Racial disparities in receipt of radiation and brachytherapy in cervical cancer patients: Do they exist in a SEER-Medicare population?

Objectives: To evaluate if race is associated with disparities in receipt of radiation (RT) and outcomes for Medicare patients with cervical cancer who are candidates for primary radiation-chemotherapy. Methods: This SEER-Medicare retrospective study included White and Black patients with stage IB1 through IVA squamous cell carcinoma or adenocarcinoma diagnosed 2000-2017 who were candidates for primary radiation-chemotherapy. Receipt of treatment by race and associated cancer specific (CSS) and overall survival (OS) outcomes were analyzed using frequency distributions, chi squared, log rank, multivariable Cox proportional-hazards models, and multivariable logistic models. Results: 1038 patients (84.9 % White and 15.1 % Black) were included. 825 (79.5 %) received RT, and 601 (57.9 %) received brachytherapy (BT). Blacks were more likely to undergo RT than Whites (86.0 % vs. 78.3 %, p = 0.028) and had similar rates of BT (58.0 % vs. 57.9 %, p = 0.986). Median RT duration was 64.0 days (IQR 52.0, 75.0), and 276 (33.5 %) completed treatment in ≤ 56 days, with no differences by race (p = 0.488, 0.303, respectively). BT was more frequently provided at larger hospitals, National Cancer Institute-designated cancer centers, and teaching hospitals. When adjusted for covariates, no significant differences in RT, BT, or RT duration by race were identified. Median unadjusted OS was 3.58 years (95 % CI 2.92, 4.42) for White patients and 2.50 years (95 % CI 2.0, 5.25) for Black patients, with no differences in OS (HR 0.93, 95 % CI 0.75, 1.13) or CSS (HR 1.13, 95 %CI 0.86, 1.43). Conclusions: Black Medicare patients with cervical cancer had greater receipt of RT than White patients, similar rates of BT, and no difference in survival.

Concomitant Use of Oral Anticoagulants with Oral Dipeptidyl Peptidase-4 Inhibitors and Serious Bleeding Events.

In a prior screening study, saxagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i), was found to have an increased rate of serious bleeding when used concomitantly with several oral anticoagulants (OACs). We aimed to confirm or refute the associations between concomitant use of individual OACs and DPP-4is and serious bleeding in a large US database, using self-controlled case series (SCCS) and case-crossover (CCO) designs. The study population was eligible Medicare beneficiaries co-exposed to a DPP-4i (precipitant) and either an OAC (object drug) or lisinopril (negative control object drug) in 2016-2020. For the SCCS, we used conditional Poisson regression to estimate adjusted rate ratios (RRs) between each co-exposure (vs. not) and serious bleeding and divided the RR by the adjusted RR for the corresponding lisinopril + precipitant pair to obtain ratios of RRs (RRRs). For the CCO, we estimated the adjusted odds ratios (ORs) of exposure to the precipitant in the focal window vs. referent window using multivariable conditional logistic regression and divided the ORs in the object drug-exposed cases over the ORs in negative object drug-exposed cases to obtain the ratios of ORs (RORs). The adjusted RRRs for serious bleeding ranged from 0.32 (0.05-1.91) for apixaban/lisinopril + saxagliptin to 3.49 (1.29-9.48) for warfarin/lisinopril + linagliptin. The adjusted RORs ranged from 0.01 (0.00-0.20) for rivaroxaban/lisinopril + saxagliptin to 2.99 (0.74-12.11) for apixaban/lisinopril + linagliptin. While we could not confirm previously identified signals because of statistical imprecision, several numerically elevated estimates still warrant caution in concomitant use and further examination.

Travel Time to Treating Center is Associated With Diagnostic Delay in Pediatric Inflammatory Bowel Disease.

