Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid-loop diuretic cascade.

BACKGROUND: Prescribing cascades are important contributors to polypharmacy. Little is known about which older adults are at highest risk of experiencing prescribing cascades. We explored which older veterans are at highest risk of the gabapentinoid (including gabapentin and pregabalin)-loop diuretic (LD) cascade, given the dramatic increase in gabapentinoid prescribing in recent years. METHODS: Using Veterans Affairs and Medicare claims data (2010-2019), we performed a prescription sequence symmetry analysis (PSSA) to assess loop diuretic initiation before and after gabapentinoid initiation among older veterans (≥66 years). To identify the cascade, we calculated the adjusted sequence ratio (aSR), which assesses the temporality of LD relative to gabapentinoid initiation. To explore high-risk groups, we used multivariable logistic regression with prescribing order modeled as a binary dependent variable. We calculated adjusted odds ratios (aORs), measuring the extent to which factors are associated with one prescribing order versus another. RESULTS: Of 151,442 veterans who initiated a gabapentinoid, there were 1,981 patients who initiated a LD within 6 months after initiating a gabapentinoid compared to 1,599 patients who initiated a LD within 6 months before initiating a gabapentinoid. In the gabapentinoid-LD group, the mean age was 73 years, 98% were male, 13% were Black, 5% were Hispanic, and 80% were White. Patients in each group were similar across patient and health utilization factors (standardized mean difference <0.10 for all comparisons). The aSR was 1.23 (95% CI: 1.13, 1.34), strongly suggesting the cascade's presence. People age ≥85 years were less likely to have the cascade (compared to 66-74 years; aOR 0.74, 95% CI: 0.56-0.96), and people taking ≥10 medications were more likely to have the cascade (compared to 0-4 drugs; aOR 1.39, 95% CI: 1.07-1.82). CONCLUSIONS: Among older adults, those who are younger and taking many medications may be at higher risk of the gabapentinoid-LD cascade, contributing to worsening polypharmacy and potential drug-related harms. We did not identify strong predictors of this cascade, suggesting that prescribing cascade prevention efforts should be widespread rather than focused on specific subgroups.

Skills laboratory faculty job satisfaction: Effects of high-contact teaching and the COVID-19 pandemic.

INTRODUCTION: The objective of this study is to describe the workload responsibilities and job satisfaction of skills laboratory faculty, both before and during the COVID-19 pandemic. METHODS: School of pharmacy (SOP) skills laboratory faculty were surveyed in fall 2021 to gather information on workload responsibilities and job satisfaction, before and during the COVID-19 pandemic. Quantitative data were reported using descriptive statistics and, when appropriate, student t-tests were used to compare responses from before and during COVID-19. Qualitative data were coded for themes by two investigators with a third investigator used to reach consensus. RESULTS: A total of 45 skills laboratory faculty from 44 of 142 SOP responded to the survey. Faculty reported an average percent effort of 43.9% laboratory teaching, 13.9% non-laboratory teaching, 12.8% service, 6.5% administration, 12.5% patient care, and 10.4% scholarship. Overall job satisfaction decreased from before COVID-19 to during COVID-19, and faculty members' satisfaction specifically with their laboratory role decreased from 7.5 to 6.6 (P = .003). Several themes were identified when respondents described what they loved most about teaching in the laboratory as well as the challenges associated, the majority of which were personnel, resources, and time. CONCLUSIONS: Skills laboratory faculty reported a high number of laboratory courses coordinated each year along with many hours dedicated each week to prepare and conduct skills laboratory activities. While the pandemic is over, the unique aspects of coordinating student-centered courses likely requires more support for skills laboratory faculty members to avoid burnout and improve job satisfaction.

Evaluating Provider and Pharmacy Discordance in Potential Calcium Channel Blocker-Loop Diuretic Prescribing Cascade.

