Skeletal muscle relaxant drug-drug-drug interactions and unintentional traumatic injury: Screening to detect three-way drug interaction signals.

AIM: The aim of this study was to identify skeletal muscle relaxant (SMR) drug-drug-drug interaction (3DI) signals associated with increased rates of unintentional traumatic injury. METHODS: We conducted automated high-throughput pharmacoepidemiologic screening of 2000-2019 healthcare data for members of United States commercial and Medicare Advantage health plans. We performed a self-controlled case series study for each drug triad consisting of an SMR base-pair (i.e., concomitant use of an SMR with another medication), and a co-dispensed medication (i.e., candidate interacting precipitant) taken during ongoing use of the base-pair. We included patients aged ≥16 years with an injury occurring during base-pair-exposed observation time. We used conditional Poisson regression to calculate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) for injury with each SMR base-pair + candidate interacting precipitant (i.e., triad) versus the SMR-containing base-pair alone. RESULTS: Among 58 478 triads, 29 were significantly positively associated with injury; confounder-adjusted RRs ranged from 1.39 (95% CI = 1.01-1.91) for tizanidine + omeprazole with gabapentin to 2.23 (95% CI = 1.02-4.87) for tizanidine + diclofenac with alprazolam. Most identified 3DI signals are new and have not been formally investigated. CONCLUSION: We identified 29 SMR 3DI signals associated with increased rates of injury. Future aetiologic studies should confirm or refute these SMR 3DI signals.

Claims-Based Frailty and Outcomes: Applying an Aging Measure to Older Adults with Parkinson's Disease.

BACKGROUND: Frailty is a geriatric syndrome with negative health impacts not captured by comorbidity and disability alone. The prevalence of frailty in Parkinson's disease (PD) has been described, but data on frailty-associated outcomes are limited. OBJECTIVE: To describe the level of frailty and investigate the association between frailty and outcomes in a Medicare sample of persons diagnosed with PD. METHODS: We used the claims-based frailty index to assess frailty in a cohort of Medicare beneficiaries with PD in 2013. Frailty was categorized as non-frail/pre-frail, mildly frail, moderately frail, and severely frail. Adjusted logistic regression models examined the relationship between frailty and mortality, hospitalization, emergency department visits, and fall-related injuries through 2014. RESULTS: Of 62,786 beneficiaries with PD in 2013, 55.3% were frail. Frail individuals were more likely to be female, older, Black, metropolitan dwelling, without neurologist care, nursing facility residents, or multimorbid. The average daily levodopa equivalent dose initially increased, then decreased from the pre-frail to the severely frail groups. Compared to non-frail/pre-frail persons, severely frail persons had higher adjusted odds of 1-year mortality (AOR 2.74, 95% CI 1.98, 3.78), hospitalization (AOR 2.34, 95% CI 1.74, 3.14), emergency department visits (AOR 2.97, 95% CI 2.14, 4.13), and fall-related injury (AOR 1.43, 95% CI 0.90, 2.26). CONCLUSIONS: Frailty is common and differentially distributed among older adults with PD. Frailty in PD is associated with adverse health outcomes and death. Observational study analyses may benefit from adjustment for frailty; claims-based frailty surveillance may identify vulnerable PD patients in health system, registry, or administrative data. © 2021 International Parkinson and Movement Disorder Society.

Pharmacosafety of fluoroquinolone and macrolide antibiotics in the clinical care of patients with myasthenia gravis.

INTRODUCTION/AIMS: Anecdotal case reports have suggested a potential association of fluoroquinolones and macrolides with myasthenia gravis (MG) exacerbation, prompting warnings against the use of these drugs in this population. However, large-scale and reliable population-based data that demonstrate this association are lacking. This study aims to examine the association between outpatient treatment with fluoroquinolones or macrolides and MG-related hospitalization. METHODS: A retrospective cohort study consisting of adult MG patients was conducted using a large de-identified healthcare claims database. Antibiotic prescription claims were identified, and MG-related hospitalizations were assessed at 15, 30, and 90 days after the date of prescription. We used mixed effects survival regression with log-logistic distribution and independent covariance matrix to estimate odds ratios (ORs) of hospitalization for each potentially exacerbating antibiotic using beta-lactam as the reference and adjusting for covariates. RESULTS: Among 1556 MG patients receiving 894 fluoroquinolone prescriptions, 729 macrolide prescriptions, and 1608 beta-lactam prescriptions during the study period, there was no difference in 15, 30, or 90-day odds of MG-related hospitalization between fluoroquinolone or macrolide users compared to prescribed beta-lactams. However, estimates were higher for fluoroquinolones than macrolides, even after covariate adjustment (adjusted OR [aOR] 4.60, 95% confidence interval [CI] 0.55-38.57 for fluoroquinolones and OR 0.56, 95% CI 0.32-0.97 for macrolides, respectively, at 15 days). DISCUSSION: Fluoroquinolone and macrolide antibiotics are prescribed frequently to patients with MG. While statistical imprecision precludes a definitive conclusion, elevated ORs for fluoroquinolones raise the possibility of an underpowered association that merits further investigation.