BACKGROUND & AIMS: Delayed diagnosis of inflammatory bowel disease (IBD) leads to prolonged symptoms and worse long-term outcomes. We sought to evaluate whether race, ethnicity, disease type, and social factors are associated with delayed diagnosis of pediatric IBD. METHODS: We performed a cross-sectional study of newly diagnosed pediatric patients with IBD at 22 United States sites from 2019 to 2022. Parents/guardians reported race, ethnicity, time between symptom onset and diagnosis, and other social determinants of health. Through bivariate and multivariable analyses using generalized estimating equations, we evaluated associations between these factors and diagnosis time defined as ≤60 days, 61 to 180 days, 181 to 365 days, and >365 days. RESULTS: We enrolled 869 participants (mean age at diagnosis, 13.1 years; 52% male; 57% Crohn's disease [CD]; 34% ulcerative colitis [UC]; 8% Hispanic; 30% non-White). Overall, the mean time to diagnosis was 265.9 days. After adjustment, factors associated with longer diagnosis time included CD vs UC (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.9-3.5), 2 or more other health conditions (OR, 1.7; 95% CI, 1.1-2.7), and longer travel time to clinic (>1 hour [OR, 1.7; 95% CI, 1.2-2.4], >2 hours (OR, 1.8; 95% CI, 1.2-2.9] each vs <30 minutes). There was no association with race, ethnicity, birth country, sex, parent education, household income, insurance type, health literacy, and health system distrust. CONCLUSIONS: Consistent with prior literature, diagnostic delay is longer for CD than UC. Reassuringly, time to diagnosis is equitable across racioethnic groups. New models of diagnostic care are needed for communities affected by longer travel times.

Provider Specialization in Inflammatory Bowel Diseases: Quality of Care and Outcomes.

BACKGROUND & AIMS: Management of inflammatory bowel diseases (IBD) is complex and variation in care has been well-documented. However, the drivers of practice variation remain unexplored. We examined variation based on the treating gastroenterologist's IBD focus (proportion of outpatient visits for IBD). METHODS: We conducted a retrospective cohort of newly diagnosed patients with IBD using data from Optum's deidentified Clinformatics Data Mart Database (2000-2020). The exposure variable was whether the treating gastroenterologist had an IBD focus (>90th percentile of IBD visits/total outpatient visits). We used adjusted regression models to evaluate associations between provider IBD focus and process measures (use of mesalamine, corticosteroid, biologic, and narcotic medications and endoscopic or radiographic imaging) and clinical outcomes (time to IBD-related hospitalization and bowel resection surgery). We tested for change in treatment patterns over time by including an interaction term for study era (2004-2012 vs 2013-2020). RESULTS: The study included 772 children treated by 493 providers and 2864 adults treated by 2076 providers. In children, none of the associations between provider focus and process or outcome measures were significant. In adults, care from an IBD-focused provider was associated with more use of biologics, combination therapy, and imaging and endoscopy, and less mesalamine use for Crohn's disease (P < .05 for all comparisons) but not with other process measures. Biologics were prescribed more frequently and narcotics less frequently during the later era (P < .05 for both). Hospitalization and surgery rates were not associated with IBD focus or era. CONCLUSIONS: IBD care for adults varies by provider specialization. Given the evolving complexity, novel methods may be needed to standardize care.

Surgery for Crohn's Disease Is Associated With a Dysbiotic Microbiome and Metabolome: Results From Two Prospective Cohorts.

BACKGROUND & AIMS: Crohn's disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn's disease surgery. METHODS: Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn's Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with 1H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry. RESULTS: Intestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, Egerthella lenta, Adlercreutzia equalofaciens, and Gordonibacter pamelaeae were lower in abundance among patients with prior surgery in both cohorts. CONCLUSIONS: In 2 different populations, prior surgery in Crohn's disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria and secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.

Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants.

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.

Incidence, Prevalence, and Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States.

BACKGROUND & AIMS: We sought to estimate the incidence, prevalence, and racial-ethnic distribution of physician-diagnosed inflammatory bowel disease (IBD) in the United States. METHODS: The study used 4 administrative claims data sets: a 20% random sample of national fee-for-service Medicare data (2007 to 2017); Medicaid data from Florida, New York, Pennsylvania, Ohio, and California (1999 to 2012); and commercial health insurance data from Anthem beneficiaries (2006 to 2018) and Optum's deidentified Clinformatics Data Mart (2000 to 2017). We used validated combinations of medical diagnoses, diagnostic procedures, and prescription medications to identify incident and prevalent diagnoses. We computed pooled age-, sex-, and race/ethnicity-specific insurance-weighted estimates and pooled estimates standardized to 2018 United States Census estimates with 95% confidence intervals (CIs). RESULTS: The age- and sex-standardized incidence of IBD per 100,000 person-years was 10.9 (95% CI, 10.6-11.2). The incidence of IBD peaked in the third decade of life, decreased to a relatively stable level across the fourth to eighth decades, and declined further. The age-, sex- and insurance-standardized prevalence of IBD was 721 per 100,000 population (95% CI, 717-726). Extrapolated to the 2020 United States Census, an estimated 2.39 million Americans are diagnosed with IBD. The prevalence of IBD per 100,000 population was 812 (95% CI, 802-823) in White, 504 (95% CI, 482-526) in Black, 403 (95% CI, 373-433) in Asian, and 458 (95% CI, 440-476) in Hispanic Americans. CONCLUSIONS: IBD is diagnosed in >0.7% of Americans. The incidence peaks in early adulthood and then plateaus at a lower rate. The disease is less commonly diagnosed in Black, Asian, and Hispanic Americans.