BACKGROUND: Prescribing cascades occur when a drug-induced adverse event is treated with a new medication. Identifying clinical scenarios in which prescribing cascades are more likely to occur may help determine ways to prevent prescribing cascades. OBJECTIVE: To understand the extent to which discordant providers and discordant pharmacies contribute to the dihydropyridine calcium channel blocker (DH CCB)-loop diuretic prescribing cascade. STUDY POPULATION AND DESIGN: A retrospective cohort study using Medicare Fee-For-Service data (2011-2018) of adults aged ≥ 66 years. EXPOSURES: Patients who initiated DH CCB with subsequent initiation of loop diuretic (DH CCB-loop diuretic dyad) within 90 days or patients who initiated angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) with subsequent initiation of a loop diuretic (ACEI/ARB-loop diuretic dyad; control). MAIN OUTCOMES: The primary outcomes were provider and pharmacy discordance for prescribing cascades and control drug pairs. Baseline clinical and socio-demographic characteristics were balanced using inverse probability of treatment weighting with propensity scores. RESULTS:  Overall, we identified 1987 DH CCB-loop diuretic dyads and 3148 ACEI/ARB-loop diuretic dyads. Discordant providers occurred in 64% of DH CCB-loop diuretic dyads and 55% of ACEI/ARB-loop diuretic dyads, while discordant pharmacies occurred in 19% of DH CCB-loop diuretic dyads and 16% of ACEI/ARB-loop diuretic dyads. After adjustment, the risk of having discordant providers was 20% {Relative Risk (RR) 1.20 [95% confidence interval (CI), 1.14-1.26]} higher in the DH CCB-loop diuretic dyad compared with the ACEI/ARB-loop diuretic dyad. Moreover, pharmacy discordance was 17% (RR 1.17 [95% CI 1.02-1.33]) higher. CONCLUSION: Our findings suggest that discordant providers and discordant pharmacies were more commonly involved in the potential prescribing cascade when compared with a similar control dyad of medications. Opportunities for enhanced care coordination and medication reconciliation should be explored to prevent unnecessary polypharmacy.

Trends and Components of Thyroid Status Evaluation in Commercially Insured Adults in the United States, 2006-2020.

CONTEXT: Thyroid-stimulating hormone (TSH) is one of the most ordered laboratory tests. OBJECTIVE: Determine trends of TSH testing rates and components of thyroid function testing. METHODS: This was a retrospective analysis of adults 18-64 years old without evidence of thyroid disease with at least 365 days of continuous enrollment between 2006 and 2020 in the IBM MarketScan Claims Database. The main outcome measures were trends of TSH tests/1000 eligible patient-months stratified by age, sex, and region and composition of thyroid function testing. RESULTS: Among 67 353 280 patients meeting eligibility criteria, we identified 25 606 518 TSH tests and 15 138 211 patients with ≥1 TSH test. Patients contributing an episode of TSH testing were most commonly 45-54 years old (29.8%) and female (63.6%). TSH testing rates remained consistent throughout the study period with 11.4 and 11.7 TSH tests/1000 person-months in the first and last study months, respectively (mean 12.2 TSH tests/1000 person-months). TSH testing rates dropped sharply in the spring of 2020 (4.2 TSH tests/1000 person-months). Females showed a nearly 2-fold higher rate of TSH testing than males (16.1 TSH tests/1000 person-months vs 8.6 TSH tests/1000 person-months). TSH testing rates increased with age (8.2 TSH tests/1000 person-months among individuals 18-34 years old vs 15.4 TSH tests/1000 person-months among individuals 55-64 years old). No difference in TSH testing rates was noted between regions. Thyroid function testing episodes included only TSH in most cases (70.8%). CONCLUSION: TSH testing rates among commercially insured individuals without known thyroid disease appears stable over time, with higher frequency in females and with increasing age.

Mapping potentially inappropriate medications in older adults using the Anatomical Therapeutic Chemical (ATC) classification system.