Annual Prevalence of Use of Potentially Inappropriate Medications for Treatment of Affective Disorders in Parkinson's Disease.

OBJECTIVE: To examine the national prevalence of pharmacological treatment of affective disorders in older adults with Parkinson's disease (PD), and determine the prevalence and risk factors for receipt of an American Geriatrics Society Beers Criteria® defined potentially inappropriate medication (PIM) for affective disorder treatment. DESIGN: Cross-sectional analysis of 2014 Medicare data. SETTING: Research Identifiable File data from the Centers for Medicare and Medicaid Services. PARTICIPANTS: Individuals ≥65 years of age with PD whose inpatient, outpatient, and prescription care is administered through the U.S. Medicare Program. MEASUREMENTS: The 2014 prevalence of affective (i.e., depressive and anxiety) disorders was calculated. We assessed prescription fills for affective disorder treatment and classified prescriptions according to PIM status. Patient and clinician factors associated with PIM prescriptions were determined. RESULTS: Of 84,323 beneficiaries with PD, 15.1% had prevalent depression only, 7.5% had anxiety only, and 8.5% had comorbid depression and anxiety. Among those with depression only, 80.7% were treated in 2014 (12.8% of treated received at least one PIM). The annual treatment prevalence was 62.9% (75.9% PIM) and 93.1% (63.9% PIM) in the anxiety only and comorbid group, respectively. In most groups, PIM use was less likely among men and those with dementia; geriatricians were less likely to prescribe PIMs. CONCLUSION: Treatment of affective disorders in persons diagnosed with PD is high. PIM use is also common, particularly in persons with anxiety. Future research will quantify the potential effects of these PIMs on clinical and patient outcomes.

Low continuation of antipsychotic therapy in Parkinson disease - intolerance, ineffectiveness, or inertia?

BACKGROUND: Antipsychotics are used in Parkinson disease (PD) to treat psychosis, mood, and behavioral disturbances. Commonly used antipsychotics differ substantially in their potential to worsen motor symptoms through dopaminergic receptor blockade. Recent real-world data on the use and continuation of antipsychotic therapy in PD are lacking. The objectives of this study are to (1) examine the continuation of overall and initial antipsychotic therapy in individuals with PD and (2) determine whether continuation varies by drug dopamine receptor blocking activity. METHODS: We conducted a retrospective cohort study using U.S. commercially insured individuals in Optum 2001-2019. Adults aged 40 years or older with PD initiating antipsychotic therapy, with continuous insurance coverage for at least 6 months following drug initiation, were included. Exposure to pimavanserin, quetiapine, clozapine, aripiprazole, risperidone, or olanzapine was identified based on pharmacy claims. Six-month continuation of overall and initial antipsychotic therapy was estimated by time to complete discontinuation or switching to a different antipsychotic. Cox proportional hazards models evaluated factors associated with discontinuation. RESULTS: Overall, 38.6% of 3566 PD patients in our sample discontinued antipsychotic therapy after the first prescription, 61.4% continued with overall treatment within 6 months of initiation. Clozapine use was too rare to include in statistical analyses. Overall therapy discontinuation was more likely for those who initiated medications with known dopamine-receptor blocking activity (adjusted hazard ratios 1.76 [95% confidence interval 1.40-2.20] for quetiapine, 2.15 [1.61-2.86] for aripiprazole, 2.12 [1.66-2.72] for risperidone, and 2.07 [1.60-2.67] for olanzapine), compared with serotonin receptor-specific pimavanserin. Initial antipsychotic therapy discontinuation also associated with greater dopamine-receptor blocking activity medication use - adjusted hazard ratios 1.57 (1.28-1.94), 1.88 (1.43-2.46), 2.00 (1.59-2.52) and 2.03 (1.60-2.58) for quetiapine, aripiprazole, risperidone, and olanzapine, respectively, compared with pimavanserin. Similar results were observed in sensitivity analyses. CONCLUSIONS: Over one-third of individuals with PD discontinued antipsychotic therapy, especially if the initial drug has greater dopamine-receptor blocking activity. Understanding the drivers of antipsychotic discontinuation, including ineffectiveness, potentially inappropriate use, clinician inertia, patient adherence and adverse effects, is needed to inform clinical management of psychosis in PD and appropriate antipsychotic use in this population.

