Publications by authors named "Almut G Winterstein"

157 Publications

Quality of opioid prescribing in older adults with or without Alzheimer disease and related dementia.

Alzheimers Res Ther 2021 Apr 12;13(1):78. Epub 2021 Apr 12.

Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, 1225 Center Drive, Health Professions Nursing Pharmacy Building, Room 3321, Gainesville, FL, 32610, USA.

Background: Pain is common among individuals with Alzheimer's disease and related dementias (ADRD), and use of opioids has been increasing over the last decade. Yet, it is unclear to what extent opioids are appropriately prescribed for patients with ADRD and whether the appropriateness of opioid prescribing differs by ADRD status. The objective of this study is to compare the quality of opioid prescribing among patients with or without ADRD who have chronic noncancer pain.

Methods: A nationally representative cohort study of Medicare beneficiaries aged 50 years or older who had chronic pain but who had no cancer, hospice, or palliative care from 2011 to 2015. Four indicators of potentially inappropriate opioid prescribing were measured in patients residing in communities (75,258 patients with and 435,870 patients without ADRD); five indicators were assessed in patients in nursing homes (NHs) (37,117 patients with and 5128 patients without ADRD). Each indicator was calculated as the proportion of eligible patients with inappropriate opioid prescribing in the year after a chronic pain diagnosis. Differences in proportions between ADRD and non-ADRD groups were estimated using a generalized linear model adjusting for covariates through inverse probability weighting.

Results: Patients with ADRD versus those without had higher concurrent use of opioids and central nervous system-active drugs (community 44.1% vs 33.3%; NH 58.8% vs 54.1%, both P < 0.001) and no opioids or scheduled pain medications for moderate or severe pain (NH 60.1% vs 52.5%, P < 0.001). The ADRD versus non-ADRD group had higher use of long-term opioids for treating neuropathic pain in communities (21.7% vs 19.5%, P = 0.003) but lower use in NHs (26.9% vs 36.0%, P < 0.001). Use of strong or high-dose opioids when naive to opioids (community 1.5% vs 2.8%; NH 2.5% vs 3.5%) and use of contraindicated opioids (community 0.08% vs 0.12%; NH 0.05% vs 0.21%) were rare for either group.

Conclusion: Potential inappropriate opioid prescribing in 2 areas of pain care was more common among patients with ADRD than among patients without ADRD in community or NH settings. Further studies aimed at understanding the factors and effects associated with opioid prescribing patterns that deviate from guidelines are warranted.
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http://dx.doi.org/10.1186/s13195-021-00818-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061026PMC
April 2021

Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Exacerbations Among Patients With Type 2 Diabetes.

Diabetes Care 2021 Apr 19. Epub 2021 Apr 19.

Department of Pharmaceutical Outcomes & Policy, College of Pharmacy, University of Florida, Gainesville, FL.

Objective: Emerging data from animal and human pilot studies suggest potential benefits of glucagon-like peptide 1 receptor agonists (GLP-1RA) on lung function. We aimed to assess the association of GLP-1RA and chronic lower respiratory disease (CLRD) exacerbation in a population with comorbid type 2 diabetes (T2D) and CLRD.

Research Design And Methods: A new-user active-comparator analysis was conducted with use of a national claims database of beneficiaries with employer-sponsored health insurance spanning 2005-2017. We included adults with T2D and CLRD who initiated GLP-1RA or dipeptidyl peptidase 4 inhibitors (DPP-4I) as an add-on therapy to their antidiabetes regimen. The primary outcome was time to first hospital admission for CLRD. The secondary outcome was a count of any CLRD exacerbation associated with an inpatient or outpatient visit. We estimated incidence rates using inverse probability of treatment weighting for each study group and compared via risk ratios.

Results: The study sample consisted of 4,150 GLP-1RA and 12,540 DPP-4I new users with comorbid T2D and CLRD. The adjusted incidence rate of first CLRD admission during follow-up was 10.7 and 20.3 per 1,000 person-years for GLP-1RA and DPP-4I users, respectively, resulting in an adjusted hazard ratio of 0.52 (95 CI 0.32-0.85). For the secondary outcome, the adjusted incidence rate ratio was 0.70 (95% CI 0.57-0.87).

Conclusions: GLP-1RA users had fewer CLRD exacerbations in comparison with DPP-4I users. Considering both plausible mechanistic pathways and this real-world evidence, potential beneficial effects of GLP-1RA may be considered in selection of an antidiabetes treatment regimen. Randomized clinical trials are warranted to confirm our findings.
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http://dx.doi.org/10.2337/dc20-1794DOI Listing
April 2021

Association of US Food and Drug Administration Removal of Indications for Use of Oral Quinolones With Prescribing Trends.

JAMA Intern Med 2021 Apr 19. Epub 2021 Apr 19.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville.

Importance: In May 2016, due to concerns of the risks outweighing the benefits, the US Food and Drug Administration (FDA) removed systemic quinolones' indications for acute, uncomplicated urinary tract infection (uUTI), acute sinusitis (AS), and acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). How the change influenced oral quinolone use is unknown.

Objective: To assess the association of oral quinolone safety warnings and indication restrictions with use.

Design, Setting, And Participants: This interrupted time series (January 2015-November 2018) analysis of the monthly prevalence of oral quinolone-treated infection episodes used a national sample of privately insured patients in outpatient care from the IBM MarketScan Database and included adults with antibiotic treatment of new uUTI, AS, or AE-COPD episodes, excluding patients with conditions that complicate infections, previous hospitalization, or other infections.

Exposures: Time before and after May 2016 when the FDA mandated label changes.

Main Outcomes And Measures: Monthly oral quinolone use prevalence by each condition before and after the label changes, overall and stratified by prescriber specialty.

