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The self-controlled case-series (SCCS) research design is increasingly used in pharmacoepidemiologic studies of drug-drug interactions (DDIs), with the target of inference being the incidence rate ratio (IRR) associated with concomitant exposure to the object plus precipitant drug versus the object drug alone. While day-level drug exposure can be inferred from dispensing claims, these inferences may be inaccurate, leading to biased IRRs. Grace periods (periods assuming continued treatment impact after days' supply exhaustion) are frequently used by researchers, but the impact of grace period decisions on bias from exposure misclassification remains unclear. Motivated by an SCCS study examining the potential DDI between clopidogrel (object) and warfarin (precipitant), we investigated bias due to precipitant or object exposure misclassification using simulations. We show that misclassified precipitant treatment always biases the estimated IRR toward the null, whereas misclassified object treatment may lead to bias in either direction or no bias, depending on the scenario. Further, including a grace period for each object dispensing may unintentionally increase the risk of misclassification bias. To minimize such bias, we recommend 1) avoiding the use of grace periods when specifying object drug exposure episodes; and 2) including a washout period following each precipitant exposed period.
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Importance: Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk. Objective: To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs. Design, Setting, and Participants: This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy. Exposure: Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy. Main Outcomes and Measures: Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs. Results: This study included 14â¯078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14â¯158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89). Conclusions and Relevance: In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.
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Anticonvulsivantes , Fibrilação Atrial , Epilepsia , Tromboembolia , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Feminino , Masculino , Tromboembolia/epidemiologia , Tromboembolia/prevenção & controle , Idoso , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Pessoa de Meia-Idade , Estudos de Coortes , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Administração Oral , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagemRESUMO
The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self-controlled estimates were adjusted using negative cases (external "control" DOAC users with the same outcomes but co-dispensings for non-interacting AHDs or ASMs). Signal thresholds were set based on P-values and false discovery rate q-values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self-controlled assessments with q-value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the P-value threshold and no signals from the q-value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with P-value thresholds yielded 3 3DI and 26 DDI signals following self-control, as well as 4 3DI signals following adjustment. No 3DI signals met the q-value threshold. The presented self- and externally-controlled approach aimed to advance paradigms for real-world higher order drug interaction screening among high-susceptibility populations with pre-existent DDI risk.
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Interações Medicamentosas , Humanos , Feminino , Masculino , Idoso , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Pessoa de Meia-Idade , Anticoagulantes/efeitos adversos , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Polimedicação , Estudos Cross-Over , Hemorragia/induzido quimicamente , Tromboembolia/prevenção & controle , Idoso de 80 Anos ou maisRESUMO
Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person-time exposed to both an SMR and one of the three most dispensed opioids-hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids-synchronically triggered, opioid-triggered, and SMR-triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone-SMR-triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23-2.82) for carisoprodol and 1.73 (1.09-2.73) for tizanidine. In the tramadol-synchronically triggered cohort, the adjusted HRs were 0.69 (0.49-0.97) for metaxalone and 0.62 (0.42-0.90) for tizanidine. In the tramadol-SMR-triggered cohort, the adjusted HRs were 1.51 (1.01-2.26) for baclofen and 1.48 (1.03-2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.
