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.

Use of 31 P magnetisation transfer magnetic resonance spectroscopy to measure ATP changes after 670 nm transcranial photobiomodulation in older adults.

Mitochondrial function declines with age, and many pathological processes in neurodegenerative diseases stem from this dysfunction when mitochondria fail to produce the necessary energy required. Photobiomodulation (PBM), long-wavelength light therapy, has been shown to rescue mitochondrial function in animal models and improve human health, but clinical uptake is limited due to uncertainty around efficacy and the mechanisms responsible. Using 31 P magnetisation transfer magnetic resonance spectroscopy (MT-MRS) we quantify, for the first time, the effects of 670 nm PBM treatment on healthy ageing human brains. We find a significant increase in the rate of ATP synthase flux in the brain after PBM in a cohort of older adults. Our study provides initial evidence of PBM therapeutic efficacy for improving mitochondrial function and restoring ATP flux with age, but recognises that wider studies are now required to confirm any resultant cognitive benefits.

Cost-effectiveness analysis of monthly, 3-monthly, and 6-monthly long-acting injectable and oral paliperidone in adults with schizophrenia.

BACKGROUND: Paliperidone is among the most cost-effective antipsychotics in adults with schizophrenia, and it has different formulations, including oral paliperidone extended-release (ER) and long-acting injectable (LAI) paliperidone formulations administered every month (PP1M), 3 months (PP3M), or 6 months (PP6M). However, cost-effectiveness analyses comparing different paliperidone formulations were limited. OBJECTIVE: To compare the cost-effectiveness across different paliperidone formulations. METHODS: A Markov model was developed to simulate 1,000 adults aged 40 years with stable schizophrenia transitioning among stable disease-medication adherent, stable disease-medication nonadherent, relapse with hospitalization, relapse with ambulatory care, and death states every 3 months for 5 years. Drug costs were estimated using the prices listed in the Veterans Affairs Federal Supply Schedule, and costs for treating complications were estimated from published studies. All costs were estimated from the US health care system perspective and standardized to 2022 US dollars using the Consumer Price Index Inflation Calculator. Quality-adjusted life-years (QALYs) were estimated using relapse rates from randomized clinical trials and health-related quality of life scores from observational studies. The estimated future costs and QALYs were discounted at 3%. We reported incremental net monetary benefits between alternative formulations at the $50,000 willingness-to-pay (WTP) threshold with a positive value indicating cost-effectiveness. The impact of parameter uncertainty on study outcomes was assessed using 1-way deterministic and probabilistic sensitivity analyses. RESULTS: In adults with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was associated with increased QALY (PP1M = 0.05, PP3M = 0.14, PP6M = 0.15) and increased cost (PP1M = 49,433, PP3M = 26,698, PP6M = 26,147), leading to a negative incremental net monetary benefit (PP1M = -$46,804, PP3M = -$19,508, PP6M = -$18,886) compared with continuing ER. Among LAI formulations, PP6M was cost-saving with the most QALYs gained (cost = $63,277, QALY = 3.731), followed by PP3M (cost = $63,828, QALY = 3.729) and PP1M (cost = $86,563, QALY = 3.638). At the $50,000 WTP threshold, the probabilities for PP1M, PP3M, and PP6M being cost-effective compared with paliperidone ER were 0.4%, 10.2%, and 9.8%, respectively. The probability of PP6M being cost-effective was 92.6% for the PP6M-PP1M pair and 55.2% for the PP6M-PP3M pair, and 91.1% of PP3M use was cost-effective in the PP3M-PP1M pair. The results were generally robust in the sensitivity analyses, even at the $190,000 WTP threshold. CONCLUSIONS: For patients with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was not cost-effective, suggesting the high drug costs for LAI may not justify the improved quality of life within 5 years. Among LAI formulations, PP6M was cost-effective over PP1M and PP3M.

Economic Impact of Universal Hepatitis C Virus Testing for Middle-Aged Adults Who Inject Drugs.