Results: In January 2015, quinolone prevalence among antibiotic-treated uUTI episodes (n = 652 235) was 41.6% (95% CI, 40.6%-42.5%); AS (n = 1 742 248) was 8.3% (95% CI, 7.9%-8.6%), and AE-COPD (n = 22 817) was 31.9% (95% CI, 30.3%-33.4%). Before the label changes, trends in monthly quinolone prevalence were nearly flat. The month of the label changes we noted an immediate reduction for uUTI (-7.2%; 95% CI, -8.6% to -5.8%); and to a lesser extent for AS (-1.2%; 95% CI, -1.5% to -0.9%) and AE-COPD (-2.6%; 95% CI, -4.1% to -1.1%), and continued monthly declines thereafter. Falsification tests confirmed an immediate decrease after the label change of quinolone use for uUTI but more obscured effects for AS and AE-COPD. Treatment shifted mostly to first-line (eg, nitrofurantoin in uUTI, amoxicillin in AS, macrolides in AE-COPD) and other second-line agents but use of not recommended antibiotics also increased (eg, tetracyclines in AE-COPD). Prescribing preferences varied, but significant reductions were seen across all prescriber specialties. At the end of the study period, quinolone was used for 19.2% of treated uUTIs, 2.9% of treated AS, and 14.6% of treated AE-COPD episodes.

Conclusions And Relevance: Label changes and their announcements was associated with an immediate reduction in oral quinolone use for uUTI and to a lesser extent for AS and AE-COPD. Quinolones continued to contribute a considerable proportion of treatments for uUTI and AE-COPD episodes at the end of the study period, pointing to opportunities for further improvement.
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http://dx.doi.org/10.1001/jamainternmed.2021.1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056313PMC
April 2021

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

Genet Med 2021 Mar 29. Epub 2021 Mar 29.

Division of Genomic Medicine, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

Purpose: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.

Methods: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation.

Results: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression.

Conclusion: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.
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http://dx.doi.org/10.1038/s41436-021-01118-9DOI Listing
March 2021

Non-steroidal anti-inflammatory drug-associated acute kidney injury: does short-term NSAID use pose a risk in hospitalized patients?

Eur J Clin Pharmacol 2021 Mar 27. Epub 2021 Mar 27.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, 1225 Center Drive, Gainesville, FL, 32611, USA.

Purpose: While renal risk associated with short-term use of non-steroidal anti-inflammatory drugs (NSAID) has been anecdotally documented, no conclusive evidence is available on the renal safety, especially among hospitalized patients with reduced renal function. This study is to evaluate the risk of acute kidney injury (AKI) associated with NSAID use in hospital.

Methods: A retrospective matched cohort study utilizing electronic health records from two large academic tertiary-care hospitals was conducted. We defined AKI based on changes in SCr according to published AKI criteria. The hospital acquired AKI risk associated with inpatient NSAID use was assessed using a time-dependent Cox proportional hazard regression in pooled cohort as well as two sub cohorts stratified by baseline renal function.

Results: A total of 18,794 admissions were included in the final cohort. Of 9397 admissions exposed to NSAIDs, 7914 and 1483 admissions were in the "without" and "with baseline renal impairment" cohort, with the same number of matching non-exposed admissions in each of the stratified cohort. The AKI incidences were 6 and 22 events per 1000 patient-days in "without" and "with preexisting renal impairment" cohort, respectively. The adjusted analyses suggested that NSAID use increased AKI risk in patients with preexisting renal impairment (hazard ratio [HR]: 1.38 [1.04-1.83]) but not in the patients without preexisting renal impairment (HR: 0.83 [95% CIs: 0.63-1.08]) or in the pooled cohort (HR: 1.01 [95% CIs: 0.83-1.24]).

Conclusion: Our findings suggested that NSAID use is associated with an increased risk of AKI in the hospitalized patients with preexisting renal impairment but the association is not statistically significant in those who have preserved renal function. Further randomized controlled trials are needed to validate these observational findings.
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http://dx.doi.org/10.1007/s00228-021-03121-0DOI Listing
March 2021

Utilization patterns of skeletal muscle relaxants among commercially insured adults in the United States from 2006 to 2018.

Pain Med 2021 Mar 4. Epub 2021 Mar 4.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida.

Objective: To examine the prevalence and duration of skeletal muscle relaxant (SMR) treatment among commercially insured adults.

Methods: We used the MarketScan Research Database to identify a cohort of adults 18 to 64 years who had ≥ two-year continuous enrollment between 2005 and 2018. We estimated the prevalence of SMR treatment using a repeated cross-sectional design and derived treatment duration using the Kaplan-Meier method. Analyses were stratified by age group, sex, geographic region, individual SMR agent, and musculoskeletal disorder.

Results: 48.7 million individuals were included. Treatment prevalence ranged from 61.5 to 68.3 per 1000. About one-third of users did not have a preceding musculoskeletal disorder diagnosis. Cyclobenzaprine was the dominant agent accounting for >50% of prescriptions. The considerable growth in the use of baclofen, tizanidine, and methocarbamol paralleled with a decline in carisoprodol and metaxalone use. The prevalence was highest in the South while lowest in the Northeast. The median treatment duration was 14 days with 4.0%, 1.9%, and 1.0% of individuals using SMRs for more than 90, 180, and 365 days. Compared with cyclobenzaprine, patients initiating baclofen, tizanidine, and carisoprodol had longer treatment duration.