Frequency of and risk factors for potentially inappropriate medication use in Parkinson's disease.

BACKGROUND: impairments in neurotransmitter pathways put Parkinson's disease (PD) patients at risk for drug-disease interactions and adverse medication events. OBJECTIVE: to determine the prevalence and risk factors for potentially inappropriate medication (PIM) prescriptions, as defined by the 2015 Beers List, in PD. METHODS: cross-sectional analysis was conducted on 2014 Medicare beneficiaries with PD who had parts A, B and D coverage. The prevalence of PIM prescriptions for older adults was determined overall, and specifically for medications that can exacerbate motor symptoms or cognitive impairment in PD. Logistic regression models were constructed to determine the association between age, sex, race, geography and poverty with PIM prescriptions. RESULTS: the final sample included 458,086 beneficiaries. In 2014, 35.8% of beneficiaries with PD filled a prescription for at least one PIM for older adults. In total, 8.7% of beneficiaries received a PIM that could exacerbate motor symptoms and 29.0% received a PIM that could worsen cognitive impairment. After adjustment, in all models, beneficiaries who were younger, female, white, urban-dwelling and eligible for Medicaid benefits were more likely to receive a PIM. CONCLUSION: PIM prescriptions are not uncommon in PD, particularly for medications that can exacerbate cognitive impairment. Future research will examine underlying drivers of sex and other disparities in PIM prescribing. Additional studies are needed to understand the impact of PIMs on disease symptoms, healthcare utilisation and patient outcomes.

Does hospitalization for thromboembolism improve oral anticoagulant adherence in patients with atrial fibrillation?

BACKGROUND: It is not known how medication adherence changes after hospitalization for a sentinel thromboembolic event. OBJECTIVE: The purpose of this study was to examine the impact of hospitalization for ischemic stroke or thromboembolism on postdischarge adherence to oral anticoagulants in patients with atrial fibrillation. METHODS: We conducted a quasi-experimental pre-post observational study using a large U.S. commercial insurance health care claims database. Adult patients with atrial fibrillation taking oral anticoagulants with a random hospitalization for a nonbleeding-related reason occurring after the first observed oral anticoagulant prescription fill, with no other admissions within the preceding and following 6 months, were identified in Optum Clinformatics (Eden Prairie, MN) from 2009 to 2016. Adherence was estimated by the proportion of days covered within 6 and 12 months before and after hospitalization. Difference-in-difference analysis using a generalized linear model was employed to compare pre- and post-hospitalization proportions of days covered (PDCs) by reasons for hospitalization (i.e., ischemic stroke or thromboembolism vs. other nonbleeding-related reasons), adjusting for imbalanced baseline characteristics. RESULTS: Of the 21,400 individuals meeting inclusion criteria, 5.4% were hospitalized for ischemic stroke or thromboembolism and 94.6% for other nonbleeding-related reasons. Baseline characteristics were quite similar between groups, except for a few covariables such as age or CHA2DS2-VASc score. Minority race or ethnicity individuals had 0.7% lower overall PDC than whites (P = 0.006). After covariate adjustment, 6-month adherence declined by 1.1% less in individuals hospitalized for ischemic stroke or thromboembolism, compared with other nonbleeding reasons, although the difference was not statistically significant (P = 0.17). Similar results were observed for the 12-month window. CONCLUSION: This real-world study suggests that more effective strategies are needed to improve adherence to oral anticoagulant, particularly after a thromboembolic event.

Potentially inappropriate medications in older adults with Parkinson disease before and after hospitalization for injury.