INTRODUCTION: The objective of this study was to estimate the economic impact of providing universal hepatitis C virus testing in commercially insured middle-aged persons who inject drugs in the U.S. METHODS: This study developed a dynamic 10-year economic model to project the clinical and economic outcomes associated with hepatitis C virus testing among middle-aged adult persons who inject drugs, from a payer's perspective. Costs related to hepatitis C virus testing, direct-acting antiviral, and liver-related outcomes between the (1) current hepatitis C virus testing rate (i.e., 8%) and (2) universal hepatitis C virus testing rate (i.e., 100%) were compared. Among patients testing positive, 21% of those without cirrhosis and 48% of those with cirrhosis were assumed to initiate direct-acting antivirals. Sensitivity analyses were performed to identify variables (e.g., direct-acting antiviral drug costs, hepatitis C virus testing costs, direct-acting antiviral treatment rate) influencing this study's conclusion. RESULTS: The model predicts that during the 10-year period, universal hepatitis C virus testing will cost an additional $242 per person who injects drugs to the payers' healthcare budgets compared with the current scenario. Sensitivity analyses showed values ranging from $1,656 additional costs to $1,085 cost savings across all varied parameters and scenarios. A total of 80% of the current direct-acting antiviral costs indicated that cost savings will be $383 per person who injects drugs. CONCLUSIONS: Universal hepatitis C virus testing among persons who inject drugs would not achieve cost savings within 10 years, with the cost of direct-acting antivirals contributing the most to the spending. To promote universal hepatitis C virus testing among persons who inject drugs, decreasing direct-acting antiviral costs and sustainable funding streams for hepatitis C virus testing should be considered.

Is Intention to Treat Still the Gold Standard or Should Health Technology Assessment Agencies Embrace a Broader Estimands Framework?: Insights and Perspectives From the National Institute for Health and Care Excellence and Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 (R1) Addendum.

OBJECTIVES: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum will have an important impact on the design and analysis of randomized controlled clinical trials, which represent crucial sources of evidence in health technology assessments, and on the intention-to-treat (ITT) principle in particular. This article brings together a task force of health economists and statisticians in academic institutes and the pharmaceutical industry, to examine the implications of the addendum from the perspective of the National Institute for Health and Care Excellence (NICE) and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) and to address the question of whether the ITT principle should be considered the gold standard for estimating treatment effects. METHODS: We review the ITT principle, as introduced in the ICH E9 guideline. We then present an overview of the ICH E9 (R1) addendum and its estimand framework, highlighting its premise and the proposed strategies for handling intercurrent events, and examine some cases among submissions to IQWiG and NICE. RESULTS: IQWiG and NICE appear to have diverging perspectives around the relevance of the ITT principle and, in particular, the acceptance of hypothetical strategies for estimating treatment effects, as suggested by examples where the sponsor proposed an alternative approach to the ITT principle when accounting for treatment switching for interventional oncology trials. CONCLUSIONS: The ICH E9 (R1) addendum supports the use of methods that depart from the ITT principle. The relevance of estimands using these methods depends on the perspectives and objectives of payers. It is challenging to design a study that meets all stakeholders' research questions. Different estimands may serve to answer different relevant questions or decision problems.

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.

Changes in overactive bladder medication following bariatric surgery: segmented regression analysis.

PURPOSE: Bariatric surgery has shown reductions in overactive bladder (OAB) symptoms; however, the impacts on OAB treatment is unknown. The goal of our study is to evaluate the impact of bariatric surgery on OAB medication utilization. METHODS: We used IBM® MarketScan® commercial databases from 2005 to 2018. We included patients aged ≥ 18 years with 360 days of continuous enrollment before and after bariatric surgery (Roux-en-Y Gastric Bypass and Sleeve Gastrectomy) with at least one fill of an OAB medication in the 360 days prior to bariatric surgery. We evaluated all included patients and stratified by surgery type and patient sex. Segmented regression analyses were used to assess the proportion of patients on OAB medications before and after bariatric surgery. We replicated our findings using hip or knee replacement surgery as a negative control. RESULTS: Among the included patients (n = 3069), 92.2% were females, 58.6% underwent Roux-en-Y Gastric Bypass. Immediately following bariatric surgery, the proportion of patients treated with an OAB medication reduced from 34.8 to 14.1% (p < 0.001) resulting in a 59.5% relative reduction. Patients who underwent Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy (63.8% vs. 55.1%) relative reduction (p = 0.009)) and females versus males [62.3% vs. 52.9% relative reduction (p < 0.001)] had a more pronounced reduction in OAB medication use. There was slight decrease in OAB medication use in the negative control analysis. CONCLUSIONS: A reduction in OAB medication use following bariatric surgery may be associated with a reduction in OAB symptoms suggesting an additional benefit of bariatric surgery.

