A simulation-based bias analysis to assess the impact of unmeasured confounding when designing non-randomized database studies.

BACKGROUND: Unmeasured confounding is often raised as a source of potential bias during the design of non-randomized studies but quantifying such concerns is challenging. METHODS: We developed a simulation-based approach to assess the potential impact of unmeasured confounding during the study design stage. The approach involved generation of hypothetical individual-level cohorts using realistic parameters including a binary treatment (prevalence 25%), a time-to-event outcome (incidence 5%), 13 measured covariates, a binary unmeasured confounder (u1, 10%), and a binary measured 'proxy' variable (p1) correlated with u1. Strength of unmeasured confounding and correlations between u1 and p1 were varied in simulation scenarios. Treatment effects were estimated with, a) no adjustment, b) adjustment for measured confounders (Level 1), c) adjustment for measured confounders and their proxy (Level 2). We computed absolute standardized mean differences in u1 and p1 and relative bias with each level of adjustment. RESULTS: Across all scenarios, Level 2 adjustment led to improvement in balance of u1, but this improvement was highly dependent on the correlation between u1 and p1. Level 2 adjustments also had lower relative bias than Level 1 adjustments (in strong u1 scenarios: relative bias of 9.2%, 12.2%, 13.5% at correlations 0.7, 0.5, and 0.3, respectively versus 16.4%, 15.8%, 15.0% for Level 1, respectively). CONCLUSION: An approach using simulated individual-level data was useful to explicitly convey the potential for bias due to unmeasured confounding while designing non-randomized studies and can be helpful in informing design choices.

Assessing the risk of intentional self-harm in montelukast users: an updated Sentinel System analysis using ICD-10 coding.

BACKGROUND: Montelukast prescribing information includes a Boxed Warning issued in March 2020 regarding neuropsychiatric adverse events. A previous Sentinel System study of asthma patients from 2000 to 2015 did not demonstrate an increased risk of intentional self-harm measured using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, with montelukast compared to inhaled corticosteroids (ICS). METHODS: Using a new user cohort study design, we examined intentional self-harm events in patients aged 10 years and older who were incident users of either montelukast or ICS as monotherapy, with a diagnosis of asthma, between October 1, 2015, to June 30, 2022, in the Sentinel System. We measured intentional self-harm using ICD-10-CM codes, which may have better accuracy for capturing suicide attempts than ICD-9-CM codes. We used inverse probability of treatment weighting to balance baseline covariates. We performed subgroup analyses by age group, sex, psychiatric history, and pre/post Boxed Warning era and conducted sensitivity analyses varying type of care setting of the outcome and exposure episode gaps. RESULTS: Among 752,230 and 724,855 patients in the montelukast and ICS exposure groups respectively, we found no association between montelukast use and self-harm compared to ICS use [Hazard Ratio (95% Confidence Interval): 0.96 (0.85, 1.08)]. This finding was consistent across all subgroups, and sensitivity analyses. CONCLUSION: Our results cannot exclude other neuropsychiatric idiosyncratic reactions to montelukast. Compared to the previous Sentinel study, this study identified about double the rate of self-harm events, suggesting a greater sensitivity of ICD-10 codes for measuring self-harm than ICD-9.

A Descriptive Cohort Study of Drug Utilization Patterns Among Patients Hospitalized With Coronavirus Disease 2019 in the United States, January 2021-February 2022.