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Analgésicos Opioides , Oxicodona , Tramadol , Humanos , Analgésicos Opioides/efeitos adversos , Estudos Retrospectivos , Masculino , Feminino , Oxicodona/efeitos adversos , Pessoa de Meia-Idade , Adulto , Tramadol/efeitos adversos , Estados Unidos/epidemiologia , Hidrocodona/efeitos adversos , Modelos de Riscos Proporcionais , Estudos de Coortes , Medicaid , Adulto Jovem , Interações Medicamentosas , Idoso , Carisoprodol/efeitos adversosRESUMO
PURPOSE: High-dimensional propensity score (hdPS) is a semiautomated method that leverages a vast number of covariates available in healthcare databases to improve confounding adjustment. A novel combined Super Learner (SL)-hdPS approach was proposed to assist with selecting the number of covariates for propensity score inclusion, and was found in plasmode simulation studies to improve bias reduction and precision compared to hdPS alone. However, the approach has not been examined in the applied setting. METHODS: We compared SL-hdPS's performance with that of several hdPS models, each with prespecified covariates and a different number of empirically-identified covariates, using a cohort study comparing real-world bleeding rates between ibrutinib- and bendamustine-rituximab (BR)-treated individuals with chronic lymphocytic leukemia in Optum's de-identified Clinformatics® Data Mart commercial claims database (2013-2020). We used inverse probability of treatment weighting for confounding adjustment and Cox proportional hazards regression to estimate hazard ratios (HRs) for bleeding outcomes. Parameters of interest included prespecified and empirically-identified covariate balance (absolute standardized difference [ASD] thresholds of <0.10 and <0.05) and outcome HR precision (95% confidence intervals). RESULTS: We identified 2423 ibrutinib- and 1102 BR-treated individuals. Including >200 empirically-identified covariates in the hdPS model compromised covariate balance at both ASD thresholds. SL-hdPS balanced more covariates than all individual hdPS models at both ASD thresholds. The bleeding HR 95% confidence intervals were generally narrower with SL-hdPS than with individual hdPS models. CONCLUSION: In a real-world application, hdPS was sensitive to the number of covariates included, while use of SL for covariate selection resulted in improved covariate balance and possibly improved precision.
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Leucemia Linfocítica Crônica de Células B , Humanos , Pontuação de Propensão , Estudos de Coortes , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Modelos de Riscos Proporcionais , Simulação por ComputadorRESUMO
Children with autism frequently present with complex mental health diagnoses and psychotropic medications are often a component of comprehensive biopsychosocial treatment plans for these conditions. The purpose of this study is to provide rates and patterns of psychotropic medication use, and predictors thereof, in children and youth with autism enrolled in Medicaid across the US. This study examined national Medicaid claims from 2008 to 2016 of all children and youth with autism ages 0-21 years enrolled in Medicaid. Psychotropic medication use was examined across several child and youth characteristics, including age, co-occurring mental health conditions, sex, and race and ethnicity. About half of children and youth with autism enrolled in Medicaid had at least one psychotropic prescription in a year, a number that decreased slightly across the study period due to decreases in the prescription of antipsychotics. As new medications for autism or co-occurring conditions are developed and deployed, and as the understanding of the characteristics of the population of children with autism evolves, studying rates of medication usage helps to understand utilization patterns and differences in access to quality care.
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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.
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Doença de Parkinson , Bexiga Urinária Hiperativa , Agentes Urológicos , Humanos , Idoso , Estados Unidos , Antagonistas Muscarínicos/efeitos adversos , Bexiga Urinária Hiperativa/diagnóstico , Estudos de Coortes , Estudos Prospectivos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Medicare , Acetanilidas/uso terapêutico , Antagonistas Colinérgicos/efeitos adversos , Resultado do Tratamento , Agentes Urológicos/uso terapêuticoRESUMO
Background: Although children aged <1 year have a relatively high rate of venous thromboembolism (VTE) compared to older children, most have additional prothrombotic risk factors. Unprovoked VTE is rare, and little is known about this population, particularly the risk of recurrent VTE. Objectives: We aimed to determine the rate of recurrent VTE in infants with prior unprovoked VTE and evaluate long-term, end-organ outcomes for infants with renal and intracranial vein thrombosis. Methods: Infants <1 year of age with an unprovoked VTE between 2003 and 2021 at a single institution were included. Time to recurrent event and anticoagulation duration were summarized using the Kaplan-Meier estimator. Neurologic outcomes were summarized with the pediatric stroke outcome measure for infants with cerebral sinovenous, medullary, or cortical vein thrombosis. Kidney outcomes were summarized with estimated glomerular filtration rates for infants with renal vein thrombosis. Anticoagulation was summarized. Results: Forty infants with intracranial, renal, portal, and extremity VTE met the inclusion criteria and were followed for a median of 4.7 years (IQR, 2.1-8.5). Most VTE events occurred during the first month of life. There was 1 recurrent event in 237 person-years of follow-up (incidence rate, 4 per 1000 [95% CI, 0.6-29.9] person-years). In outpatient follow-up, 40% of infants with intracranial thrombosis met criteria for moderate or severe neurologic outcomes and two-thirds of infants with a prior renal vein thrombosis had abnormal kidney function (estimated glomerular filtration rate < 90 mL/min/1.73 m2). Conclusion: There is a low rate of recurrent VTE but significant end-organ morbidity in infants with unprovoked VTE.