Lewis acid-base adducts of Al(N(C6F5)2)3 and Ga(N(C6F5)2)3 - structural features and dissociation enthalpies.

Herein we present the molecular structures of six neutral Lewis acid-base adducts of the Lewis superacid Al(N(C6F5)2)3 and its higher homolog Ga(N(C6F5)2)3 with the electron pair donors MeCN, CNtBu, THF and PMe3. The crystal structures reveal crucial structural changes compared to the free Lewis acids as a consequence of the adduct formation. Furthermore, we calculated the corresponding dissociation enthalpies of the adducts which lie between 69 and 141 kJ mol-1 and are therefore considerably lower compared to the values for the formation of the anionic fluoride or chloride metallates.

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.

Twelve-month prevalence of haemarthrosis and joint disease using the Haemophilia Joint Health score: evaluation of the UK National Haemophilia Database and Haemtrack patient reported data: an observational study.

OBJECTIVES: To report the 12-month prevalence of joint bleeds from the National Haemophilia Database (NHD) and Haemtrack, a patient-reported online treatment diary and concurrent joint disease status using the haemophilia joint health score (HJHS) at individual joint level, in children and adults with severe haemophilia A and B (HA/HB) without a current inhibitor. DESIGN: A 2018 retrospective database study of NHD from which 2238 cases were identified, 463 patients had fully itemised HJHS of whom 273 were compliant in recording treatment using Haemtrack. SETTING: England, Wales and Scotland, UK. PARTICIPANTS: Children (<18 years) and adults (≥18 years) with severe HA and HB (factor VIII/factor IX, <0.01 iu/mL) without a current inhibitor. PRIMARY AND SECONDARY OUTCOMES: Prevalence of joint haemarthrosis and concurrent joint health measured using the HJHS. RESULTS: The median (IQR) age of children was 10 (6-13) and adults 40 (29-50) years. Haemarthrosis prevalence in HA/HB children was 33% and 47%, respectively, and 60% and 42%, respectively, in adults. The most common site of haemarthrosis in children was the knee in HA and ankle in HB. In adults, the incidence of haemarthrosis at the ankles and elbows was equal. The median total HJHS in HA/HB children was 0 and in adults with HA/HB, were 18 and 11, respectively. In adults with HA/HB, the median ankle HJHS of 4.0 was higher than the median HJHS of 1.0 for both the knee and elbow. CONCLUSION: Despite therapeutic advances, only two-thirds of children and one-third of adults were bleed-free, even in a UK cohort selected for high compliance with prophylaxis. The median HJHS of zero in children suggests joint health is relatively unaffected during childhood. In adults, bleed rates were highest in ankles and elbows, but the ankles led to substantially worse joint health scores.

Co-utilization of opioids and nonbenzodiazepine hypnotic drugs in U.S. ambulatory care visits, 2006-2016.