Background: There is a dearth of drug utilization studies for coronavirus disease 2019 (COVID-19) treatments in 2021 and beyond after the introduction of vaccines and updated guidelines; such studies are needed to contextualize ongoing COVID-19 treatment effectiveness studies during these time periods. This study describes utilization patterns for corticosteroids, interleukin-6 (IL-6) inhibitors, Janus kinase inhibitors, and remdesivir among hospitalized adults with COVID-19, over the entire hospitalization, and within hospitalization periods categorized by respiratory support requirements. Methods: This descriptive cohort study included United States adults hospitalized with COVID-19 admitted from 1 January 2021 through 1 February 2022; data included HealthVerity claims and hospital chargemaster. The number and distribution of patients were reported for the first 3 drug regimen lines initiated. Results: The cohort included 51 066 patients; the most common initial drug regimens were corticosteroids (23.4%), corticosteroids plus remdesivir (25.1%), and remdesivir (4.4%). IL-6 inhibitors and Janus kinase inhibitors were included in later drug regimens and were more commonly administered with both corticosteroids and remdesivir than with corticosteroids alone. IL-6 inhibitors were more commonly administered than Janus kinase inhibitors when patients received high-flow oxygen or ventilation. Conclusions: These findings provide important context for comparative studies of COVID-19 treatments with study periods extending into 2021 and later. While prescribing generally aligned with National Institutes of Health COVID-19 treatment guidelines during this period, these findings suggest that prescribing preference, potential confounding by indication, and confounding by prior/concomitant use of other therapeutics should be considered in the design and interpretation of comparative studies.

A collaborative study of the impact of N-nitrosamines presence and ARB recall on ARB utilization - results from IQVIA™ Disease Analyzer Germany.

PURPOSE: Regulators are increasingly concerned with  the impact of recalls on drug adherence. In 2018, N-nitrosamines impurities were detected in valsartan containing medical products. Concerned products were immediately recalled in July 2018 by regulatory agencies internationally. In Germany, recalls were issued for valsartan, losartan and irbesartan from July 2018 to March 2019. This study examined angiotensin II receptor blocker (ARB) utilization trends and switching patterns in Germany before and after July 2018. METHODS: Patients prescribed ARBs from January 2014 to June 2020 in general practices in Germany were included in a collaborative framework common protocol drug utilization study led by the US Food and Drug Administration. Trends in monthly and quarterly proportions of total ARB prescribing were analysed for individual ARBs using descriptive statistics and interrupted time series analysis. The rate of switching to an alternative ARB was analysed before and after the recalls. RESULTS: The proportion of valsartan prescriptions immediately decreased from 35.9 to 17.8% following the first recalls in July 2018, mirrored by an increased proportion for candesartan. Increased switching from valsartan to candesartan was observed. No increased switching was observed after losartan recalls, whereas for irbesartan, increased switching was observed 6-12 months after the last recall. Increased switching from ARBs to angiotensin-converting enzyme (ACE) inhibitors or ARB treatment discontinuations were not observed. CONCLUSION: This study showed that patients were able to continue ARB treatment despite the July 2018-March 2019 recalls, although many patients needed to switch to an alternative ARB. The duration of the impact of ARB recalls appeared to be limited.

Valsartan, Losartan and Irbesartan use in the USA, UK, Canada and Denmark after the nitrosamine recalls: a descriptive cohort study.

OBJECTIVES: To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first Angiotensin-Receptor-Blocker (ARB) (valsartan) was recalled. DESIGN: Retrospective cohort study. SETTING: USA, Canadian administrative healthcare data, Danish National Prescription Registry and UK primary care electronic health records. PARTICIPANTS: Patients aged 18 years and older between January 2014 and December 2020. INTERVENTION: Valsartan, losartan and irbesartan. MAIN OUTCOME: Monthly percentages of individual ARB episodes, new users and switches to another ARB, ACE inhibitors (ACEI) or calcium channel blockers containing products. RESULTS: We identified 10.8, 3.2, 1.8 and 1.2 million ARB users in the USA, UK, Canada and Denmark, respectively. Overall proportions of valsartan, losartan and irbesartan use were 18.4%, 67.9% and 5.2% in the USA; 3.1%, 48.3% and 10.2% in the UK, 16.3%, 11.4% and 18.3% in Canada, 1%, 93.5% and 0.6% in Denmark. In July 2018, we observed an immediate steep decline in the proportion of valsartan use in the USA and Canada. A similar trend was observed in Denmark; however, the decline was only minimal. We observed no change in trends of ARB use in the UK. Accompanying the valsartan decline was an increase in switching to other ARBs in the USA, Canada and Denmark. There was a small increase in switching to ACEI relative to the valsartan-to-other-ARBs switch. We also observed increased switching from other affected ARBs, losartan and irbesartan, to other ARBs throughout 2019, in the USA and Canada, although the usage trends in the USA remained unchanged. CONCLUSION: The first recall notice for valsartan resulted in substantial decline in usage due to increased switching to other ARBs. Subsequent notices for losartan and irbesartan were also associated with increased switching around the time of the recall, however, overall usage trends remained unchanged.

