ACEIs and ARBs continue to increase even after generics were introduced to the market.