Comparing Patient-Reported Outcomes Among Anti-TNF Experienced Patients With Ulcerative Colitis Initiating Vedolizumab Versus Tofacitinib.

Background: Primary and secondary nonresponse to anti-tumor necrosis factor (TNF) therapy is common in patients with ulcerative colitis (UC), yet limited research has compared the effectiveness of subsequent biological therapy. Objective: We sought to compare the effectiveness of vedolizumab and tofacitinib in anti-TNF experienced patients with UC, focusing on patient-prioritized patient-reported outcomes (PROs). Methods: We conducted a prospective cohort study nested within the Crohn's & Colitis Foundation's IBD Partners and SPARC IBD initiatives. We identified anti-TNF experienced patients with UC initiating vedolizumab or tofacitinib and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included PRO2, treatment persistence, and need for colectomy. Results: We compared 72 vedolizumab initiators and 33 tofacitinib initiators. At follow-up, Pain Interference (P = .04), but not Fatigue (P = .53) was lower among tofacitinib initiators. A trend toward higher Social Role Satisfaction was not significant. The remainder of secondary outcomes (PRO2, treatment persistence, colectomy) did not differ between treatment groups. Conclusions: Among anti-TNF experienced patients with UC, Pain Interference 4-10 months after treatment initiation was lower among tofacitinib users as compared with vedolizumab users. Many, but not all, secondary endpoints and subanalyses also favored tofacitinib. Future studies with larger sample sizes are needed to further evaluate these findings.

Development and Validation of Claims-Based Definitions to Identify Incident and Prevalent Inflammatory Bowel Disease in Administrative Healthcare Databases.

BACKGROUND: To facilitate inflammatory bowel disease (IBD) research in the United States, we developed and validated claims-based definitions to identify incident and prevalent IBD diagnoses using administrative healthcare claims data among multiple payers. METHODS: We used data from Medicare, Medicaid, and the HealthCore Integrated Research Database (Anthem commercial and Medicare Advantage claims). The gold standard for validation was review of medical records. We evaluated 1 incidence and 4 prevalence algorithms based on a combination of International Classification of Diseases codes, National Drug Codes, and Current Procedural Terminology codes. The claims-based incident diagnosis date needed to be within ±90 days of that recorded in the medical record to be valid. RESULTS: We reviewed 111 charts of patients with a potentially incident diagnosis. The positive predictive value (PPV) of the claims algorithm was 91% (95% confidence interval [CI], 81%-97%). We reviewed 332 charts to validate prevalent case definition algorithms. The PPV was 94% (95% CI, 86%-98%) for ≥2 IBD diagnoses and presence of prescriptions for IBD medications, 92% (95% CI, 85%-97%) for ≥2 diagnoses without any medications, 78% (95% CI, 67%-87%) for a single diagnosis and presence of an IBD medication, and 35% (95% CI, 25%-46%) for 1 physician diagnosis and no IBD medications. CONCLUSIONS: Through a combination of diagnosis, procedural, and medication codes in insurance claims data, we were able to identify incident and prevalent IBD cases with high accuracy. These algorithms can be useful for the ascertainment of IBD cases in future studies.

Antidepressant drug-drug-drug interactions associated with unintentional traumatic injury: Screening for signals in real-world data.

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.

Misinformation about vaccine safety and uptake of COVID-19 vaccines among adults and 5-11-year-olds in the United States.