OBJECTIVE(S): This study aimed to characterize the co-utilization of non-benzodiazepine sedative 'Z'-drugs with opioids at ambulatory care visits in the United States. DESIGN: A cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2016 was completed. SETTING AND PARTICIPANTS: Ambulatory care visits in the United States involving adult patients with an opioid prescription were included in the analysis. OUTCOME MEASURES: The primary outcome was initiation or continuation of a Z-drug (zolpidem, eszopiclone, or zaleplon) in a patient visit in conjunction with an opioid medication. RESULTS: The authors analyzed 564,090,296 visits (weighted from a sample of 28,773) with a reported opioid prescription. Co-utilization of opioids with Z-drugs fluctuated during the study period beginning at 4.0% in 2006 (95% CI 2.2%-5.7%), 6.3% in 2012 (3.7%-8.9%), and 4.7% in 2016 (2.8%-6.5%). Among all opioid visits in the study period, co-utilization with a Z-drug was not significantly different among female patients compared with male patients (5.26% vs. 4.63%, P = 0.26). Among visits with concomitant opioid and Z-drugs, 7.0% reported new initiation of both medications in the same visit. CONCLUSION: At ambulatory care visits between 2006 and 2016, co-utilization of opioids and Z-drugs fluctuated with some differences by sex. Major regulatory advisories and policy changes during this period may have contributed to these varying rates of utilization. Additional work is needed to identify predictors of co-utilization and downstream consequences more widely.

Polyreactivity and polyspecificity in therapeutic antibody development: risk factors for failure in preclinical and clinical development campaigns.

Antibody-based drugs, which now represent the dominant biologic therapeutic modality, are used to modulate disparate signaling pathways across diverse disease indications. One fundamental premise that has driven this therapeutic antibody revolution is the belief that each monoclonal antibody exhibits exquisitely specific binding to a single-drug target. Herein, we review emerging evidence in antibody off-target binding and relate current key findings to the risk of failure in therapeutic development. We further summarize the current state of understanding of structural mechanisms underpining the different phenomena that may drive polyreactivity and polyspecificity, and highlight current thinking on how de-risking studies may be best implemented in the screening triage. We conclude with a summary of what we believe to be key observations in the field to date, and a call for the wider antibody research community to work together to build the tools needed to maximize our understanding in this nascent area.

Health care utilization and costs associated with direct-acting antivirals for patients with substance use disorders and chronic hepatitis C.

BACKGROUND: Patients with substance use disorders (SUD) and chronic hepatitis C virus infection (HCV) have limited access to direct-acting antivirals (DAAs) due to multilevel issues related to providers (eg, concern about reinfection); patients (eg, refusal); payers (eg, prior authorization); and health system structure, although clinical guidelines recommend timely DAA treatment for patients with SUD and HCV. Effects of DAAs on real-world health care utilization and costs among these patients is unknown. OBJECTIVE: To compare changes in medical service utilization and costs related to liver, SUD, and all-cause morbidity in patients with SUD and HCV treated with DAAs (DAA group) vs not treated with DAAs (non-DAA group). METHODS: We conducted a retrospective cohort study using MarketScan Commercial and Medicare Supplemental Claims databases (2012-2018) for newly diagnosed HCV treatment-naive adults with SUD. We used difference-in-differences analyses, stratified by cirrhosis status, to determine the adjusted ratio of rate ratio (RoRR) to assess the difference in the relative changes from the pre- to posttreatment periods between the 2 groups. RESULTS: 6,266 patients with SUD and HCV were identified. Of these patients who also had cirrhosis (n = 607), 49% (n = 298) initiated DAA therapy for HCV, whereas of those without cirrhosis (n = 5,659), 22% (n = 1,219) initiated DAAs. For patients with cirrhosis (n = 607), the liver-related costs decreased by $6,213 (95% CI = -$8,571, -$3,856) for the DAA group and $1,585 (95% CI = -$4,659, $1,490) for the non-DAA group. The relative decreases in the rate of liver-related costs were larger for the DAA group than for the non-DAA group, and the relative changes between groups were significantly different (RoRR = 0.37, 95% CI = 0.19-0.73). There was no difference in the relative changes after DAAs in the rate of SUD-related visits/costs or all-cause costs between the 2 groups. For patients without cirrhosis (n = 5,659), a similar association was observed. Besides, the relative decreases in the rate of SUD-related emergency department (ED) visits (RoRR = 0.54, 95% CI = 0.38-0.77); SUD-related long-term care visits (RoRR = 0.30, 95% CI = 0.13-0.73); all-cause ED visits (RoRR = 0.75, 95% CI = 0.64-0.88); and all-cause long term-care visits (RoRR = 0.36, 95% CI = 0.18-0.72) were larger in the DAA group than in the non-DAA group. CONCLUSIONS: DAAs are associated with a significant decrease in the rate of SUD-related ED visits and liver-related costs without increasing the rate of all-cause costs among patients with SUD and HCV, suggesting that the benefits of DAAs extended beyond liver-related outcomes, especially in this disadvantaged population. DISCLOSURES: Research reported in this publication was supported in part by the National Institute on Drug Abuse of the National Institutes of Health (K01DA045618). The funder did not have a role in the design, the execution, the analyses, the interpretation of the data, or the decision to submit the results of this study. The authors have no potential conflicts of interest.