A new analytic tool for assessing the impact of the US Food and Drug Administration regulatory actions.

PURPOSE: Develop and test a flexible, scalable tool using interrupted time series (ITS) analysis to assess the impact of Food and Drug Administration (FDA) regulatory actions on drug use. METHODS: We applied the tool in the Sentinel Distributed Database to assess the impact of FDA's 2010 drug safety communications (DSC) concerning the safety of long-acting beta2-agonists (LABA) in adult asthma patients. We evaluated changes in LABA use by measuring the initiation of LABA alone and concomitant use of LABA and asthma controller medications (ACM) after the DSCs. The tool generated ITS graphs and used segmented regression to estimate baseline slope, level change, slope change, and absolute and relative changes at up to two user-specified time point (s) after the intervention. We tested the tool and compared our results against prior analyses that used similar measures. RESULTS: Initiation of LABA alone declined among asthma patients aged 18-45 years before FDA DSCs (-0.10% per quarter; 95%CI: -0.11% to -0.09%) and the downward trend continued after. Concomitant use of LABA and ACM was stable before FDA DSCs. After FDA DSCs, there was a small trend decrease of 0.006% per quarter (95% CI, -0.008% to -0.003%). We found similar results among those aged 46-64 years and patients with poorly-controlled asthma. Our results were consistent with previous studies, confirming the performance of the new tool. CONCLUSIONS: We developed and tested a reusable ITS tool in real-world databases formatted to the Sentinel Common Data Model that can assess the impact of regulatory actions on drug use.

Testosterone therapy and cancer risks among men in the SEER-Medicare linked database.

BACKGROUND: We examined associations between two forms of testosterone therapy (TT) and risks of seven cancers among men. METHODS: SEER-Medicare combines cancer registry data from the Surveillance, Epidemiology, and End Results programme with Medicare claims. Our population-based case-control study included incident cancer cases diagnosed between 1992-2015: prostate (n = 130,713), lung (n = 105,466), colorectal (n = 56,433), bladder (n = 38,873), non-Hodgkin lymphoma (n = 17,854), melanoma (n = 14,241), and oesophageal (n = 9116). We selected 100,000 controls from a 5% random sample of Medicare beneficiaries and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: TT was associated with lower risk of distant-stage prostate cancer (injection/implantation OR = 0.72, 95% CI: 0.60-0.86; topical OR = 0.50, 95% CI: 0.24-1.03). We also observed inverse associations for distant-stage colorectal cancer (injection/implantation OR = 0.75, 95% CI: 0.62-0.90; topical OR = 0.11, 95% CI: 0.05-0.24). Risks of distant-stage colorectal and prostate cancers decreased with time after initiating TT by injection/implantation. By contrast, TT was positively associated with distant-stage melanoma (injection/implantation OR = 1.70, 95% CI: 1.37-2.11). TT was not associated with bladder cancer, oesophageal cancer, lung cancer or non-Hodgkin lymphoma. CONCLUSION: TT was inversely associated with distant-stage prostate and colorectal cancers but was positively associated with distant-stage melanoma. These observations may suggest an aetiologic role for TT or the presence of residual confounding.