BACKGROUND: Parkinson disease (PD) patients are at increased risk of serious injury, such as fall-related fractures. Prescription medications are a modifiable factor for injury risk. OBJECTIVES: To determine the extent to which a serious injury requiring hospitalization affects prescribing of potentially inappropriate medications (PIMs) among older adults with PD. METHODS: We conducted a quasi-experimental difference-in-difference (DID) study using 2013-2017 Medicare data. The cohort consisted of beneficiaries with PD hospitalized for injury versus for other reasons. PIMs were classified into PD and injury-relevant categories (CNS-active PIMs, PD motor symptom PIMs, PD non-motor symptom PIMs, PIMs that reduce bone mineral density). We estimated mean standardized daily doses (SDDs) of medications within each PIM category before and at 3, 6, and 12 months after hospitalization. We used generalized linear regression models to compare changes in mean SDDs for each PIM category between the injury and non-injury group at each timepoint, adjusting for biological, clinical and social determinants of health variables. RESULTS: Both groups discontinued PIMs and/or reduced PIM doses after hospitalization. There were no between-group differences in mean SDD changes, after covariate adjustment, for any PIM category, except for the CNS-active PIMs category at 3 months (DID p-value = 0.00) and for the category of PIMs that reduce bone mineral density at all timepoints (DID p-values = 0.02, 0.04, 0.02 at 3, 6, and 12 months). CONCLUSIONS: Similar patterns of PIM among persons with PD after hospitalization for serious injury versus for other reasons may represent a missed opportunity to deprescribe high-risk medications during care transitions.

Comparative safety of antimuscarinics versus mirabegron for overactive bladder in Parkinson disease.

BACKGROUND: Overactive bladder (OAB) is a common non-motor symptom of Parkinson disease (PD), often treated with antimuscarinics or beta-3 agonists. There is lack of evidence to guide OAB management in PD. OBJECTIVES: To assess the comparative safety of antimuscarinics versus beta-3 agonists for OAB treatment in PD. METHODS: We employed a new-user, active-comparator cohort study design. We included Medicare beneficiaries age ≥65 years with PD who were new users of either antimuscarinic or beta-3 agonist. The primary outcome was any acute care encounter (i.e., non-elective hospitalization or emergency department visit) within 90 days of OAB drug initiation. The main secondary outcome was a composite measure of acute care encounters for anticholinergic related adverse events (AEs). Matching on high-dimensional propensity score (hdPS) was used to address potential confounding. We used Cox proportional hazards models to examine the association between OAB drug category and outcomes. We repeated analyses for 30- and 180-day follow-up periods. RESULTS: We identified 27,091 individuals meeting inclusion criteria (mean age: 77.8 years). After hdPS matching, antimuscarinic users had increased risks for any acute care encounter (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.12-1.37) and encounters for anticholinergic related AEs (HR 1.18, 95% CI 1.04-1.34) compared to beta-3 agonist users. Similar associations were observed for sensitivity analyses. CONCLUSIONS: Among persons with PD, anticholinergic initiation was associated with a higher risk of acute care encounters compared with beta-3 agonist initiation. The long-term safety of anticholinergic vs. beta-3 agonist therapy in the PD population should be evaluated in a prospective study.

Geographic Barriers Drive Disparities in Specialty Center Access for Older Adults with Huntington's Disease.

BACKGROUND: Huntington's Disease Society of America Centers of Excellence (HDSA COEs) are primary hubs for Huntington's disease (HD) research opportunities and accessing new treatments. Data on the extent to which HDSA COEs are accessible to individuals with HD, particularly those older or disabled, are lacking. OBJECTIVE: To describe persons with HD in the U.S. Medicare program and characterize this population by proximity to an HDSA COE. METHODS: We conducted a cross-sectional study of Medicare beneficiaries ages ≥65 with HD in 2017. We analyzed data on benefit entitlement, demographics, and comorbidities. QGis software and Google Maps Interface were employed to estimate the distance from each patient to the nearest HDSA COE, and the proportion of individuals residing within 100 miles of these COEs at the state level. RESULTS: Among 9,056 Medicare beneficiaries with HD, 54.5% were female, 83.0% were white; 48.5% were ≥65 years, but 64.9% originally qualified for Medicare due to disability. Common comorbidities were dementia (32.4%) and depression (35.9%), and these were more common in HD vs. non-HD patients. Overall, 5,144 (57.1%) lived within 100 miles of a COE. Race/ethnicity, sex, age, and poverty markers were not associated with below-average proximity to HDSA COEs. The proportion of patients living within 100 miles of a center varied from < 10% (16 states) to > 90% (7 states). Most underserved states were in the Mountain and West Central divisions. CONCLUSION: Older Medicare beneficiaries with HD are frequently disabled and have a distinct comorbidity profile. Geographical, rather than sociodemographic factors, define the HD population with limited access to HDSA COEs.