Cascade of Hepatitis C Virus Care Among Patients With Substance Use Disorders.

INTRODUCTION: Hepatitis C virus testing is recommended for people at high risk for infection, including those with substance use disorders. Little is known about the cascade of hepatitis C virus care (including testing, diagnosis, and treatments) among patients with substance use disorders in real-world clinical practice. This study aims to characterize the hepatitis C virus cascade of care and identify the factors associated with hepatitis C virus testing and diagnosis among Florida Medicaid beneficiaries with substance use disorders. METHODS: A retrospective cohort analysis of Florida Medicaid data (2013-2018) was conducted in 2020 for patients aged 18-64 years with newly diagnosed substance use disorders (year 2012 was used to ascertain 1-year previous enrollment). A generalized estimating equation identified the factors associated with hepatitis C virus testing; a multivariable logistic model identified the factors associated with hepatitis C virus diagnosis. RESULTS: Of the 156,770 patients with substance use disorders, 18% were tested for hepatitis C virus at least once. Among the tested patients, 8% had hepatitis C virus diagnoses. Among the 2,177 patients having a hepatitis C virus diagnosis, 11% initiated hepatitis C virus treatments, and 96% of them completed the hepatitis C virus treatments. Factors associated with being less likely to receive hepatitis C virus testing included being male (AOR=0.73, 95% CI=0.71, 0.75) and White (AOR=0.85, 95% CI=0.83, 0.87), whereas individuals who were male (AOR=1.49, 95% CI=1.35, 1.66) and White (AOR=2.71, 95% CI=2.38, 3.08) were more likely to be diagnosed with hepatitis C virus. The odds of receiving hepatitis C virus testing significantly increased annually (AOR=1.06, 95% CI=1.05, 1.07). CONCLUSIONS: Future studies are warranted to investigate the barriers to access hepatitis C virus testing and treatment among Florida Medicaid beneficiaries with substance use disorders, especially for White male individuals.

Use of negative controls in a prescription sequence symmetry analysis to reduce time-varying bias.

PURPOSE: There is an increased use in the (prescription) sequence symmetry analysis (PSSA); however, limited studies have incorporated a negative control, and no study has formally quantified and controlled for within-patient time-varying bias using a negative control. Our aim was to develop a process to incorporate the effect of negative controls into the main analysis of a PSSA. METHODS: Using a previously assessed dihydropyridine calcium channel blocker (DH-CCB) and loop diuretic PSSA, we directly compared the adjusted sequence ratios (aSRs) of DH-CCBs to each of the two negative control index drugs (levothyroxine and angiotensin converting enzyme [ACE] inhibitor/angiotensin-2 receptor blocker [ARB]) using the ratio of the aSRs to estimate a relative aSR with a Z test. Further, we utilized the relative aSR in stratum-specific analyses and varying exposure windows. RESULTS: The relative aSR of DH-CCBs decreased from 1.87 to 1.72 (95% CI 1.66-1.78) using levothyroxine as a negative control index drug. ACE inhibitor/ARB negative control index drug resulted in an aSR of 1.27 thus reducing the relative aSR for DH-CBB from 1.84 to 1.45 (95% CI 1.41-1.49). When restricting the exposure window to 180 and 90 days, the relative aSR of DH-CCBs increased to 1.68 (95% CI 1.62-1.74) and 1.86 (95% CI 1.78-1.94), respectively, relative to the ACE inhibitor/ARB negative control index drug. CONCLUSION: We illustrated how to incorporate negative control index drugs into a PSSA and generate relative aSRs. Stratum-specific assessments and varying the exposure windows while using negative control index drugs can yield more informative results.