Conclusions: SMRs are widely used in the United States. Their use slightly increased in recent years but trends varied among individual agents, patient groups, and geographic regions. Despite limited evidence to support efficacy, a sizable number of U.S. adults used SMRs for long-term and off-label conditions. Further study is needed to understand determinants of treatment as well as outcomes associated with such use.
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http://dx.doi.org/10.1093/pm/pnab088DOI Listing
March 2021

Real-World Fetal Exposure to Acne Treatments in the United States: A Retrospective Analysis from 2006 to 2015.

Drug Saf 2021 Apr 8;44(4):447-454. Epub 2021 Mar 8.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Introduction: Several studies have evaluated the effects of changes in isotretinoin risk mitigation programs, but little is known about actual fetal exposure rates in the context of other acne treatments.

Objective: Our objective was to quantify fetal exposure rates during the use of common acne treatments.

Methods: Employing the insurance claims data of > 100,000 acne treatment users between 2006 and 2015, we created three user cohorts: (1) isotretinoin (strong teratogen/mandatory risk mitigation program), (2) doxycycline/minocycline (mild teratogen, label warning), and (3) topical clindamycin/erythromycin (no fetal risk). Fetal exposure rates overall and stratified by age were compared after adjusting for potential confounders.

Results: Contraceptive use during acne treatment was < 50% in isotretinoin users and < 30% in the other study groups. Long-acting contraceptives contributed to 1% of all contraceptives used, with 90% being oral contraceptives. Isotretinoin users had 19.2 (95% confidence interval [CI] 20.3 to 17.9) fewer fetal exposures per 1000 person-years of use compared with doxycycline/minocycline users, which in turn had 28.8 (95% CI 31.2 to 26.3) fewer pregnancies compared with clindamycin/erythromycin users. Stratification by age showed attenuated differences in fetal exposure among acne treatment groups for teenagers.

Conclusion: Fetal exposure to acne treatments varied according to levels of teratogenicity, with reduced rates among users of isotretinoin and to a lesser extent doxycycline/minocycline. Teenagers had low pregnancy rates but less pronounced differences in fetal exposure across acne treatments.
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http://dx.doi.org/10.1007/s40264-021-01053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994218PMC
April 2021

Using machine learning to identify diabetes patients with canagliflozin prescriptions at high-risk of lower extremity amputation using real-world data.

Pharmacoepidemiol Drug Saf 2021 May 2;30(5):644-651. Epub 2021 Mar 2.

Department of Pharmaceutical Outcomes & Policy, University of Florida, Gainesville, Florida, USA.

Aims: Canagliflozin, a sodium-glucose cotransporter 2 inhibitor indicated for lowering glucose, has been increasingly used in diabetes patients because of its beneficial effects on cardiovascular and renal outcomes. However, clinical trials have documented an increased risk of lower extremity amputations (LEA) associated with canagliflozin. We applied machine learning methods to predict LEA among diabetes patients treated with canagliflozin.

Methods: Using claims data from a 5% random sample of Medicare beneficiaries, we identified 13 904 diabetes individuals initiating canagliflozin between April 2013 and December 2016. The samples were randomly and equally split into training and testing sets. We identified 41 predictor candidates using information from the year prior to canagliflozin initiation, and applied four machine learning approaches (elastic net, least absolute shrinkage and selection operator [LASSO], gradient boosting machine and random forests) to predict LEA risk after canagliflozin initiation.

Results: The incidence rate of LEA was 0.57% over a median 1.5 years follow-up. LASSO produced the best prediction, yielding a C-statistic of 0.81 (95% CI: 0.76, 0.86). Among individuals categorized in the top 5% of the risk score, the actual incidence rate of LEA was 3.74%. Among the 16 factors selected by LASSO, history of LEA [adjusted odds ratio (aOR): 33.6 (13.8, 81.9)] and loop diuretic use [aOR: 3.6 (1.8,7.3)] had the strongest associations with LEA incidence.

Conclusions: Our machine learning model efficiently predicted the risk of LEA among diabetes patients undergoing canagliflozin treatment. The risk score may support optimized treatment decisions and thus improve health outcomes of diabetes patients.
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http://dx.doi.org/10.1002/pds.5206DOI Listing
May 2021

Opportunity for Genotype-Guided Prescribing Among Adult Patients in 11 US Health Systems.

Clin Pharmacol Ther 2021 Jan 11. Epub 2021 Jan 11.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene-drug pairs as "level A," for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)-affiliated health systems across the US. Inpatient and/or outpatient electronic-prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658-15,781) in 2011 to 17,335 (CI: 17,283-17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632-7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype-guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.
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http://dx.doi.org/10.1002/cpt.2161DOI Listing
January 2021

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients.

JAMA Netw Open 2020 12 1;3(12):e2029411. Epub 2020 Dec 1.

Personalized Medicine Initiative, Nicklaus Children's Health System, Miami, Florida.

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation.

Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions.

Design, Setting, And Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020.

Exposures: Prescription of 38 level A medications based on electronic health records.

Main Outcomes And Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally.

Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes.

Conclusions And Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737091PMC
December 2020

A Pharmacoepidemiologic Approach to Evaluate Real-world Effectiveness of Hormonal Contraceptives in the Presence of Drug-drug Interactions.

Epidemiology 2021 Mar;32(2):268-276

From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.

Background: Accurate estimation of conception is critical in the assessment of the effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OCs), where misclassification of conception relative to OC exposure may obscure effect estimates.

Methods: We studied OC failure, in a large claims database, among women who used antiepileptic drugs with metabolizing enzyme-inducing properties (carbamazepine or oxcarbazepine), which reduce OC's effectiveness or enzyme-neutral properties (lamotrigine or levetiracetam), with no expected impact on OC effectiveness. We compared conception rates in women 12-48 years of age concomitantly using OCs and enzyme-inducing drugs with rates in concomitant users of OCs and enzyme-neutral drugs. We measured conception with a validated algorithm that estimates gestational age based on pregnancy endpoints. We estimated relative and attributable risk using generalized estimating equation models after standardized mortality ratio weighting.