BACKGROUND: Potentially inappropriate medications (PIMs) in older adults are medications in which risks often outweigh benefits and are suggested to be avoided. Worldwide, many distinct guidelines and tools classify PIMs in older adults. Collating these guidelines and tools, mapping them to a medication classification system, and creating a crosswalk will enhance the utility of PIM guidance for research and clinical practice. METHODS: We used the Anatomical Therapeutic Chemical (ATC) Classification System, a hierarchical classification system, to map PIMs from eight distinct guidelines and tools (2019 Beers Criteria, Screening Tool for Older Person's Appropriate Prescriptions [STOPP], STOPP-Japan, German PRISCUS, European Union-7 Potentially Inappropriate Medication [PIM] list, Centers for Medicare & Medicaid Services [CMS] High-Risk Medication, Anticholinergic Burden Scale, and Drug Burden Index). Each PIM was mapped to ATC Level 5 (drug) and to ATC Level 4 (drug class). We then used the crosswalk (1) to compare PIMs and PIM drug classes across guidelines and tools to determine the number of PIMs that were index (drug-induced adverse event) or marker (treatment of drug-induced adverse event) drug of prescribing cascades, and (2) estimate the prevalence of PIM use in older adults continuously enrolled with fee-for-service Medicare in 2018 as use cases. Data visualization and descriptive statistics were used to assess guidelines and tools for both use cases. RESULTS: Out of 480 unique PIMs identified, only three medications-amitriptyline, clomipramine, and imipramine and two drug classes-N06AA (tricyclic antidepressants) and N06AB (selective serotonin reuptake inhibitors), were noted in all eight guidelines and tools. Using the crosswalk, 50% of classes of index drugs and 47% of classes of marker drugs of known prescribing cascades were PIMs. Additionally, 88% of Medicare beneficiaries were dispensed ≥1 PIM across the eight guidelines and tools. CONCLUSION: We created a crosswalk of eight PIM guidelines and tools to the ATC classification system and created two use cases. Our findings could be used to expand the ease of PIM identification and harmonization for research and clinical practice purposes.

Machine learning-based prediction models for home discharge in patients with COVID-19: Development and evaluation using electronic health records.

OBJECTIVE: This study aimed to develop and validate predictive models using electronic health records (EHR) data to determine whether hospitalized COVID-19-positive patients would be admitted to alternative medical care or discharged home. METHODS: We conducted a retrospective cohort study using deidentified data from the University of Florida Health Integrated Data Repository. The study included 1,578 adult patients (≥18 years) who tested positive for COVID-19 while hospitalized, comprising 960 (60.8%) female patients with a mean (SD) age of 51.86 (18.49) years and 618 (39.2%) male patients with a mean (SD) age of 54.35 (18.48) years. Machine learning (ML) model training involved cross-validation to assess their performance in predicting patient disposition. RESULTS: We developed and validated six supervised ML-based prediction models (logistic regression, Gaussian Naïve Bayes, k-nearest neighbors, decision trees, random forest, and support vector machine classifier) to predict patient discharge status. The models were evaluated based on the area under the receiver operating characteristic curve (ROC-AUC), precision, accuracy, F1 score, and Brier score. The random forest classifier exhibited the highest performance, achieving an accuracy of 0.84 and an AUC of 0.72. Logistic regression (accuracy: 0.85, AUC: 0.71), k-nearest neighbor (accuracy: 0.84, AUC: 0.63), decision tree (accuracy: 0.84, AUC: 0.61), Gaussian Naïve Bayes (accuracy: 0.84, AUC: 0.66), and support vector machine classifier (accuracy: 0.84, AUC: 0.67) also demonstrated valuable predictive capabilities. SIGNIFICANCE: This study's findings are crucial for efficiently allocating healthcare resources during pandemics like COVID-19. By harnessing ML techniques and EHR data, we can create predictive tools to identify patients at greater risk of severe symptoms based on their medical histories. The models developed here serve as a foundation for expanding the toolkit available to healthcare professionals and organizations. Additionally, explainable ML methods, such as Shapley Additive Explanations, aid in uncovering underlying data features that inform healthcare decision-making processes.

Modifiable statin characteristics associated with potential statin-related prescribing cascades.

STUDY OBJECTIVE: Clinicians may prescribe new medications (marker drug) to treat statin-related (index drug) adverse events, constituting a prescribing cascade. We aimed to identify modifiable statin characteristics (intensity and individual statin agents) associated with lower risk of prescribing cascades to inform clinical decisions in the presence of statin-related adverse events. DESIGN: A secondary analysis based on our previous work, a high-throughput sequence symmetry analysis screening for potential statin-related prescribing cascades. DATA SOURCE: MarketScan Commercial and Medicare Supplemental Insurance claims databases between 2005 and 2019. PATIENTS: Adults who initiated a statin between 2007 and 2018, and who were continuously enrolled in the same healthcare plan for at least 720 days before and 360 days after statin initiation. INTERVENTION: Among the previously identified 57 potential prescribing cascades, 42 statin-marker class dyad with a sample size of ≥ 500 were assessed in this study. MEASUREMENTS: We measured patients' baseline characteristics within -360 days of statin initiation and reported by modifiable statin characteristics. We also performed logistic regression and reported the adjusted odds ratios (aOR) with 95% confidence intervals (CI) of modifiable statin characteristics after adjusting for baseline characteristics. MAIN RESULTS: We identified 1,307,867 statin initiators who met the study criteria (21% elderly, 52% female). Compared with patients initiating low-intensity statins, those initiating moderate- or high-intensity statins had significantly greater odds to develop 29 (69%) prescribing cascades, including antidiabetic drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors (aOR 1.22; 95% CI, 1.11-1.35) and glucagon-like peptide-1 (GLP-1) analogs (aOR 1.31; 95% CI, 1.16-1.47), and opioids (aOR 1.18; 95% CI, 1.13-1.23). Individual statin agent selection also had a differential effect on 34 (81%) of the prescribing cascades. For example, compared with simvastatin initiators, the probability of initiating osmotically acting laxatives was significantly higher for lovastatin initiators (aOR 1.09; 95% CI, 1.03-1.15) and significantly lower in atorvastatin initiators (aOR 0.92; 95% CI, 0.89-0.94). CONCLUSION: Compared with low-intensity statins, high-intensity statins are associated with increased risk in many potential prescribing cascades, while the choice of individual statin agents affects the risk of prescribing cascades bidirectionally.