Atypical antipsychotic use and mortality risk in Parkinson disease.

INTRODUCTION: Dopamine receptor blocking atypical antipsychotic (DRB-AAP) use has previously been associated with increased adverse effects and mortality risk among persons with Parkinson disease (PD). Pimavanserin, the only AAP indicated for PD psychosis in the U.S., is a serotonin receptor inverse agonist/antagonist with no known DRB activity. Early observational data have reported inconsistent findings regarding mortality risk associated with pimavanserin. The objective of this study was to estimate all-cause mortality risks of pimavanserin as compared to DRB-AAPs. METHODS: We conducted a retrospective cohort study using a large U.S. commercial insurance database. Cox proportional hazards models were used to compare all-cause mortality risks between propensity score-matched groups of PD patients who were new users of pimavanserin or a DRB-AAP, further dividing DRB-AAPs into preferred (quetiapine, clozapine) and non-preferred (other remaining AAPs). RESULTS: We identified 775, 4,563, and 1,297 individuals on pimavanserin, preferred, and non-preferred DRB-AAPs, respectively. There was no difference in mortality risk for pimavanserin vs. preferred DRB-AAPs [adjusted hazard ratio (aHR) 0.99, 95% CI: 0.81-1.20], or pimavanserin vs. non-preferred DRB-AAPs (aHR 0.98, 95% CI: 0.79-1.22) in intention-to-treat analyses. CONCLUSION: Mortality risk among PD patients using AAPs did not differ by antipsychotic drug categorization based on mechanism of action. Research on the comparative efficacy and morbidity of AAPs, and the mortality associated with psychosis itself is needed to guide clinical decision-making in the PD population.

Population-based screening to detect benzodiazepine drug-drug-drug interaction signals associated with unintentional traumatic injury.

Drug interactions involving benzodiazepines and related drugs (BZDs) are increasingly recognized as a contributor to increased risk of unintentional traumatic injury. Yet, it remains unknown to what extent drug interaction triads (3DIs) may amplify BZDs' inherent injury risk. We identified BZD 3DI signals associated with increased injury rates by conducting high-throughput pharmacoepidemiologic screening of 2000-2019 Optum's health insurance data. Using self-controlled case series design, we included patients aged ≥ 16 years with an injury while using a BZD + co-dispensed medication (i.e., base pair). During base pair-exposed observation time, we identified other co-dispensed medications as candidate interacting precipitants. Within each patient, we compared injury rates during time exposed to the drug triad versus to the base pair only using conditional Poisson regression, adjusting for time-varying covariates. We calculated rate ratios (RRs) with 95% confidence intervals (CIs) and accounted for multiple estimation via semi-Bayes shrinkage. Among the 65,123 BZD triads examined, 79 (0.1%) were associated with increased injury rates and considered 3DI signals. Adjusted RRs for signals ranged from 3.01 (95% CI = 1.53-5.94) for clonazepam + atorvastatin with cefuroxime to 1.42 (95% CI = 1.00-2.02, p = 0.049) for alprazolam + hydrocodone with tizanidine. These signals may help researchers prioritize future etiologic studies to investigate higher-order BZD interactions.

Population-based signals of benzodiazepine drug interactions associated with unintentional traumatic injury.

Benzodiazepine receptor agonists and related medications, such as Z-drugs and dual orexin receptor antagonists (BZDs), have been associated with unintentional traumatic injury due to their central nervous system (CNS)-depressant effects. Drug-drug interactions (DDIs) may contribute to the known relationship between BZD use and unintentional traumatic injury, yet evidence is still lacking. We conducted high-throughput pharmacoepidemiologic screening using the self-controlled case series design in a large US commercial health insurance database to identify potentially clinically relevant DDI signals among new users of BZDs. We used conditional Poisson regression to estimate rate ratios (RRs) between each co-exposure (vs. not) and unintentional traumatic injury (primary outcome), typical hip fracture (secondary outcome), and motor vehicle crash (secondary outcome). We identified 48 potential DDI signals (1.1%, involving 39 unique co-dispensed drugs), i.e., with statistically significant elevated adjusted RRs for injury. Signals were strongest for DDI pairs involving zolpidem, lorazepam, temazepam, alprazolam, eszopiclone, triazolam, and clonazepam. We also identified four potential DDI signals for typical hip fracture, but none for motor vehicle crash. Many signals have biologically plausible explanations through additive or synergistic pharmacodynamic effects of co-dispensed antidepressants, opioids, or muscle relaxants on CNS depression, impaired psychomotor and cognitive function, and/or somnolence. While other signals that lack an obvious mechanism may represent true associations that place patients at risk of injury, it is also prudent to consider the roles of chance, reverse causation, and/or confounding by indication, which merit further exploration. Given the high-throughput nature of our investigation, findings should be interpreted as hypothesis generating.