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BACKGROUND: Usage of medication brand names in electronic health records may introduce conflicts of interest, perpetuate false perceptions of brand superiority, alter prescribing practices, and cause confusion leading to errors. OBJECTIVE: We sought to identify the frequency of brand name medication usage in clinical documentation, as well as factors associated with increased usage. DESIGNS, SETTINGS, AND PARTICIPANTS: We conducted a retrospective analysis of all clinical documentation written at our healthcare system (a multifacility academic urban healthcare system) between 2015 and 2020. MAIN OUTCOMES AND MEASURES: We used string-matching and regular expressions to identify medication mentions. We conducted bivariate analyses to identify associations between brand name usage and author-, note-, and medication-level factors, and a multivariate Poisson regression to clarify independent associations between individual factors and brand usage. RESULTS: A total of 104,456,653 notes from 37,285 unique authors were included in our analysis. A total of 162,906,009 medication mentions were identified, of which 36.0% were brand name mentions with a steady year-over-year decrease. Factors associated with the usage of a brand name include: author role, years since release, length and syllabic complexity of the generic name, service type, and encounter context. Over-the-counter availability did not affect usage. There was sizable individual variation between note writers.
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Documentação , Registros Eletrônicos de Saúde , Humanos , Estudos Retrospectivos , Atenção à SaúdeRESUMO
This study aimed to examine differential prescribing due to channeling and propensity score non-overlap over time in new versus established treatments for common neurological conditions. We conducted cross-sectional analyses on a national sample of US commercially insured adults using 2005-2019 data. We compared new users of recently approved versus established medications for management of diabetic peripheral neuropathy (pregabalin versus gabapentin), Parkinson disease psychosis (pimavanserin versus quetiapine), and epilepsy (brivaracetam versus levetiracetam). Within these drug pairs, we compared demographic, clinical, and healthcare utilization characteristics of recipients of each drug. In addition, we fit yearly propensity score models for each condition and assessed propensity score non-overlap over time. For all three drug pairs, users of the more recently approved medications more frequently had prior treatment (pregabalin = 73.9%, gabapentin = 38.7%; pimavanserin = 41.1%, quetiapine = 14.0%; brivaracetam = 93.4%, levetiracetam = 32.1%). Propensity score non-overlap and its resulting sample loss after trimming were the greatest in the first year that the more recently approved medication was available (diabetic peripheral neuropathy, 12.4% non-overlap; Parkinson disease psychosis, 6.1%; epilepsy, 43.2%) and subsequently improved. Newer neuropsychiatric therapies appear to be channeled to individuals with refractory disease or intolerance to other treatments, leading to potential confounding and biased comparative effectiveness and safety study findings when compared to established treatments. Propensity score non-overlap should be reported in comparative studies that include newer medications. When studies comparing newer and established treatments are critically needed as soon as new treatments enter the market, investigators should recognize the potential for channeling bias and implement methodological approaches like those demonstrated in this study to understand and improve this issue in such studies.
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Neuropatias Diabéticas , Epilepsia , Doença de Parkinson , Adulto , Humanos , Gabapentina/uso terapêutico , Pregabalina/uso terapêutico , Levetiracetam/uso terapêutico , Fumarato de Quetiapina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Estudos Transversais , Neuropatias Diabéticas/tratamento farmacológico , Epilepsia/tratamento farmacológicoRESUMO
BACKGROUND: Unprovoked venous thromboembolism (VTE) is rare in pediatrics. Current recommendations for anticoagulation duration after unprovoked VTE differ for pediatric and adult populations. OBJECTIVES: This single-center, retrospective cohort study aimed to determine the incidence rate of recurrent VTE in children and adolescents with unprovoked VTE, evaluate the potential risk factors for recurrence, and describe the anticoagulation regimens and bleeding in this population. METHODS: Children with an index, unprovoked VTE at the age of 1 to <21 years between 2003 and 2021 were included. The time to recurrent VTE and anticoagulation duration were summarized using Kaplan-Meier estimators. Clinical covariates were assessed for association with recurrence using stratified Kaplan-Meier curves and univariate Cox proportional hazards regression. RESULTS: Eighty-five children met the inclusion criteria, and there were 26 recurrent events in 250 person-years of follow-up (incidence rate = 104 [95% CI, 71-153] per 1000 person-years). An age of ≥12 years at index VTE (hazard ratio [HR], 7.56; 95% CI, 1.60-35.83) and inherited thrombophilia (HR, 2.28; 95% CI, 1.05-4.95) were significantly associated with recurrent VTE. Female sex had a nonstatistically significant decreased hazard of recurrence (HR, 0.56; 95% CI, 0.25-1.27). Duration of anticoagulation was variable, with a median duration of 274 days (IQR, 101-2357) for outpatient therapeutic anticoagulation. Twelve of the 26 (46%) recurrent events occurred while anticoagulation was prescribed. CONCLUSION: The incidence rate of recurrent VTE in pediatric patients with a prior unprovoked VTE is high, particularly for adolescents and those with inherited thrombophilia. Therefore, future research should focus on the efficacy of prolonged anticoagulation for this population.