A lot in a little: Assessment of skills laboratory course structures and faculty workloads.

INTRODUCTION: Pharmacy skills development is essential to pharmacy programs to ensure "practice-ready" graduates. The objective was to describe the landscape of skills laboratory (lab) courses and faculty workload across United States schools and colleges of pharmacy (S/COP). METHODS: The American Association of Colleges of Pharmacy Laboratory Instructors Special Interest Group disseminated an anonymous questionnaire to collect faculty demographics, skills lab format, faculty workload, and job satisfaction. Descriptive statistics were generated, and paired t-tests were used to assess changes before and during COVID-19. RESULTS: Faculty from 44 of 142 S/COP responded. Participants (n = 45) were more frequently assistant professors (49%), non-tenure track (80%), and female (98%). A mean of 103 students per class, with a mean of two lab courses in both the first and second years and 1.6 in the third year were reported. Courses had a mean 1.6 lab coordinators each. Many institutions leverage non-lab faculty, pharmacy volunteers, post-graduate trainees, and senior professional students to assist. Faculty reported a mean 28.2 hours per week related to lab activities. The mean assigned percent effort was 44% for teaching in the skills lab, demonstrating consistency with effort calculations. Job satisfaction (scale 1-10) decreased from 7.6 before COVID-19 to 6.4 during COVID-19 (P < .01), with satisfaction specifically with their lab role decreasing from 7.5 to 6.6 (P = .003). CONCLUSIONS: Skills lab faculty reported significant time coordinating labs and identified the need for additional support. S/COP should ensure appropriate personnel resources are available to provide quality clinical skills training.

Drivers of Individual and Regional Variation in CMS Hierarchical Condition Categories Among Florida Beneficiaries.

Objective: To explore hierarchical condition categories (HCC) risk score variation among Florida Fee for Service (FFS) Medicare beneficiaries between 2016 and 2018. Data Sources: This study analyzed HCC risk score variation using Medicare claims data for Florida beneficiaries enrolled in Parts A & B between 2016 and 2018. Study Design: The CMS methodology analyzed HCC risk score variation using annual mean county- and beneficiary-level risk score changes. The association between variation and beneficiary characteristics, diagnoses, and geographic location was characterized using mixed-effects negative binomial regression models. Data Collection: Not applicable. Principal Findings: Counties in the Northeast [marginal effect (ME)=-0.003], Central (ME=-0.021), and Southwest (ME=-0.009) Florida have relatively lower mean risk scores. A higher number of lifetime (ME=0.246) and treatable (ME=0.288) conditions were associated with higher county-level risk scores, while more preventable conditions (ME=-0.249) were associated with lower risk scores. Counties with older beneficiaries (ME=0.015) and more Blacks (ME=0.070) have higher risk scores, while having female beneficiaries reduced risk scores (ME=-0.005). Individual risk scores did not vary by age (ME=0.000), but Blacks (ME=0.001) had higher rates of variation relative to Whites, while other races had comparatively lower variation (ME=-0.003). In addition, individuals diagnosed with more lifetime (ME=0.129), treatable (ME=0.235), and preventable (ME=0.001) conditions had higher risk score variation. Most condition-specific indicators showed small associations with risk score changes; however, metastatic cancer/acute leukemia, respirator dependence/tracheostomy, and pressure ulcers of the skin were significantly associated with both types of HCC risk score variation. Conclusion: Results showed demographics, HCC condition classifications (ie, lifetime, preventable, and treatable), and some specific conditions were associated with higher variation in mean county-level and individual risk scores. Results suggest consistent coding and reductions in the prevalence of certain treatable or preventable conditions could reduce the county and individual HCC risk score year-to-year change.