Despite increasing rates of vaccination for COVID-19 in the US, hesitancy continues to be a barrier to the full immunization of the eligible population. Hesitancy appears to be particularly pronounced among adults deciding whether to recommend that children be vaccinated against COVID-19. In this research, we tested whether embrace of misinformation about the safety of vaccination is associated with hesitancy to vaccinate oneself and to recommend vaccination of a 5-11-year-old child for COVID-19. In a national probability panel created in April 2021, we assessed belief in both general vaccination misinformation and misinformation about COVID-19 vaccines, in particular. As hypothesized, belief in general vaccination misinformation predicted the uptake in reported vaccination among adults through September 2021, and likelihood to recommend COVID-19 vaccination of children aged 5-11 in January 2022, three months after the approval of that vaccine. In addition, misinformation about COVID-19 vaccines that arose over time correlated highly with more general vaccination misinformation. For both outcomes, general vaccine misinformation predicted vaccination hesitancy beyond concerns about the health risks of contracting COVID-19 for one's family and children ages 5-11. The findings indicate that continued efforts are needed to bolster beliefs about the safety of authorized and approved vaccines of many types and not just those for COVID-19. Some strategies to achieve this objective are suggested.

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.

Thromboembolic Events in Users of Warfarin Treated with Different Skeletal Muscle Relaxants.

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.

Evaluation of Spending Differences Between Beneficiaries in Medicare Advantage and the Medicare Shared Savings Program.

Importance: The 2 primary efforts of Medicare to advance value-based care are Medicare Advantage (MA) and the fee-for-service-based Medicare Shared Savings Program (MSSP). It is unknown how spending differs between the 2 programs after accounting for differences in patient clinical risk. Objective: To examine how spending and utilization differ between MA and MSSP beneficiaries after accounting for differences in clinical risk using data from administrative claims and electronic health records. Design, Setting, and Participants: This retrospective economic evaluation used data from 15 763 propensity score-matched beneficiaries who were continuously enrolled in MA or MSSP from January 1, 2014, to December 31, 2018, with diabetes, congestive heart failure (CHF), chronic kidney disease (CKD), or hypertension. Participants received care at a large nonprofit academic health system in the southern United States that bears risk for Medicare beneficiaries through both the MA and MSSP programs. Differences in beneficiary risk were mitigated by propensity score matching using validated clinical criteria based on data from administrative claims and electronic health records. Data were analyzed from January 2019 to May 2022. Exposures: Enrollment in MA or attribution to an accountable care organization in the MSSP program. Main Outcomes and Measures: Per-beneficiary annual total spending and subcomponents, including inpatient hospital, outpatient hospital, skilled nursing facility, emergency department, primary care, and specialist spending. Results: The sample of 15 763 participants included 12 720 (81%) MA and 3043 (19%) MSSP beneficiaries. MA beneficiaries, compared with MSSP beneficiaries, were more likely to be older (median [IQR] age, 75.0 [69.9-81.8] years vs 73.1 [68.3-79.8] years), male (5515 [43%] vs 1119 [37%]), and White (9644 [76%] vs 2046 [69%]) and less likely to live in low-income zip codes (2338 [19%] vs 750 [25%]). The mean unadjusted per-member per-year spending difference between MSSP and MA disease-specific subcohorts was $2159 in diabetes, $4074 in CHF, $2560 in CKD, and $2330 in hypertension. After matching on clinical risk and demographic factors, MSSP spending was higher for patients with diabetes (mean per-member per-year spending difference in 2015: $2454; 95% CI, $1431-$3574), CHF ($3699; 95% CI, $1235-$6523), CKD ($2478; 95% CI, $1172-$3920), and hypertension ($2258; 95% CI, $1616-2,939). Higher MSSP spending among matched beneficiaries was consistent over time. In the matched cohort in 2018, MSSP total spending ranged from 23% (CHF) to 30% (CKD) higher than MA. Adjusting for differential trends in coding intensity did not affect these results. Higher outpatient hospital spending among MSSP beneficiaries contributed most to spending differences between MSSP and MA, representing 49% to 62% of spending differences across disease cohorts. Conclusions and Relevance: In this study, utilization and spending were consistently higher for MSSP than MA beneficiaries within the same health system even after adjusting for granular metrics of clinical risk. Nonclinical factors likely contribute to the large differences in MA vs MSSP spending, which may create challenges for health systems participating in MSSP relative to their participation in MA.

Identifying Clinically Relevant Drug-Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection.