Results: We identified 89,777 concomitant use episodes with adjusted contraceptive failure rates of 1.6 (95% confidence interval (CI) = 1.4, 1.8) per 100 person-years among users of enzyme-neutral drugs and 18,964 episodes with a rate of 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The relative risk of conception for enzyme-inducing group was 1.4 (1.1, 1.8), and the rate difference was 0.7 (0.2, 1.2).

Conclusions: OCs in combination with antiepileptic drugs that interact with metabolic enzymes were associated with increased contraceptive failure rates. Measurement of conception in claims data had adequate accuracy to uncover a strong drug-drug interaction, offering promise for broader application in comparative effectiveness studies on hormonal contraceptives to inform clinical and regulatory decisionmaking.
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http://dx.doi.org/10.1097/EDE.0000000000001302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850590PMC
March 2021

Medical Costs and Productivity Loss Due to Mild, Moderate, and Severe Asthma in the United States.

J Asthma Allergy 2020 29;13:545-555. Epub 2020 Oct 29.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Background: Little is known about economic and productivity loss by severity of asthma. We investigate health-care utilization, direct medical costs, and indirect costs due to productivity loss from asthma by severity.

Methods: We conducted a cross-sectional analysis of the Medical Expenditure Panel Survey database (2010-2017) of patients with asthma aged ≥12 years and categorized them into mild, moderate, and severe asthma groups based on symptom control medications. Study outcomes included health-care utilization, direct medical costs, and indirect costs of asthma-related absenteeism. We used zero-inflated Poisson regression models to estimate incremental health-care utilization and generalized linear models to estimate incremental annual direct medical costs compared to patients without asthma.

Results: An estimated 139 million persons had an asthma diagnosis. Of patients with asthma, 77.1%, 22.2%, and 0.7% had mild, moderate, and severe asthma, respectively. Compared to patients without asthma, patients with asthma had incremental mean differences of 4.16 outpatient visits, 0.18 emergency department visits, and 0.07 hospitalizations per year. Annual direct medical costs were significantly associated with asthma severity ($3305 in mild, $7250 in moderate, and $9175 in severe asthma) ( < 0.05). Patients with mild, moderate, and severe asthma reported 0.76, 2.31, and 7.19 missed work or school days, resulting in $106, $321, and $1000 indirect costs per person per year, respectively.

Conclusion: Asthma-related direct and indirect costs are significantly associated with asthma severity, with severe asthma medical costs being about three times higher than mild. Controlling asthma symptoms is important to reduce the economic and social burden of asthma.
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http://dx.doi.org/10.2147/JAA.S272681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605920PMC
October 2020

Impact of the Transition from ICD-9-CM to ICD-10-CM on the Identification of Pregnancy Episodes in US Health Insurance Claims Data.

Clin Epidemiol 2020 15;12:1129-1138. Epub 2020 Oct 15.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy and Center for Drug Evaluation and Safety (CoDES), University of Florida, Gainesville, FL, USA.

Background: Before October 2015, pregnancy cohorts assembled from US health insurance claims have relied on medical encounters with International Classification of Diseases-ninth revision-clinical modification (ICD-9-CM) codes. We aimed to extend existing pregnancy identification algorithms into the ICD-10-CM era and evaluate performance.

Methods: We used national private insurance claims data (2005-2018) to develop and test a pregnancy identification algorithm. We considered validated ICD-9-CM diagnosis and procedure codes that identify medical encounters for live birth, stillbirth, ectopic pregnancy, abortions, and prenatal screening to identify pregnancies. We then mapped these codes to the ICD-10-CM system using general equivalent mapping tools and reconciled outputs with literature and expert opinion. Both versions were applied to the respective coding period to identify pregnancies. We required 45 weeks of health plan enrollment from estimated conception to ensure the capture of all pregnancy endpoints.

Results: We identified 7,060,675 pregnancy episodes, of which 50.1% met insurance enrollment requirements. Live-born deliveries comprised the majority (76.5%) of episodes, followed by abortions (20.3%). The annual prevalence for all pregnancy types was stable across the ICD transition period except for postterm pregnancies, which increased from 0.5% to 3.4%. We observed that ICD codes indicating gestational age were available for 86.8% of live-born deliveries in the ICD-10 era compared to 23.5% in the ICD-9 era. Patterns of prenatal tests remained stable across the transition period.

Conclusion: Translation of existing ICD-9-CM pregnancy algorithms into ICD-10-CM codes provided reasonable consistency in identifying pregnancy episodes across the ICD transition period. New codes for gestational age can potentially improve the precision of conception estimates and minimize measurement biases.
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http://dx.doi.org/10.2147/CLEP.S269400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571578PMC
October 2020

Age of First Use of Prescription Opioids and Prescription Opioid Non-Medical Use among Older Adolescents.

Subst Use Misuse 2020 15;55(14):2420-2427. Epub 2020 Oct 15.

Department of Epidemiology, University of Florida, Gainesville, Florida, USA.