Analysis of Prescriptions Dispensed After Death and Associated Medicare Spending Following Reimbursement Policy Changes in Medicare.

This cohort study examined the association of a prescription drug event edit policy change with prescriptions dispensed after the deaths of beneficiaries and estimated Medicare spending.

High-throughput screening for prescribing cascades among real world statin initiators.

PURPOSE: Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin-related prescribing cascades has been performed to our knowledge. METHODS: We utilized sequence symmetry analysis to iteratively screen prescribing sequences of all therapeutic classes ("marker" classes) based on Level 4 Anatomical Therapeutic Chemical codes among adult statin initiators, using IBM Marketscan commercial and Medicare supplemental claims databases (2005-2019). Order of initiation and secular trend-adjusted sequence ratios were calculated for each statin-marker class dyad, among marker class initiators ±90 days of statin initiation. Among signals classified as prescribing cascades, we calculated naturalistic number needed to harm (NNTH) within 1 year as the inverse of the excess risk among exposed. RESULTS: We identified 2 265 519 statin initiators (mean ± SD age, 56.4 ± 12.0 years; 48.7% women; 7.5% with cardiovascular disease). Simvastatin (34.4% of statin initiators) and atorvastatin (33.9%) were the most commonly initiated statins. We identified 160 significant statin-marker class dyad signals, of which 35.6% (n = 57) were classified as potential prescribing cascades. Of the top 25 strongest signals (lowest NNTH), 12 were classified as potential prescribing cascades, including osmotically acting laxatives (NNTH, 44, 95% CI 43-46), opioids + non-opioid combination analgesics (81, 95% CI 74-91), and first-generation cephalosporins (204, 95% CI 175-246). CONCLUSIONS: Using high-throughput sequence symmetry analysis screening, we identified previously known prescribing cascades as well as potentially new prescribing cascades based on known and unknown statin-related adverse events.

Continued potassium supplementation use following loop diuretic discontinuation in older adults: An evaluation of a prescribing cascade relic.

BACKGROUND: The use of a new medication (e.g., potassium supplementation) for managing a drug-induced adverse event (e.g., loop diuretic-induced hypokalemia) constitutes a prescribing cascade. However, loop diuretics are often stopped while potassium may be unnecessarily continued (i.e., relic). We aimed to quantify the occurrence of relics using older adults previously experiencing a loop diuretic-potassium prescribing cascade as an example. METHODS: We conducted a prescription sequence symmetry analysis using the population-based Medicare Fee-For-Service data (2011-2018) and partitioned the 150 days following potassium initiation by day to assess the daily treatment scenarios (i.e., loop diuretics alone, potassium alone, combination of loop diuretics and potassium, or neither). We calculated the proportion of patients developing the relic, proportion of person-days under potassium alone, the daily probability of the relic, and the proportion of patients filling potassium after loop diuretic discontinuation. We also identified the risk factors of the relic. RESULTS: We identified 284,369 loop diuretic initiators who were 8 times more likely to receive potassium supplementation simultaneously or after (i.e., the prescribing cascade), rather than before, loop diuretic initiation (aSR 8.0, 95% CI 7.9-8.2). Among the 66,451 loop diuretic initiators who subsequently (≤30 days) initiated potassium, 20,445 (30.8%) patients remained on potassium after loop diuretic discontinuation, and 9365 (14.1%) patients subsequently filled another potassium supplementation. Following loop diuretic initiation, 4.0% of person-days were for potassium alone, and daily probability of the relic was the highest after day 90 of loop diuretic initiation (5.6%). Older age, female sex, higher diuretic daily dose, and greater baseline comorbidities were risk factors for the relic, while patients having the same prescriber or pharmacy involved in the use of both medications were less likely to experience the relic. CONCLUSIONS: Our findings suggest the need for clinicians to be aware of the potential of relic to avoid unnecessary drug use.

Improvement in Clinical Outcomes and Access to Care With Pharmacist-Led Chronic Care Management Services at a Rural Family Medicine Clinic.