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Trombofilia , Tromboembolia Venosa , Adulto , Humanos , Feminino , Adolescente , Criança , Lactente , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Anticoagulantes/uso terapêutico , Estudos Retrospectivos , Coagulação Sanguínea , Fatores de Risco , Trombofilia/complicações , Trombofilia/diagnóstico , Trombofilia/tratamento farmacológico , RecidivaRESUMO
Antidepressants are associated with traumatic injury and are widely used with other medications. It remains unknown how drug-drug-drug interactions (3DIs) between antidepressants and two other drugs may impact potential injury risks associated with antidepressants. We aimed to generate hypotheses regarding antidepressant 3DI signals associated with elevated injury rates. Using 2000-2020 Optum's de-identified Clinformatics Data Mart, we performed a self-controlled case series study for each drug triad consisting of an antidepressant + codispensed drug (base-pair) with a candidate interacting medication (precipitant). We included persons aged greater than or equal to 16 years who (1) experienced an injury and (2) used a candidate precipitant, during base-pair therapy. We compared injury rates during observation time exposed to the drug triad versus the base-pair only, adjusting for time-varying covariates. We calculated adjusted rate ratios (RRs) using conditional Poisson regression and accounted for multiple comparisons via semi-Bayes shrinkage. Among 147,747 eligible antidepressant users with an injury, we studied 120,714 antidepressant triads, of which 334 (0.3%) were positively associated with elevated injury rates and thus considered potential 3DI signals. Adjusted RRs for signals ranged from 1.31 (1.04-1.65) for sertraline + levothyroxine with tramadol (vs. without tramadol) to 6.60 (3.23-13.46) for escitalopram + simvastatin with aripiprazole (vs. without aripiprazole). Nearly half of the signals (137, 41.0%) had adjusted RRs greater than or equal to 2, suggesting strong associations with injury. The identified signals may represent antidepressant 3DIs of potential clinical concern and warrant future etiologic studies to test these hypotheses.
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Tramadol , Humanos , Idoso , Aripiprazol , Teorema de Bayes , Antidepressivos/efeitos adversos , Interações MedicamentosasRESUMO
INTRODUCTION: Approximately 30% to 50% of hospital discharge antimicrobials are inappropriate. Limited data exist on approaches to improve antimicrobial prescribing practices at the time of discharge from a community hospital. Objective: To assess the impact of a comprehensive pharmacist-led antimicrobial stewardship intervention at discharge. METHODS: We conducted a quasi-experimental, pre-post study. A biphasic intervention took place on 2 medicine units from November 2019 to May 2020 at a community hospital. Baseline data were collected, followed by prescriber education on antimicrobial stewardship to both units (education phase). Next, a pharmacist-led intervention took place on one unit (intervention phase). The primary outcome was composite appropriateness of an oral antimicrobial prescribed to an adult at the time of discharge, defined by narrow spectrum of activity, dosing, and duration of therapy. The primary outcome was assessed using Fisher exact test. RESULTS: Baseline composite appropriateness was 30% (n = 12) on the control unit and 30.8% (n = 20) on the intervention unit. From baseline to posteducation, no significant change in composite appropriateness was found on the control (30% to 26.7%, P = 0.256) or intervention (30.8% to 19.4%, P = 0.09) unit. There was no significant difference between the education to intervention phase (26.7% vs 35%, P = 0.254) on the control unit. On the intervention unit, a significant difference in composite appropriateness was found from the education to intervention phase (19.4% vs 47.8%, P = 0.017). CONCLUSION AND RELEVANCE: A pharmacist-led intervention improved appropriateness of oral antimicrobials prescribed at discharge. One-time education was insufficient for improving antimicrobial stewardship.