Background: Non-medical use (NMU) of prescription opioids is of concern due to the opioid epidemic in the United States. We examined sex differences in the effect of age of first use of prescription opioids on prescription opioid NMU among 17- and 18-year olds. The National Monitoring of Adolescent Prescription Stimulants Study (N-MAPSS) recruited youth 10-18 years from 10 United States cities between 2008 and 2011 ( = 11,048). The cross-sectional survey included questions on past 30 day prescription opioid use (10,965 provided responses; 278 age 17 to 18 years who used opioids in past 30 days), with NMU defined as non-oral use and/or use of someone else's opioids. Nonparametric survival analysis with lifetable estimates was used to examine age at first use. Binomial logistic regression was conducted predicting any NMU, adjusted for covariates. Among 278 youth 17 to 18 years, a significant difference in age of first use between those with MU only and any NMU ( < .0001) was observed. Each one year increase in age resulted in a 33% decrease in the odds of any prescription opioid NMU compared to MU only, after controlling for covariates (Odds Ratio = 0.67, 95% Confidence Interval: 0.47,0.96). Sex differences in age at first use were not observed. Risk of past 30 day prescription opioid NMU decreased by a third for each one year increase in age of first use, after adjustment for other covariates. Use of prescription opioids in young adolescents may need to be limited where possible and researched further.
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http://dx.doi.org/10.1080/10826084.2020.1823420DOI Listing
October 2020

Calibration of Chronic Lung Disease Severity as a Risk Factor for Respiratory Syncytial Virus Hospitalization.

J Pediatric Infect Dis Soc 2021 Apr;10(3):317-325

Department of Pharmaceutical Outcomes & Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Background: Guidelines assume children with chronic lung disease (CLD) who require medical support within 6 months before the second respiratory syncytial virus (RSV) season remains at high risk of severe RSV disease. We determined the number of days since the last treatment (DSL) when the risk of RSV hospitalization among children with CLD becomes equivalent to the risk for those not qualified for immunoprophylaxis.

Methods: The study cohort was assembled using Medicaid billing records from 1999 to 2010 linked to Florida and Texas birth certificate records. We developed DSL-trend discrete time logistic regression models within a survival analysis framework, adjusting for use of immunoprophylaxis, to compare the hospitalization risk of CLD infants at 4 age points to that of term infants at 1 month of age with siblings.

Results: The study cohort included 858 830 healthy term and 5562 preterm infants with CLD. Among 1-month-old term infants, the RSV hospitalization risk averaged across all covariate strata was 14.8 (95% confidence interval [CI], 13.5-16.1) per 1000 patient season-months. Risk for preterm CLD children reached the threshold derived from term infants when DSL was 76 (95% CI, 22-198.5), 52 (95% CI, 6.5-123), 35 (95% CI, 0-93.5), and 12 (95% CI, 0-61.5) at the respective ages of 12, 15, 17.2, and 21 months.

Conclusions: The 180-day threshold used to define CLD severity at season start can be shortened to 120 days, 90 days, and 60 days for children with CLD at age 15, 17.2, and 21 months, respectively.
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http://dx.doi.org/10.1093/jpids/piaa107DOI Listing
April 2021

Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical trials.

Pharmacoepidemiol Drug Saf 2020 11 4;29(11):1382-1392. Epub 2020 Oct 4.

Global Epidemiology, Johnson & Johnson, Titusville, New Jersey, USA.

Purpose: Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long-term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness.

Methods: We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps.

Results: Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences.

Conclusion: This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.
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http://dx.doi.org/10.1002/pds.5141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756307PMC
November 2020

Validation of algorithms to estimate gestational age at birth in the Medicaid Analytic eXtract-Quantifying the misclassification of maternal drug exposure during pregnancy.

Pharmacoepidemiol Drug Saf 2020 11 9;29(11):1414-1422. Epub 2020 Sep 9.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Purpose: Accurate ascertainment of gestational age (GA) has been a challenge in perinatal epidemiologic research. To date, no study has validated GA algorithms in Medicaid Analytic eXtract (MAX).

Methods: We linked livebirths of mothers enrolled in Medicaid ≥30 days after delivery in 1999-2010 MAX to state birth certificates. We used clinical/obstetric estimate of gestation on the birth certificates as gold standard to validate claims-based GA algorithms. We calculated the proportions of deliveries with algorithm-estimated GA within 1-/2-weeks of the gold standard, the sensitivity, specificity, and positive/negative predictive value (PPV/NPV) of exposure to select medications during specific gestation windows, and quantified the impact of exposure misclassification on hypothetical relative risk (RR) estimates.

Results: We linked 1 336 495 eligible deliveries. Within 1-week agreement was 77%-80% overall and 47%-56% for preterm deliveries. The trimester-specific drug exposure status had high sensitivities and PPVs (88.5%-98.5%), and specificities and NPVs (>99.0%). Assuming a hypothetical RR of 2.0, bias associated with exposure misclassification during first trimester ranged from 10% to 40% under non-differential/differential misclassification assumptions.

Conclusions: Claims-based GA algorithms had good agreement with the gold standard overall, but lower agreement among preterm deliveries, potentially resulting in biased risk estimated for pregnancy exposure evaluations.
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http://dx.doi.org/10.1002/pds.5126DOI Listing
November 2020

Randomization versus Real-World Evidence.

N Engl J Med 2020 07;383(4):e21

Syddansk Universitet, Odense, Denmark.

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http://dx.doi.org/10.1056/NEJMc2020020DOI Listing
July 2020

Agreement of Minimum Data Set 3.0 depression and behavioral symptoms with clinical diagnosis in a nursing home.

Aging Ment Health 2020 May 25:1-6. Epub 2020 May 25.

Department of Pharmaceutical Outcomes & Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA.