Signals of Muscle Relaxant Drug Interactions Associated with Unintentional Traumatic Injury: A Population-Based Screening Study.

BACKGROUND: Use of muscle relaxants is rapidly increasing in the USA. Little is understood about the role of drug interactions in the known association between muscle relaxants and unintentional traumatic injury, a clinically important endpoint causing substantial morbidity, disability, and death. OBJECTIVE: We examined potential associations between concomitant drugs (i.e., precipitants) taken with muscle relaxants (affected drugs, i.e., objects) and hospital presentation for unintentional traumatic injury. METHODS: In a series of self-controlled case series studies, we screened to identify drug interaction signals for muscle relaxant + precipitant pairs and unintentional traumatic injury. We used Optum's de-identified Clinformatics® Data Mart Database, 2000-2019. We included new users of a muscle relaxant, aged 16-90 years, who were dispensed at least one precipitant drug and experienced an unintentional traumatic injury during the observation period. We classified each observation day as precipitant exposed or precipitant unexposed. The outcome was an emergency department or inpatient discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to estimate rate ratios adjusting for time-varying confounders and then accounted for multiple estimation via semi-Bayes shrinkage. RESULTS: We identified 74,657 people who initiated muscle relaxants and experienced an unintentional traumatic injury, in whom we studied concomitant use of 2543 muscle relaxant + precipitant pairs. After adjusting for time-varying confounders, 16 (0.6%) pairs were statistically significantly and positively associated with injury, and therefore deemed signals of a potential drug interaction. Among signals, semi-Bayes shrunk, confounder-adjusted rate ratios ranged from 1.29 (95% confidence interval 1.04-1.62) for baclofen + sertraline to 2.28 (95% confidence interval 1.14-4.55) for methocarbamol + lamotrigine. CONCLUSIONS: Using real-world data, we identified several new signals of potential muscle relaxant drug interactions associated with unintentional traumatic injury. Only one among 16 signals is currently reported in a major drug interaction knowledge base. Future studies should seek to confirm or refute these signals.

Multiple sclerosis hospitalizations among users of oral disease-modifying therapies.

BACKGROUND: Oral disease-modifying therapies, namely dimethyl fumarate, fingolimod and teriflunomide, have become standard treatments for multiple sclerosis. Clinical trials demonstrated a reduction in annual relapse rate, but real-world data is lacking, particularly in older adults. The objective of our study is to evaluate the real-world effectiveness of oral disease-modifying therapies among individuals with multiple sclerosis. METHODS: We used OptumTM ClinformaticsTM Data Mart, a large dataset representative of commercially insured individuals in the United States, to conduct a retrospective cohort study of adult users of three oral disease-modifying therapies from September 2010 through September 2015. The therapies of interest included dimethyl fumarate, teriflunomide, and fingolimod. Hospitalization for multiple sclerosis, an approximation of the clinical trial endpoint for relapse, was the study outcome. Cox proportional hazards models were built to evaluate the association of demographic and clinical factors with multiple sclerosis hospitalization. A subgroup analysis was performed on individuals ages 55 years or older. RESULTS: We identified 1,823, 318, and 1,156 users of dimethyl fumarate, teriflunomide, and fingolimod that met our inclusion criteria, respectively. Rates of hospitalizations for multiple sclerosis were low among these 3,297 persons (1,041 ages 55+): 36/1,000 patient-years for dimethyl fumarate, 43/1,000 for teriflunomide, and 45/1,000 for fingolimod. Multiple sclerosis hospitalization was associated with therapy switching (adjusted hazard ratio 2.21, 95% confidence interval 1.57-2.84), minority (1.44, 1.10-1.89), and history of relapse in the year preceding oral therapy initiation (5.25, 3.89-7.09). CONCLUSION: Oral disease-modifying therapies are comparably effective for the outcome of multiple sclerosis hospitalization, even in older adults.

Evaluation of serious bleeding signals during concomitant use of clopidogrel and hypnotic drugs.