Background: Chronic care management (CCM) can significantly impact the management of chronic diseases in rural patient populations. To date, few practice models have addressed its impact on clinical outcomes and access to care in rural practice settings. Objective: Implement a sustainable pharmacist-led CCM practice model while tracking clinical outcomes and healthcare access at a rural, medically underserved family medicine clinic. Methods: This study retrospectively examined data from the clinic's CCM program from October 2020 through May 2021 and included total clinical encounters at three- and 6-months intervals, as well as changes in clinical outcomes like A1c and systolic blood pressure (SBP) at three- and 6-months intervals. Results: Over an 8-month period, 46 patients were enrolled in pharmacist-led CCM services. Those with a CCM encounter or office visit within 3 months of enrollment showed a mean A1c reduction of 1.07% after 3 months (95% CI -1.70 to -.44, P = .0016), while those with an encounter or office visit within 6 months of enrollment displayed a mean A1c reduction of 1.64% after 6 months (95% CI -2.35 to -.92, P < .001). There was a 73.8% increase in total clinical encounters in the 6 months after CCM enrollment compared to the 6 months preceding it, signifying increased access to care. Conclusion: Patients with CCM encounters or office visits within the first 3-6 months experienced statistically significant reductions in A1c. Moreover, total clinical encounters markedly increased in the 6 months after enrollment, allowing for more frequent engagement between ambulatory pharmacists and traditionally challenging rural patients.

Association between gabapentinoids and oedema treated with loop diuretics: A pooled sequence symmetry analysis from the USA and Denmark.

AIMS: To assess the gabapentinoid-oedema-loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark. METHODS: This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs. RESULTS: Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06-1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75-0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23-2.04). Pooled estimated incidence of the gabapentinoid-loop diuretic prescribing cascade was 8.14 (95% CI, 1.92-34.49) events per 1000 patient-years. CONCLUSION: We identified evidence of the gabapentinoid-oedema-loop diuretic prescribing cascade in 2 countries.

Evaluation of a Beta-Blocker-Edema-Loop Diuretic Prescribing Cascade: A Prescription Sequence Symmetry Analysis.

BACKGROUND: Drug-related adverse events associated with antihypertensive therapy may result in subsequent prescribing of other potentially harmful medications, known as prescribing cascades. The aim of this study was to assess the magnitude and characteristics of a beta-blocker-edema-loop diuretic prescribing cascade. METHODS: A prescription sequence symmetry analysis was used to assess loop diuretic initiation before and after initiation of beta-blockers among patients 20 years or older without heart failure, atrial fibrillation, other arrythmias, or use of calcium channel blocker within a U.S. private insurance claims database (2005-2018). The temporality of loop diuretic initiation relative to a beta-blocker or negative control (renin-angiotensin system blocker) initiation was tabulated. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) compared the initiation of loop diuretic 90 days before and after initiation of beta-blockers. RESULTS: Among 988,675 beta-blocker initiators, 9,489 patients initiated a new loop diuretic prescription 90 days after and 5,245 patients before beta-blocker initiation, resulting in an aSR of 1.78 (95% CI, 1.72-1.84). An estimated 1.72 beta-blocker initiators per 100 patient-years experienced the prescribing cascade in the first 90 days. The aSR was disproportionately higher among older adults (aSR 1.97), men (aSR 2.25), and patients who initiated metoprolol tartrate (aSR 2.48), labetalol (aSR 2.18), or metoprolol succinate (aSR 2.11). Negative control results (aSR 1.09, 95% CI, 1.05-1.13) generally corroborated our findings, but suggested modest within-person time-varying confounding. CONCLUSIONS: We observed excess use of loop diuretics following beta-blocker initiation that was only partially explained by secular trends or hypertension progression.

Evaluation of the key prescription sequence symmetry analysis assumption using the calcium channel blocker: Loop diuretic prescribing cascade.