Describing characteristics and treatment patterns of patients hospitalized with COVID-19 by race and ethnicity in a national RWD during the early months of the pandemic.

OBJECTIVE: To describe differences by race and ethnicity in treatment patterns among hospitalized COVID-19 patients in the US from March-August 2020. METHODS: Among patients in de-identified Optum electronic health record data hospitalized with COVID-19 (March-August 2020), we estimated odds ratios of receiving COVID-19 treatments of interest (azithromycin, dexamethasone, hydroxychloroquine, remdesivir, and other steroids) at hospital admission, by race and ethnicity, after adjusting for key covariates of interest. RESULTS: After adjusting for key covariates, Black/African American patients were less likely to receive dexamethasone (adj. OR [95% CI]: 0.83 [0.71, 0.96]) and more likely to receive other steroids corticosteroids (adj. OR [95% CI]: 2.13 [1.90, 2.39]), relative to White patients. Hispanic/Latino patients were less likely to receive dexamethasone than Not Hispanic/Latino patients (adj. OR [95% CI]: 0.69 [0.58, 0.82]). CONCLUSIONS: Our findings suggest that COVID-19 treatments patients received in Optum varied by race and ethnicity after adjustment for other possible explanatory factors. In the face of rapidly evolving treatment landscapes, policies are needed to ensure equitable access to novel and repurposed therapeutics to avoid disparities in care by race and ethnicity.

Categorization of COVID-19 severity to determine mortality risk.

PURPOSE: Algorithms for classification of inpatient COVID-19 severity are necessary for confounding control in studies using real-world data. METHODS: Using Healthverity chargemaster and claims data, we selected patients hospitalized with COVID-19 between April 2020 and February 2021, and classified them by severity at admission using an algorithm we developed based on respiratory support requirements (supplemental oxygen or non-invasive ventilation, O2/NIV, invasive mechanical ventilation, IMV, or NEITHER). To evaluate the utility of the algorithm, patients were followed from admission until death, discharge, or a 28-day maximum to report mortality risks and rates overall and by stratified by severity. Trends for heterogeneity in mortality risk and rate across severity classifications were evaluated using Cochran-Armitage and Logrank trend tests, respectively. RESULTS: Among 118 117 patients, the algorithm categorized patients in increasing severity as NEITHER (36.7%), O2/NIV (54.3%), and IMV (9.0%). Associated mortality risk (and 95% CI) was 11.8% (11.6-12.0%) overall and increased with severity [3.4% (3.2-3.5%), 11.5% (11.3-11.8%), 47.3% (46.3-48.2%); p < 0.001]. Mortality rate per 1000 person-days (and 95% CI) was 15.1 (14.9-15.4) overall and increased with severity [5.7 (5.4-6.0), 14.5 (14.2-14.9), 32.7 (31.8-33.6); p < 0.001]. CONCLUSION: As expected, we observed a positive association between the algorithm-defined severity on admission and 28-day mortality risk and rate. Although performance remains to be validated, this provides some assurance that this algorithm may be used for confounding control or stratification in treatment effect studies.

Deintensification of Treatment With Sulfonylurea and Insulin After Severe Hypoglycemia Among Older Adults With Diabetes.