Changes in utilization of immediate-release, extended-release, and liquid formulation medications relative to bariatric surgery: a segmented regression analysis.

BACKGROUND: Changes in gut anatomy following bariatric surgery impacts medication absorption, often requiring changes in medication formulations. OBJECTIVES: To assess changes in utilization of extended-release (ER), immediate-release (IR), and liquid formulations 360 days before and after bariatric surgery. SETTING: Large U.S. administrative claims database of privately insured beneficiaries, January 2005 through December 2018. METHODS: We included patients aged ≥18 years with 360 days of continuous enrollment before and after date of bariatric surgery (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). The proportion of each formulation (ER, IR, or liquid) of oral prescription medications filled during the study period were assessed in twelve 30-day windows before and after bariatric surgery and stratified by bariatric surgery type. Segmented regression analysis was used to assess filled medication categorized by formulation before and after bariatric surgery overall and RYGB relative to SG. RESULTS: Among 122,866 included patients, there were increases in the proportion of patients on each formulation before and after surgery attributed to proton pump inhibitors, opioids, antiemetics, and ursodiol. After removing these acutely used medications, we found a 40% immediate reduction in patients on ER medications (P < .0001), 15% immediate reduction in patients on IR medications (P < .0001), and a nonsignificant increase in patients on liquid formulations (P = .1340). CONCLUSION: Despite reductions in ER formulations, many patients continued on this formulation which may potentially contribute to poor outcomes.

Evaluation of statin discontinuation stratified by primary versus secondary prevention following bariatric surgery: a retrospective cohort study.

BACKGROUND: Bariatric surgery leads to an improvement in hyperlipidemia and a subsequent decline in the use of hyperlipidemia-related medications, including statins. In patients with a history of atherosclerotic cardiovascular disease (ASCVD), it is recommended to continue statins; however, it is unknown whether there is a differential risk for statin discontinuation in patients with and without a history of ASCVD. OBJECTIVES: To estimate the rates and factors associated with statin discontinuation following bariatric surgery. SETTING: Large U.S. administrative claims database of privately insured beneficiaries, January 2005 through December 2017. METHODS: We identified patients aged ≥19 years who were statin users at the time of bariatric surgery. Patients were stratified into primary prevention and secondary prevention (patients with a history of ASCVD) groups. Time to statin discontinuation was defined as the first 90-day gap after exhausting the last day's supply of the last statin prescription. Factors associated with statin discontinuation were assessed using the Cox proportional hazards regression model. RESULTS: We identified 19,332 statin users at the time of bariatric surgery, of whom 84% (16,221) used statins for primary prevention. At 6 months, 62% and 53% of patients in the primary and the secondary prevention treatment groups, respectively, discontinued statin use. Patients in the primary prevention treatment group were 18% more likely to discontinue statin therapy compared with the patients in the secondary prevention treatment group (hazard ratio, 1.18; 95% confidence interval, 1.13-1.24) according to a multivariable analysis. CONCLUSIONS: Our findings suggest that the rate of discontinuation of statin therapy after bariatric surgery was more pronounced in the primary versus secondary prevention treatment group.

Changes in Quantity of Opioids Dispensed following Florida's Restriction Law for Acute Pain Prescriptions.