OBJECTIVES: To evaluate the prescription sequence symmetry analysis assumption regarding balance between marker drug (i.e., medication used to treat a drug-induced adverse event) initiation rates before and after initiation of an index drug (i.e., medication that is potentially associated with the drug-induced adverse event) in the absence of prescribing cascades, we used a well-described example of loop diuretic initiation to treat dihydropyridine calcium channel blockers (DH CCB)-induced edema. STUDY DESIGN AND SETTING: The University of Florida Health Integrated Data Repository from June 2011 and July 2018 was used to assess temporal prescribing of DH CCB and loop diuretics within the prescription sequence symmetry analysis framework. Validation of the prescribing cascade was performed via clinical expert chart review. RESULTS: Among patients without heart failure who were initiated on DH CCB, 26 and 64 loop diuretics initiators started within 360 days before versus after DH CCB initiation, respectively, resulting in an adjusted sequence ratio (aSR) of 2.27 (95% CI, 1.44-3.58). Overall, 35 (54.7%) patients were determined to have a prescribing cascade. Removing patients who experienced a prescribing cascade resulted in an aSR of 1.05, 95% CI 0.62-1.78). CONCLUSION: Loop diuretic initiation rates before and after DH CCB initiation for reasons other a prescribing cascade were similar, thus confirming the prescription sequence symmetry analysis assumption.

Evaluating the use of prescription sequence symmetry analysis as a pharmacovigilance tool: A scoping review.

BACKGROUND: The (prescription) sequence symmetry analysis (PSSA) design has been used to identify potential prescribing cascade signals by assessing the prescribing sequence of an index drug relative to a marker drug presumed to treat an adverse drug event provoked by the index drug. OBJECTIVES: This review aimed to explore the use of the PSSA design as a pharmacovigilance tool with a particular focus on the breadth of identified signals and advances in PSSA methodology. METHODS: We searched Embase, PubMed/Medline, Google Scholar, Web of Science and grey literature to identify studies that used the PSSA methodology. Two reviewers independently extracted relevant data for each included article. Study characteristics including signals identified, exposure time window, stratified analyses, and use of controls were extracted. RESULTS: We identified 53 studies which reported original results obtained using PSSA methodology or quantified the validity of components of the PSSA design. Of those, nine studies provided validation metrics showing reasonable sensitivity and high specificity of PSSA to identify prescribing cascade signals. We identified 340 unique index drug - marker drug signals published in the PSSA literature, representing 281 unique index - marker pharmacological class dyads (i.e., unique fourth-level Anatomical Therapeutic Chemical [ATC] classification dyads). Commonly observed signals were identified for index drugs acting upon the nervous system (34%), cardiovascular system (21%), and blood and blood-forming organs (15%), and many marker drugs were related to the nervous system (25%), alimentary tract and metabolism (23%), cardiovascular system (17%), and genitourinary system and sex hormones (14%). Negative controls and positive controls were utilized in 21% and 13% of studies, respectively. CONCLUSIONS: The PSSA methodology has been used in 53 studies worldwide to detect and evaluate over 300 unique prescribing cascades signals. Researchers should consider sensitivity analyses incorporating negative and/or positive controls and additional time windows to evaluate time-varying biases when designing PSSA studies.

A Mapping Literature Review of Medical Cannabis Clinical Outcomes and Quality of Evidence in Approved Conditions in the USA from 2016 to 2019.

In 2017, a National Academies of Sciences, Engineering, and Medicine (NASEM) report comprehensively evaluated the body of evidence regarding cannabis health effects through the year 2016. The objectives of this study are to identify and map the most recently (2016-2019) published literature across approved conditions for medical cannabis and to evaluate the quality of identified recent systematic reviews, published following the NASEM report. Following the literature search from 5 databases and consultation with experts, 11 conditions were identified for evidence compilation and evaluation: amyotrophic lateral sclerosis, autism, cancer, chronic noncancer pain, Crohn's disease, epilepsy, glaucoma, human immunodeficiency virus/AIDS, multiple sclerosis (MS), Parkinson's disease, and posttraumatic stress disorder. A total of 198 studies were included after screening for condition-specific relevance and after imposing the following exclusion criteria: preclinical focus, non-English language, abstracts only, editorials/commentary, case studies/series, and non-U.S. study setting. Data extracted from studies included: study design type, outcome definition, intervention definition, sample size, study setting, and reported effect size. Few completed randomized controlled trials (RCTs) were identified. Studies classified as systematic reviews were graded using the Assessing the Methodological Quality of Systematic Reviews-2 tool to evaluate the quality of evidence. Few high-quality systematic reviews were available for most conditions, with the exceptions of MS (9 of 9 graded moderate/high quality; evidence for 2/9 indicating cannabis improved outcomes; evidence for 7/9 indicating cannabis inconclusive), epilepsy (3 of 4 graded moderate/high quality; 3 indicating cannabis improved outcomes; 1 indicating cannabis inconclusive), and chronic noncancer pain (12 of 13 graded moderate/high quality; evidence for 7/13 indicating cannabis improved outcomes; evidence from 6/7 indicating cannabis inconclusive). Among RCTs, we identified few studies of substantial rigor and quality to contribute to the evidence base. However, there are some conditions for which significant evidence suggests that select dosage forms and routes of administration likely have favorable risk-benefit ratios (i.e., epilepsy and chronic noncancer pain). The body of evidence for medical cannabis requires more rigorous evaluation before consideration as a treatment option for many conditions, and evidence necessary to inform policy and treatment guidelines is currently insufficient for many conditions.