Importance: Practice guidelines recommend deintensification of hypoglycemic agents among older adults with diabetes who are at high risk of hypoglycemia, yet real-world treatment deintensification practices are not well characterized. Objective: To examine the incidence of sulfonylurea and insulin deintensification after a hypoglycemia-associated emergency department (ED) visit or hospitalization among older adults with diabetes and to identify factors associated with deintensification of treatment. Design, Setting, and Participants: This retrospective cohort study included a random sample of 20% of nationwide fee-for-service US Medicare beneficiaries aged 65 years and older with concurrent Medicare parts A, B, and D coverage between January 1, 2007, and December 31, 2017. Individuals with diabetes who had at least 1 hypoglycemia-associated ED visit or hospitalization were included. Data were analyzed from August 1, 2020, to August 1, 2021. Exposures: Baseline medication for the treatment of diabetes (sulfonylurea, insulin, or both). Main Outcomes and Measures: Incidence of treatment deintensification (yes or no) in the 100 days after a severe hypoglycemic episode requiring an ED visit or hospitalization, with treatment deintensification defined as (1) a decrease in sulfonylurea dose, (2) a change from long-acting to short-acting sulfonylurea (glipizide), (3) discontinuation of sulfonylurea, or (4) discontinuation of insulin based on pharmacy dispensing claims. Results: Among 76 278 distinct Medicare beneficiaries who had a hypoglycemia-associated ED visit or hospitalization, the mean (SD) age was 76.6 (7.6) years. Of 106 293 total hypoglycemic episodes requiring hospital attention, 69 084 (65.0%) occurred among women, 26 056 (24.5%) among Black individuals; 4761 (4.5%) among Hispanic individuals; 69 704 (65.6%) among White individuals; and 5772 (5.4%) among individuals of other races and ethnicities (comprising Asian, North American Native, unknown race or ethnicity, and unspecified race or ethnicity). A total of 32 074 episodes (30.2%) occurred among those receiving sulfonylurea only, 60 350 (56.8%) occurred among those receiving insulin only, and 13 869 (13.0%) occurred among those receiving both sulfonylurea and insulin. Treatment deintensification rates were highest among individuals receiving both sulfonylurea and insulin therapies at the time of their hypoglycemic episode (6677 episodes [48.1%]), followed by individuals receiving sulfonylurea only (14 192 episodes [44.2%]) and insulin only (14 495 episodes [24.0%]). Treatment deintensification rates increased between 2007 and 2017 (sulfonylurea only: from 41.4% to 49.7%; P < .001 for trend; insulin only: from 21.3% to 25.9%; P < .001 for trend; sulfonylurea and insulin: from 45.9% to 49.6%; P = .005 for trend). Lower socioeconomic status (as indicated by the receipt of low-income subsidies) was associated with lower odds of deintensification, regardless of baseline hypoglycemic regimen (sulfonylurea only: adjusted odds ratio [AOR], 0.74 [95% CI, 0.70-0.78]; insulin only: AOR, 0.71 [95% CI, 0.68-0.75]; sulfonylurea and insulin: AOR, 0.72 [95% CI, 0.66-0.78]). A number of patient factors were associated with higher odds of treatment deintensification: higher frailty (eg, ≥40% probability of needing assistance with activities of daily living among those receiving sulfonylurea and insulin: AOR, 1.50; 95% CI, 1.32-1.71), chronic kidney disease (eg, sulfonylurea and insulin: AOR, 1.29; 95% CI, 1.19-1.40), a history of falls (eg, sulfonylurea and insulin: AOR, 1.20; 95% CI, 1.09-1.33), and depression (eg, sulfonylurea and insulin: AOR, 1.11; 95% CI, 1.02-1.20). Conclusions and Relevance: In this cohort study, deintensification of sulfonylurea and/or insulin therapy within 100 days after a hypoglycemia-associated ED visit or hospitalization occurred in fewer than 50% of older adults with diabetes; however, these deintensification rates may be increasing over time, and deintensification of insulin was likely underestimated because of challenges in capturing changes to insulin dosing using administrative claims data. These results suggest that greater efforts are needed to identify individuals at high risk of hypoglycemia to encourage appropriate treatment deintensification in accordance with current evidence.

Severe Hypoglycemia Risk With Long-Acting Insulin Analogs vs Neutral Protamine Hagedorn Insulin.

Importance: Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. Objective: To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. Design, Setting, and Participants: This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Exposures: Insulin glargine, insulin detemir, and NPH insulin. Main Outcomes and Measures: The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score-weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Results: Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. Conclusions and Relevance: In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

Risk of Nonmelanoma Skin Cancer in Association With Use of Hydrochlorothiazide-Containing Products in the United States.