OBJECTIVE: To assess the impact of Florida's 3-day opioid prescription supply law, effective July 2018, on opioids dispensed for acute pain patients. METHODS: Pharmacy claims from a health plan serving a large Florida employer from January 2015 through March 2019 were analyzed. We used an interrupted time series study design accounting for autocorrelation of trends before and after policy change. Acute pain patients met inclusion criteria if they had not received any opioid containing medications in the past 180 days. Patients could contribute to additional new use time if subsequent opioid claims occurred ≥180 days since the previous claim. Outcomes included mean number of units dispensed of the initial opioid prescription, mean morphine milligram equivalents (MMEs) per day of initial prescription by month, and mean total MMEs per initial prescription by month. RESULTS: A total of 8,375 enrollees had 10,583 unique opioid starts in the given timeframe. Following the policy, there was an immediate significant decrease in the units dispensed per prescription of 4.9 (95% confidence interval [CI] -8.95, -.82 units). Additionally, there was a significant immediate reduction in total MMEs dispensed per prescription of 25.6 (95% CI -44.76, -6.44 MMEs). CONCLUSIONS: Among a group of privately-insured plan enrollees in Florida, and as a result of the law, there were significant decreases in the number of units dispensed, and total MMEs of opioid prescriptions. The immediate reduction in new opioid utilization following policy implementation suggests effective policy; however, impacts on chronic pain patients were not assessed.

Effects of hydrocodone rescheduling on opioid use outcomes: A systematic review.

OBJECTIVE: To evaluate opioid prescribing, dispensing, and use in relation to hydrocodone-containing product (HCP) rescheduling. METHODS: Seven biomedical databases and grey literature sources were searched with keywords and database-specific controlled vocabulary relevant to HCP rescheduling for items published between January 2014 and July 2019. We included English-language quasi-experimental studies that assessed changes in HCP and other opioid prescribing, dispensing, utilization, and opioid-related health outcomes before and after HCP rescheduling. A data extraction sheet was created for this review. Two authors evaluated risk of bias for each included study. Two of 4 authors each independently extracted patient demographics and opioid-related outcomes from the included studies. Conflicts were resolved by a third author. RESULTS: All studies identified (n = 44) were quasi-experimental in design with 10 using an interrupted time series approach. A total of 24 studies reported a decrease in HCP prescribing by 3.1%-66.0%. Six studies reported a decrease in HCP days' supply or doses by 14.0%-80.8%. There was increased prescribing of oxycodone-containing products by 4.5%-13.9% in 5 studies, tramadol by 2.7%-53.0% in 9 studies, codeine-containing products by 0.8%-1352.9% in 8 studies). Five studies reported a decrease in morphine equivalents by at least 10%, whereas 2 studies reported an increase in morphine equivalents. Differences in populations, sample sizes, and approaches did not allow for a meta-analysis. Details regarding approach and findings were limited in published conference abstracts (n = 16). CONCLUSIONS: Hydrocodone rescheduling was associated with reductions in prescribing and use of HCPs but was also associated with increased prescribing and use of other opioids, both schedule II and nonschedule II.

Order of discontinuation of glucose-lowering medications following bariatric surgery.

AIMS: To assess the order of glucose-lowering medication (GLM) discontinuation following bariatric surgery among patients taking ≥2 GLMs. METHODS: Patients with diabetes mellitus taking ≥2 GLM classes who underwent bariatric surgery were identified using health claims data from the United States. The order of discontinuation was assessed in patients taking ≥2 GLM classes by comparing each GLM class to the other classes in aggregate. Descriptive statistics and Poisson regression were used to assess the order of discontinuation and changes in trends in the order of discontinuation. RESULTS: Overall, 12,244 of 26,651 patients with type 2 diabetes who underwent bariatric surgery were taking ≥2 GLM classes. When each GLM class was assessed separately, fewer than 50% of patients had metformin, sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, glucosidase inhibitor, or insulin discontinued first when compared to the other classes in aggregate. Between 2008 and 2014, thiazolidinediones were increasingly more likely to be the first GLM discontinued (p = 0.0432). Slightly more than 50% of patients whose GLM regimen included a sulfonylurea discontinued the sulfonylurea first despite clinical recommendations. CONCLUSIONS: From a population level, there was no consistent approach in the order of discontinuation of GLM classes in patients following bariatric surgery.