While the Minimum Data Set (MDS) 3.0 has adopted Patient Health Questionnaire (PHQ)-9 to screen for depression and rephrased language for behavioral symptoms among nursing home residents, it remains unclear how well the assessment data agree with medical records. Using a retrospective review of MDS 3.0 linked to medical records between October 2010 and November 2017, we included residents with at least one quarterly or short-term (day 30 or day 60) MDS 3.0 assessment of depression PHQ-9 ( = 446) or behavioral symptoms ( = 460). For each resident of each cohort, we randomly selected an eligible MDS 3.0 depression and behavioral symptom assessment and compared against the respective medical diagnoses recorded within 30 days before the MDS 3.0 assessment. Percent agreement was high for depression (90.1%) and behavioral symptoms (89.3%). Negative agreement was high for depression (94.8%) and behavioral symptoms (94.3%), while positive agreement was low for both conditions (4.3% and 10.9%).: MDS 3.0 depression and behavioral symptoms had high overall and negative agreement, but low positive agreement with clinician diagnoses. MDS 3.0 data may be useful in ruling out depression and behavioral symptoms. Confirmation of the findings in a representative sample of nursing homes is warranted.
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http://dx.doi.org/10.1080/13607863.2020.1758921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686050PMC
May 2020

An evaluation of co-use of chloroquine or hydroxychloroquine plus azithromycin on cardiac outcomes: A pharmacoepidemiological study to inform use during the COVID19 pandemic.

Res Social Adm Pharm 2021 01 30;17(1):2012-2017. Epub 2020 Apr 30.

Department of Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville, FL, USA; Center for Drug Evaluation and Safety, University of Florida, Gainesville, FL, USA. Electronic address:

Background: Chloroquine or hydroxychloroquine (chloroquine) plus azithromycin is considered as therapy for COVID-19. With benefit evaluations underway, safety concerns due to potential additive effects on QTc prolongation should be addressed.

Objective: We compared risk of cardiac adverse events between combinations of chloroquine and azithromycin and chloroquine and amoxicillin.

Methods: We conducted a retrospective cohort study using the IBM MarketScan Commercial Claims and Medicare Supplemental Databases, 2005-2018. We included autoimmune disease patients aged ≥18 years initiating azithromycin or amoxicillin for ≥5 days during chloroquine treatment. Patients had continuous insurance coverage ≥6 months before combination use until 5 days thereafter or inpatient death. Two outcomes were sudden cardiac arrest/ventricular arrhythmias (SCA/VA) and cardiac symptoms. We followed patients for up to 5 days to estimate hazard ratios (HR). Covariates were adjusted using stabilized inverse probability treatment weighting.

Results: We identified two SVC/VA events among >145,000 combination users. The adjusted incidence of cardiac symptoms among azithromycin and amoxicillin users was 276 vs 254 per 10,000 person-years with an adjusted HR of 1.10 (95%CI, 0.62-1.95).

Conclusion: Combination use of chloroquine and azithromycin at routine doses did not show pronounced increases in arrhythmias in this real-world population, though small sample size and outcome rates limit conclusions.
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http://dx.doi.org/10.1016/j.sapharm.2020.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190482PMC
January 2021

Risk of pregnancy loss in patients exposed to mycophenolate compared to azathioprine: A retrospective cohort study.

Pharmacoepidemiol Drug Saf 2020 06 29;29(6):716-724. Epub 2020 Apr 29.

Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA.

Purpose: To evaluate the relative risk of pregnancy loss associated with mycophenolate (MPA) vs azathioprine (AZA) use.

Methods: We conducted a retrospective cohort study using the IBM MarketScan Research Databases (2005-2015). Patients with ≥1 MPA or AZA prescription claim during the first trimester were included. The study outcome was pregnancy loss (spontaneous abortion or stillbirth). Potential confounders included age, drug indications, comorbidities, other teratogenic medication use, and gestational age at first MPA or AZA prescription fill. The risk for pregnancy loss was estimated using a generalized estimating equation model with stabilized inverse probability of treatment weighting. In sensitivity analyses, we varied the exposure definition, outcome definition, and the analytical method.

Results: Among 111 pregnancies exposed to MPA, 55 resulted in pregnancy loss (49.5%). Among 471 pregnancies exposed to AZA, 113 had pregnancy loss (24.0%). The unadjusted relative risk for pregnancy loss was 2.0 (95% CI 1.6, 2.6), and the adjusted relative risk was 1.9 (95% CI, 1.6, 2.3) compared to AZA. Relative risk estimates were stable in all sensitivity analyses.

Conclusion: Exposure to MPA during early pregnancy was associated with a 2-fold increase in pregnancy loss risk.
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http://dx.doi.org/10.1002/pds.5017DOI Listing
June 2020

Medication Use for ADHD and the Risk of Driving Citations and Crashes Among Teenage Drivers: A Population-Based Cohort Study.

J Atten Disord 2020 Apr 26:1087054720915768. Epub 2020 Apr 26.

University of Florida, Gainesville, USA.

To evaluate the real-world effectiveness of ADHD medications on adverse driving outcomes in teenage drivers with ADHD. We retrospectively followed 15- to 20-year-old ADHD patients with valid driver's license to compare the risk for crashes and citations between periods with and without ADHD medication use, using Florida Medicaid records linked to Department of Motor Vehicles data from 1999 to 2004. Patient-level demographic, clinical, and driver licensing characteristics as well as county-level crash and traffic statistics were adjusted in Cox models. A total of 2,049 patients had 67 crashes and 319 citations. Adjusted hazard ratios comparing ADHD medication use versus no use were 1.22 (95% confidence interval [CI] = [0.66, 1.90]) and 0.89 (95% CI = [0.69, 1.13]) for crashes and citations, respectively. Our study showed no evidence that ADHD medication use was associated with a reduced risk of adverse driving outcomes among teenage drivers enrolled in Medicaid programs. Limitations in interpreting this finding are presented.
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http://dx.doi.org/10.1177/1087054720915768DOI Listing
April 2020

Characteristics of Older Adults Who Were Early Adopters of Medical Cannabis in the Florida Medical Marijuana Use Registry.

J Clin Med 2020 Apr 18;9(4). Epub 2020 Apr 18.