Methadone and buprenorphine have pharmacologic properties that are concerning for a high risk of drug-drug interactions (DDIs). We performed high-throughput screening for clinically relevant DDIs with methadone or buprenorphine by combining pharmacoepidemiologic and pharmacokinetic approaches. We conducted pharmacoepidemiologic screening via a series of self-controlled case series studies (SCCS) in Optum claims data from 2000 to 2019. We included persons 18 years or older who experienced an outcome of interest during target drug treatment. Exposures were all overlapping medications (i.e., the candidate precipitants) during target drug treatment. Outcomes were opioid overdose, non-overdose adverse effects, and cardiac arrest. We used conditional Poisson regression to calculate rate ratios, accounting for multiple comparisons with semi-Bayes shrinkage. We explored the impact of key study design choices in analyses that varied the exposure definitions of the target drugs and the candidate precipitant drugs. Pharmacokinetic screening was conducted by incorporating published data on CYP enzyme metabolism into an equation-based static model. In SCCS analysis, 1,432 events were included from 248,069 new users of methadone or buprenorphine. In the primary analysis, statistically significant DDIs included gabapentinoids with either methadone or buprenorphine; baclofen with methadone; and benzodiazepines with methadone. In sensitivity analysis, additional statistically significant DDIs included methocarbamol, quetiapine, or simvastatin with methadone. Pharmacokinetic screening identified two moderate-to-strong potential DDIs (clonidine and fluconazole with buprenorphine). The combination of clonidine and buprenorphine was also associated with a significantly increased risk of opioid overdose in pharmacoepidemiologic screening. These DDI signals may be the most important targets for future confirmation studies.

Opioid Drug-Drug-Drug Interactions and Unintentional Traumatic Injury: Screening to Detect Three-Way Drug Interaction Signals.

Growing evidence suggests that drug interactions may be responsible for much of the known association between opioid use and unintentional traumatic injury. While prior research has focused on pairwise drug interactions, the role of higher-order (i.e., drug-drug-drug) interactions (3DIs) has not been examined. We aimed to identify signals of opioid 3DIs with commonly co-dispensed medications leading to unintentional traumatic injury, using semi-automated high-throughput screening of US commercial health insurance data. We conducted bi-directional, self-controlled case series studies using 2000-2015 Optum Data Mart database. Rates of unintentional traumatic injury were examined in individuals dispensed opioid-precipitant base pairs during time exposed vs unexposed to a candidate interacting precipitant. Underlying cohorts consisted of 16-90-year-olds with new use of opioid-precipitant base pairs and ≥1 injury during observation periods. We used conditional Poisson regression to estimate rate ratios adjusted for time-varying confounders, and semi-Bayes shrinkage to address multiple estimation. For hydrocodone, tramadol, and oxycodone (the most commonly used opioids), we examined 16,024, 8185, and 9330 drug triplets, respectively. Among these, 75 (0.5%; hydrocodone), 57 (0.7%; tramadol), and 42 (0.5%; oxycodone) were significantly positively associated with unintentional traumatic injury (50 unique base precipitants, 34 unique candidate precipitants) and therefore deemed potential 3DI signals. The signals found in this study provide valuable foundations for future research into opioid 3DIs, generating hypotheses to motivate crucially needed etiologic investigations. Further, this study applies a novel approach for 3DI signal detection using pharmacoepidemiologic screening of health insurance data, which could have broad applicability across drug classes and databases.

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.

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.

Intensity of end-of-life care for gynecologic cancer patients by primary oncologist specialty.

OBJECTIVE: The association of primary oncologist specialty, medical oncology versus gynecologic oncology, on intensity of care at the end of life in elderly patients with gynecologic cancer is unclear. METHODS: This retrospective cohort study used Surveillance, Epidemiology and End Results-Medicare (SEER-M) data. Subjects were fee-for-service Medicare enrollees aged 65 years and older who died of a gynecologic cancer between January 2006 and December 2015. The primary outcome was a composite score for high-intensity care received in the last month of life. Secondary outcomes included invasive procedures and Medicare spending in the last month of life. Simple and multivariable linear and logistic regression analyses evaluated differences in outcomes by primary oncologist specialty. Linear regressions were repeated after creating a more similar control group through nearest-neighbor propensity score matching. RESULTS: Of 12 189 patients, 7705 (63%) had a medical primary oncologist in the last year of life. In adjusted analyses, patients with a gynecologic versus medical primary oncologist received lower rates of high-intensity end-of-life care (53.9% vs 56.6%; p=0.018). Results were similar for the propensity score-matched cohorts. However, having a gynecologic versus medical primary oncologist was associated with higher rates of invasive procedures in the last month of life (43% vs 41%; p=0.014) and higher Medicare spending ($83 859 vs $74 849; p=0.004). CONCLUSIONS: Both specialties engage in overall high levels of intense end-of-life care, with differences by specialty in aspects of aggressive care and spending at the end of life. Physician-level training could be a target for educational or quality improvement initiatives to improve end-of-life cancer care delivery.