BACKGROUND: In a previous drug-drug interaction (DDI) screening study intended to generate hypotheses, clopidogrel + either eszopiclone or zolpidem (vs. clopidogrel alone) were associated with serious bleeding. OBJECTIVES: To confirm or refute these DDI signals and examine associations with other hypnotics in an independent population of United States Medicaid beneficiaries METHODS: We employed a bi-directional self-controlled case series design in eligible individuals concomitantly exposed to one of 12 hypnotics (precipitants, exposures of interest) plus either clopidogrel (the object drug) or pravastatin (the negative control object drug). The outcome was hospital presentation with serious bleeding. Using conditional Poisson regression, we calculated confounder-adjusted rate ratios (RRs) and 95% confidence intervals for serious bleeding during clopidogrel + precipitant use (vs. clopidogrel alone). To distinguish a DDI from a precipitant's inherent effect on bleeding, we divided effect measures by the adjusted RR for the corresponding pravastatin + precipitant pair to obtain ratios of RR (RRRs). RESULTS: Among 23,194 users of clopidogrel and 3824 of pravastatin who experienced serious bleeding during an active prescription for one of these agents, confounder-adjusted RRRs for serious bleeding were 6.63 (0.39-113.01) and 0.77 (0.53-1.11) with eszopiclone and zolpidem, respectively, whereas confounder-adjusted RRRs for other hypnotics ranged from 0.18 (0.04-0.85) for triazolam to 1.79 (0.16-20.44) for zaleplon. Statistical imprecision therefore precluded us from confirming or refuting these prior signals with eszopiclone and zolpidem. CONCLUSIONS: While we could not confirm or refute previously identified DDI signals, numerically elevated RRRs for serious bleeding with several clopidogrel + hypnotic pairs warrant further examination.

Population-Based Signals of Antidepressant Drug Interactions Associated With Unintentional Traumatic Injury.

Antidepressants are very widely used and associated with traumatic injury, yet little is known about their potential for harmful drug interactions. We aimed to identify potential drug interaction signals by assessing concomitant medications (precipitant drugs) taken with individual antidepressants (object drugs) that were associated with unintentional traumatic injury. We conducted pharmacoepidemiologic screening of 2000-2015 Optum Clinformatics data, identifying drug interaction signals by performing self-controlled case series studies for antidepressant + precipitant pairs and injury. We included persons aged 16-90 years codispensed an antidepressant and ≥ 1 precipitant drug(s), with an injury during antidepressant therapy. We classified antidepressant person-days as either precipitant-exposed or precipitant-unexposed. The outcome was an emergency department or inpatient discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to calculate confounder adjusted rate ratios (RRs) and accounted for multiple estimation via semi-Bayes shrinkage. We identified 330,884 new users of antidepressants who experienced an injury. Among such persons, we studied concomitant use of 7,953 antidepressant + precipitant pairs. Two hundred fifty-six (3.2%) pairs were positively associated with injury and deemed potential drug interaction signals; 22 of these signals had adjusted RRs > 2.00. Adjusted RRs ranged from 1.06 (95% confidence interval: 1.00-1.12, P = 0.04) for citalopram + gabapentin to 3.06 (1.42-6.60) for nefazodone + levonorgestrel. Sixty-five (25.4%) signals are currently reported in a seminal drug interaction knowledgebase. We identified numerous new population-based signals of antidepressant drug interactions associated with unintentional traumatic injury. Future studies, intended to test hypotheses, should confirm or refute these potential interactions.

Impact of Hospitalization and Medication Switching on Post-discharge Adherence to Oral Anticoagulants in Patients With Atrial Fibrillation.