Center for Drug Evaluation & Safety, Department of Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.

Use of medical marijuana is increasing in the United States and older adults are the fastest growing user group. There is little information about the characteristics and outcomes related to medical marijuana use. This study is a descriptive analysis of older adults (aged ≥50 years old) who were early adopters of a medical marijuana program in the U.S. state of Florida. Per state legislation, initial and follow-up treatment plans were submitted to the University of Florida College of Pharmacy. Data collection included demographics, clinical history, medical conditions, substance use history, prescription history, and health status. Follow-up treatment plans noted changes in the chief complaint and actions taken since the initial visit. Of the state's 7548 registered users between August 2016 and July 2017, = 4447 (58.9%) were older adults. Patients utilized cannabidiol (CBD)-only preparations (45%), preparations that had both tetrahydrocannabinol (THC) and CBD (33.3%) or were recorded to use both CBD-only and THC + CBD products (21.7%). The chief complaints indicating medical cannabis treatment were musculoskeletal disorders and spasms (48.4%) and chronic pain (45.4%). Among other prescription medications, patients utilized antidepressants (23.8%), anxiolytics and benzodiazepines (23.5%), opioids (28.6%), and cardiovascular agents (27.9%). Among all drug classes with potential sedating effects, 44.8% of the cohort were exposed to at least one. Patients with follow-up visits (27.5%) exhibited marked improvement as assessed by the authorizing physicians. However, the patient registry lacked detailed records and linkable information to other data resources to achieve complete follow up in order to assess safety or efficacy. Future improvements to registries are needed to more adequately capture patient information to fill knowledge gaps related to the safety and effectiveness of medical marijuana, particularly in the older adult population.
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http://dx.doi.org/10.3390/jcm9041166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230351PMC
April 2020

Letter by Alipour Haris et al Regarding Article, "Marijuana Use Among Young Adults (18-44 Years of Age) and Risk of Stroke: A Behavioral Risk Factor Surveillance System Survey Analysis".

Stroke 2020 05 7;51(5):e91. Epub 2020 Apr 7.

Department of Pharmaceutical Outcomes & Policy, College of Pharmacy, University of Florida, Gainesville.

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http://dx.doi.org/10.1161/STROKEAHA.120.029273DOI Listing
May 2020

Quality of Evidence Supporting Major Psychotropic Drug-Drug Interaction Warnings: A Systematic Literature Review.

Pharmacotherapy 2020 05 23;40(5):455-468. Epub 2020 Mar 23.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida.

Among pharmacodynamic and pharmacokinetic drug-drug interactions (DDIs), psychotropic drug-drug interactions (pDDIs) are of particular interest because psychopharmacologic agents mark one of the fastest growing therapeutic drug classes over the past 2 decades, and prescribing multiple psychotropic drugs has become increasingly prevalent in clinical practice. However, the documentation of pDDIs across drug references has lacked consistency. Thus we set out to review the primary evidence directly supporting 58 pDDIs that were uniformly reported as "major" or "contraindicated" in three prominent drug references: Clinical Pharmacology, Micromedex, and Lexicomp. We identified 134 citations from Micromedex in December 2017 and 4251 citations from Medline in March 2018 involving any of the 58 pDDIs. The included articles directly observed a clinical adverse effect or effects on drug plasma concentrations from the concomitant use of the two listed drugs in each pDDI. These articles were classified as controlled studies (e.g., randomized controlled trials, clinical trials, or observational studies) or uncontrolled studies (case reports). A total of 124 studies with 2716 patients were included in this review. Commonly evaluated adverse effects related to the studied pDDIs included decreased effectiveness, central nervous system depression, neurotoxicity, QT-interval prolongation, and serotonin syndrome. Among the 58 pDDIs, 18 (31%) were not supported by any primary studies. Among the remaining 35 pDDIs supported by studies on clinical adverse effects, only 14 (40%) included evidence from controlled study designs. Only 7 (12.1%) of the 58 pDDIs had evidence from studies with a combined sample size of more than 100 patients. This literature review highlights the poor quality of evidence supporting major or contraindicated psychotropic DDI warnings. Most DDIs lacked support from controlled studies that evaluated clinically significant adverse effects, leaving uncertainty about the clinical relevance of the warning. More postmarketing studies are needed to evaluate the safety of psychotropic combination therapy.
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http://dx.doi.org/10.1002/phar.2382DOI Listing
May 2020

Development and Validation of an Administrative Claims-based Measure for All-cause 30-day Risk-standardized Readmissions After Discharge From Inpatient Psychiatric Facilities.

Med Care 2020 03;58(3):225-233

Health Services Advisory Group (HSAG), Tampa, FL.

Objective: The objective of this study was to develop and test a measure that estimates unplanned, 30-day, all-cause risk-standardized readmission rates (RSRRs) after inpatient psychiatric facility (IPF) discharge.

Participants: We established a retrospective cohort of adults with a principal diagnosis of psychiatric illness or dementia discharged from IPFs to nonacute care settings, using 2012-2013 Medicare fee-for-service claims data.

Measures: All-cause unplanned readmissions within 3-30 days post-IPF discharge were assessed by constructing then validating a parsimonious logistic regression model of 56 risk factors (selected via empirical data, systematic literature review, clinical expert opinion) for readmission using bootstrapping. RSRRs were calculated from the ratio of predicted versus expected readmission rates for each IPF using hierarchical regression. Measure reliability and validity were assessed via multiple strategies.