Antitumor properties of novel sesquiterpene lactone analogs as NFκB inhibitors that bind to the IKKß ubiquitin-like domain (ULD).

Melampomagnolide B (MMB, 3) is a parthenolide (PTL, 1) based sesquiterpene lactone that has been used as a template for the synthesis of a plethora of lead anticancer agents owing to its reactive C-10 primary hydroxyl group. Such compounds have been shown to inhibit the IKKß subunit, preventing phosphorylation of the cytoplasmic IκB inhibitory complex. The present study focuses on the synthesis and in vitro antitumor properties of novel benzyl and phenethyl carbamates of MMB (7a-7k). Screening of these MMB carbamates identified analogs with potent growth inhibition properties against a panel of 60 human cancer cell lines (71% of the molecules screened had GI50 values < 2 µM). Two analogs, the benzyl carbamate 7b and the phenethyl carbamate7k, were the most active compounds. Lead compound 7b inhibited cell proliferation in M9 ENL AML cells, and in TMD-231, OV-MD-231 and SUM149 breast cancer cell lines. Interestingly, mechanistic studies showed that 7b did not inhibit p65 phosphorylation in M9 ENL AML and OV-MD-231 cells, but did inhibit phophorylation of both p65 and IκBα in SUM149 cells. 7b also reduced NFκB binding to DNA in both OV-MD-231 and SUM149 cells. Molecular docking studies indicated that 7b and 7k are both predicted to interact with the ubiquitin-like domain (ULD) of the IKKß subunit. These data suggest that in SUM149 cells, 7b is likely acting as an allosteric inhibitor of IKKß, whereas in M9 ENL AML and OV-MD-231 cells 7b is able to inhibit an event after IκB/p65/p50 phosphorylation by IKKß that leads to inhibition of NFκB activation and reduction in NFκB-DNA binding. Analog 7b was by far the most potent compound in either carbamate series, and was considered an important lead compound for further optimization and development as an anticancer agent.

Differences in Health-Related Quality of Life Among Adults with a Potential Dihydropyridine Calcium Channel Blocker-Loop Diuretic Prescribing Cascade.

BACKGROUND: Dihydropyridine calcium channel blockers (DH CCBs) are commonly used for hypertension in older adults. However, loop diuretics can be inappropriately added to treat DH CCB-induced edema, putting individuals at increased risk for adverse events and potential decreases in quality of life. METHODS: We conducted a cross-sectional analysis using United States Medical Expenditure Panel Survey (MEPS) data from 2003 to 2015. Adults aged ≥ 55 years without congestive heart failure, nephrotic syndrome, chronic kidney disease, renal failure, and cirrhosis who had consecutive rounds of DH CCB use (round 1 and 2 or round 3 and 4) and completed the self-administered questionnaire (SAQ) were included. Patients initiated on loop diuretics in round 2 or 4 were compared to those not initiated. Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were analyzed using multivariable linear regression models. RESULTS: Among 5,458,467 DH CCB users (weighted), 3.4% of individuals were identified with new loop diuretic use (185,130 weighted). After adjusting for covariates, DH CCB plus loop diuretic use was associated with a PCS score 3.12 units lower (95% confidence interval - 5.40 to - 0.83; p = 0.008) than DH CCB use alone. We observed no significant difference in MCS score (p = 0.160) among DH CCB plus loop diuretic users compared to DH CCB users alone. CONCLUSIONS: New loop diuretic use was associated with lower physical functioning among DH CCB users. These findings suggest that this potential prescribing cascade may result in both significant and clinically meaningful decreases in health-related quality of life. It is important for clinicians to avoid or intervene on this inappropriate prescribing cascade when possible.