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Anti-Infecciosos , Gestão de Antimicrobianos , Adulto , Humanos , Alta do Paciente , Farmacêuticos , Anti-Infecciosos/uso terapêutico , Hospitais Comunitários , Antibacterianos/uso terapêuticoRESUMO
Epidemiological training often requires specialization in a subdiscipline (e.g., pharmacoepidemiology, genetic epidemiology, social epidemiology, or infectious disease epidemiology). While specialization is necessary and beneficial, it comes at the cost of decreased awareness of scientific developments in other subdisciplines of epidemiology. In this commentary, we argue for the importance of promoting an exchange of ideas across seemingly disparate epidemiologic subdisciplines. Such an exchange can lead to invaluable opportunities to learn from and merge knowledge across subdisciplines. It can promote "innovation at the edges," a process of borrowing and transforming methods from one subdiscipline in order to develop something new and advance another subdiscipline. Further, we outline specific actionable steps at the researcher, institution, and professional society level that can promote such innovation.
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Epidemiologia , Farmacoepidemiologia , Humanos , Epidemiologia Molecular , Epidemiologia/educaçãoRESUMO
OBJECTIVE: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE. DESIGN: We used nested case-control study design. SETTING: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA. PARTICIPANTS: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban. RESULTS: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18). CONCLUSION: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.
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Fibrilação Atrial , COVID-19 , Adulto , Humanos , Rivaroxabana/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Anticoagulantes/efeitos adversos , Estudos de Casos e Controles , Dabigatrana/uso terapêutico , Tratamento Farmacológico da COVID-19 , Piridonas/efeitos adversos , Interações Medicamentosas , Dexametasona/efeitos adversos , Administração Oral , Fibrilação Atrial/tratamento farmacológico , Estudos RetrospectivosRESUMO
Background: Periodic surveillance of the hepatitis C virus (HCV) care cascade is important for tracking progress toward HCV elimination goals, identifying gaps in care, and prioritizing resource allocation. In the pre-direct-acting antiviral (DAA) era, it was estimated that 50% of HCV-infected individuals were diagnosed and that 16% had been prescribed interferon-based therapy. Since then, few studies utilizing nationally representative data from the DAA era have been conducted in the United States. Methods: We performed a cross-sectional study to describe the HCV care cascade in the United States using the Optum de-identified Clinformatics® Data Mart Database to identify a nationally representative sample of commercially insured beneficiaries between January 1, 2014 and December 31, 2019. We estimated the number of HCV-viremic individuals in Optum based on national HCV prevalence estimates and determined the proportion who had: (1) recorded diagnosis of HCV infection, (2) recorded HCV diagnosis and underwent HCV RNA testing, (3) DAA treatment dispensed, and (4) assessment for cure. Results: Among 120,311 individuals estimated to have HCV viremia in Optum during the study period, 109,233 (90.8%; 95% CI, 90.6%-91.0%) had a recorded diagnosis of HCV infection, 75,549 (62.8%; 95% CI, 62.5%-63.1%) had a recorded diagnosis of HCV infection and underwent HCV RNA testing, 41,102 (34.2%; 95% CI, 33.9%-34.4%) were dispensed DAA treatment, and 25,760 (21.4%; 95% CI, 21.2%-21.6%) were assessed for cure. Conclusions: Gaps remain between the delivery of HCV-related care and national treatment goals among commercially insured adults. Efforts are needed to increase HCV treatment among people diagnosed with chronic HCV infection to achieve national elimination goals.
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Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999−2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13−0.77) for metaxalone to 3.44 (95% confidence interval: 1.53−7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.
Assuntos
Fármacos Neuromusculares , Tromboembolia , Anticoagulantes/efeitos adversos , Humanos , Estudos Retrospectivos , Tromboembolia/epidemiologia , Varfarina/efeitos adversosRESUMO
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.