Results: The measure development cohort included 716,174 admissions to 1679 IPFs and 149,475 (20.9%) readmissions. Most readmissions (>80%) had principal diagnoses of mood, schizoaffective or substance use disorders, delirium/dementia, infections or drug/substance poisoning. Facility RSRRs ranged from 11.0% to 35.4%. The risk adjustment model showed good calibration and moderate discrimination similar to other readmission risk models (c statistic 0.66). Sensitivity analyses solidified the risk modeling approach. The intraclass correlation coefficient of estimated IPF RSRRs was 0.78, indicating good reliability. The measure identified 8.3% of hospitals as having better and 13.4% as having worse RSRRs than the national readmission rate.

Conclusions: The measure provides an assessment of facility-level quality and insight into risk factors useful for informing preventive interventions. The measure will be included in the Centers for Medicare and Medicaid Services (CMS) Inpatient Psychiatric Quality Reporting program in 2019.
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http://dx.doi.org/10.1097/MLR.0000000000001275DOI Listing
March 2020

Risk of Opioid Overdose Associated With Concomitant Use of Opioids and Skeletal Muscle Relaxants: A Population-Based Cohort Study.

Clin Pharmacol Ther 2020 07 17;108(1):81-89. Epub 2020 Mar 17.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

The recent opioid prescribing guideline cautions about the concomitant prescribing of opioids and skeletal muscle relaxants (SMRs) given the additive central nervous system depressant effect. However, the clinical relevance remains unclear. In this retrospective cohort study, we compared the risk of opioid overdose associated with concomitant use of opioids and SMRs vs. opioid use alone. Adjusted hazard ratios were 1.09 (95% confidence interval (CI), 0.74-1.62) and 1.26 (95% CI, 1.00-1.58) in the incident and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21 (95% CI, 1.00-1.48). This risk seemed to increase with treatment duration (≤ 14 days: 0.91 and 95% CI, 0.67-1.22; 15-60 days: 1.37 and 95% CI, 0.81-2.37; >60 days: 1.80 and 95% CI, 1.30-2.48) and for baclofen (1.83 and 95% CI, 1.11-3.04) and carisoprodol (1.84 and 95% CI, 1.34-2.54). Concomitant users with daily opioid dose ≥50 mg (1.50 and 95% CI, 1.18-1.92) and benzodiazepine use (1.39 and 95% CI, 1.08-1.79) also had elevated risk. Clinicians should be cautious about these potentially unsafe practices to optimize pain care and improve patient safety.
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http://dx.doi.org/10.1002/cpt.1807DOI Listing
July 2020

Thiazide Exposure and Cardiovascular Risk in Type 2 Diabetes Mellitus: A Point of Clarification.

Hypertension 2020 03 3;75(3):e2-e5. Epub 2020 Feb 3.

From the Department of Pharmacotherapy and Translational Research (S.M.S., R.M.C.-D.), University of Florida, Gainesville.

A recently published analysis in suggests that thiazide use, versus nonuse, is associated with excess risk of adverse cardiovascular outcomes in patients with diabetes mellitus enrolled in the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes). Here, we replicate these findings using the same publicly available datasets and following their reported methods. We further show that possible misclassification of thiazide exposure exists in the original analysis. We perform alternative analyses that correct for this misclassification to highlight the impact that misclassification can have on observed associations between an exposure (eg, thiazides) and outcomes (eg, stroke and major adverse cardiovascular events).
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035168PMC
March 2020

Redefining Resistant Hypertension: A Comparison of Cardiovascular Risk Associated With the 2018 Versus 2008 American Heart Association Definitions for Resistant Hypertension.

Circ Cardiovasc Qual Outcomes 2020 02 3;13(2):e005979. Epub 2020 Feb 3.

Department of Pharmacotherapy & Translational Research (S.M.S., R.M.C.-D.), College of Medicine, University of Florida, Gainesville.

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http://dx.doi.org/10.1161/CIRCOUTCOMES.119.005979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006690PMC
February 2020

Towards Automating Adverse Event Review: A Prediction Model for Case Report Utility.

Drug Saf 2020 04;43(4):329-338

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Introduction: The rapidly expanding size of the Food and Drug Administration's (FDA) Adverse Event Reporting System database requires modernized pharmacovigilance practices. Techniques to systematically identify high utility individual case safety reports (ICSRs) will support safety signal management.

Objectives: The aim of this study was to develop and validate a model predictive of an ICSR's pharmacovigilance utility (PVU).

Methods: PVU was operationalized as an ICSR's inclusion in an FDA-authored pharmacovigilance review's case series supporting a recommendation to modify product labeling. Multivariable logistic regression models were used to examine the association between PVU and ICSR features. The best performing model was selected for bootstrapping validation. As a sensitivity analysis, we evaluated the model's performance across subgroups of safety issues.

Results: We identified 10,381 ICSRs evaluated in 69 pharmacovigilance reviews, of which 2115 ICSRs were included in a case series. The strongest predictors of ICSR inclusion were reporting of a designated medical event (odds ratio (OR) 1.93, 95% CI 1.54-2.43) and positive dechallenge (OR 1.67, 95% CI 1.50-1.87). The strongest predictors of ICSR exclusion were death reported as the only outcome (OR 2.72, 95% CI 1.76-4.35), more than three suspect products (OR 2.69, 95% CI 2.23-3.24), and > 15 preferred terms reported (OR 2.69, 95% CI 1.90-3.82). The validated model showed modest discriminative ability (C-statistic of 0.71). Our sensitivity analysis demonstrated heterogeneity in model performance by safety issue (C-statistic range 0.58-0.74).

Conclusions: Our model demonstrated the feasibility of developing a tool predictive of ICSR utility. The model's modest discriminative ability highlights opportunities for further enhancement and suggests algorithms tailored to safety issues may be beneficial.
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http://dx.doi.org/10.1007/s40264-019-00897-0DOI Listing
April 2020