BACKGROUND: Adherence to chronic medications remains poor in practice. There is limited evidence on how hospitalization affects post-discharge adherence to oral anticoagulants (OACs) in individuals with atrial fibrillation. The aim of this study was to examine the impact of hospitalization and medication switching on post-discharge adherence to OACs in the population with atrial fibrillation. METHODS: A quasi-experimental pre-post observational study was conducted using United States commercial insurance health care claims from the 2009 to 2016 Optum database. Adults with atrial fibrillation taking OACs who had a random hospitalization occurring after the first observed OAC prescription fill and no other admission in the preceding and following 6 months were identified. OAC adherence was estimated by the proportion of days covered within 6 and 12 months before and after hospitalization. Difference-in-difference analysis was employed to compare the pre-hospitalization and post-hospitalization proportion of days covered, stratified by reasons for hospitalization (i.e., bleeding vs non-bleeding-related reasons) and adjusting for imbalanced baseline characteristics between groups. Change in adherence when the OAC was switched at discharge was also examined. RESULTS: The 22,429 individuals who met study criteria were predominantly male (52.4%), white (77.2%), and older age (median 74 years). A clinically significant hemorrhage was the reason for 1029 (4.5%) of qualifying hospitalizations. After covariate adjustment, there was a reduction in the proportion of days covered after discharge, regardless of admission diagnosis (p<0.0001). The 6-month difference-in-difference analyses revealed that adherence was incrementally reduced by 3.2% (p=0.0003) in the bleeding group compared with the nonbleeding group, whereas switching from warfarin to a direct oral anticoagulant after hospitalization was associated with a smaller reduction by 3.4% in adherence (p=0.0342) compared with other switchers, regardless of the reason for hospitalization. The 12-month difference-in-difference analyses revealed similar results. CONCLUSIONS: Hospitalization is temporally associated with a reduction in adherence to OACs, regardless of reason for hospitalization. More effective strategies are needed to improve OAC adherence, particularly during transition of care.

Screening to identify signals of opioid drug interactions leading to unintentional traumatic injury.

BACKGROUND: Efforts to minimize harms from opioid drug interactions may be hampered by limited evidence on which drugs, when taken concomitantly with opioids, result in adverse clinical outcomes. OBJECTIVE: To identify signals of opioid drug interactions by identifying concomitant medications (precipitant drugs) taken with individual opioids (object drugs) that are associated with unintentional traumatic injury DESIGN: We conducted pharmacoepidemiologic screening of Optum Clinformatics Data Mart, identifying drug interaction signals by performing confounder-adjusted self-controlled case series studies for opioid + precipitant pairs and injury. SETTING: Beneficiaries of a major United States-based commercial health insurer during 2000-2015 PATIENTS: Persons aged 16-90 years co-dispensed an opioid and ≥1 precipitant drug(s), with an unintentional traumatic injury event during opioid therapy, as dictated by the case-only design EXPOSURE: Precipitant-exposed (vs. precipitant-unexposed) person-days during opioid therapy. OUTCOME: Emergency department or inpatient International Classification of Diseases discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to generate confounder adjusted rate ratios. We accounted for multiple estimation via semi-Bayes shrinkage. RESULTS: We identified 25,019, 12,650, and 10,826 new users of hydrocodone, tramadol, and oxycodone who experienced an unintentional traumatic injury. Among 464, 376, and 389 hydrocodone-, tramadol-, and oxycodone-precipitant pairs examined, 20, 17, and 16 (i.e., 53 pairs, 34 unique precipitants) were positively associated with unintentional traumatic injury and deemed potential drug interaction signals. Adjusted rate ratios ranged from 1.23 (95 % confidence interval: 1.05-1.44) for hydrocodone + amoxicillin-clavulanate to 4.21 (1.88-9.42) for oxycodone + telmisartan. Twenty (37.7 %) of 53 signals are currently reported in a major drug interaction knowledgebase. LIMITATIONS: Potential for reverse causation, confounding by indication, and chance CONCLUSIONS: We identified previously undescribed and/or unappreciated signals of opioid drug interactions associated with unintentional traumatic injury. Subsequent etiologic studies should confirm (or refute) and elucidate these potential drug interactions.

Clopidogrel Drug Interactions and Serious Bleeding: Generating Real-World Evidence via Automated High-Throughput Pharmacoepidemiologic Screening.

Few population-based studies have examined bleeding associated with clopidogrel drug-drug interactions (DDIs). We sought to identify precipitant drugs taken concomitantly with clopidogrel (an object drug) that increased serious bleeding rates. We screened 2000-2015 Optum commercial health insurance claims to identify DDI signals. We performed self-controlled case series studies for clopidogrel plus precipitant pairs, examining associations with gastrointestinal bleeding or intracranial hemorrhage. To distinguish native bleeding effects of a precipitant, we reexamined associations using pravastatin as a negative control object drug. Among 431 analyses, 28 clopidogrel plus precipitant pairs were statistically significantly positively associated with serious bleeding. Ratios of rate ratios ranged from 1.13-3.94. Among these pairs, 13 were expected given precipitant drugs alone increased and/or were harbingers of serious bleeding. The remaining 15 pairs constituted new DDI signals, none of which are currently listed in two major DDI knowledge bases.