Background: European studies reported an increased risk of nonmelanoma skin cancer associated with hydrochlorothiazide (HCTZ)-containing products. We examined the risks of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with HCTZ compared with angiotensin-converting enzyme inhibitors (ACEIs) in a US population. Methods: We conducted a retrospective cohort study in the US Food and Drug Administration's Sentinel System. From the date of HCTZ or ACEI dispensing, patients were followed until a SCC or BCC diagnosis requiring excision or topical chemotherapy treatment on or within 30 days after the diagnosis date or a censoring event. Using Cox proportional hazards regression models, we estimated the hazard ratios (HRs), overall and separately by age, sex, and race. We also examined site- and age-adjusted incidence rate ratios (IRRs) by cumulative HCTZ dose within the matched cohort. Results: Among 5.2 million propensity-score matched HCTZ and ACEI users, the incidence rate (per 1000 person-years) of BCC was 2.78 and 2.82, respectively, and 1.66 and 1.60 for SCC. Overall, there was no difference in risk between HCTZ and ACEIs for BCC (HR = 0.99, 95% confidence interval [CI] = 0.97 to 1.00), but there was an increased risk for SCC (HR = 1.04, 95% CI = 1.02 to 1.06). HCTZ use was associated with higher risks of BCC (HR = 1.09, 95% CI = 1.07 to 1.11) and SCC (HR = 1.15, 95% CI = 1.12 to 1.17) among Caucasians. Cumulative HCTZ dose of 50 000 mg or more was associated with an increased risk of SCC in the overall population (IRR = 1.19, 95% CI = 1.05 to 1.35) and among Caucasians (IRR = 1.27, 95% CI = 1.10 to 1.47). Conclusions: Among Caucasians, we identified small increased risks of BCC and SCC with HCTZ compared with ACEI. Appropriate risk mitigation strategies should be taken while using HCTZ.

Potentially inappropriate prescribing in dementia, multi-morbidity and incidence of adverse health outcomes.

IMPORTANCE: treatment of dementia in individuals with comorbidities is complex, leading to potentially inappropriate prescribing (PIP). The impact of PIP in this population is unknown. OBJECTIVE: to estimate the rate of PIP and its effect on adverse health outcomes (AHO). DESIGN: retrospective cohort. SETTING: primary care electronic health records linked to hospital discharge data from England. SUBJECTS: 11,175 individuals with dementia aged over 65 years in 2016 and 43,463 age- and sex-matched controls. METHODS: Screening Tool of Older Persons' Prescriptions V2 defined PIP. Logistic regression tested associations with comorbidities at baseline, and survival analyses risk of incident AHO, adjusted for age, gender, deprivation and 14 comorbidities. RESULTS: the dementia group had increased risk of PIP (73% prevalence; odds ratio [OR]: 1.92; confidence interval [CI]: 83-103%; P < 0.01) after adjusting for comorbidities. Most frequent PIP criteria were related to anti-cholinergic drugs and therapeutic duplication. Risk of PIP was higher in patients also diagnosed with coronary-heart disease (odds OR: 2.17; CI: 1.91-2.46; P < 0.01), severe mental illness (OR: 2.09; CI: 1.62-2.70; P < 0.01); and depression (OR: 1.81; CI: 1.62-2.01; P < 0.01). During follow-up (1 year), PIP was associated with increased all-cause mortality (hazard ratio: 1.14; CI: 1.02-1.26; P < 0.02), skin ulcer and pressure sores (hazard ratio: 1.66; CI: 1.12-2.46; P < 0.01), falls (hazard ratio: 1.37; CI: 1.15-1.63; P < 0.01), anaemia (hazard ratio: 1.61; CI: 1.10-2.38; P < 0.02) and osteoporosis (hazard ratio: 1.62; CI: 1.02-2.57; P < 0.04). CONCLUSION: patients with dementia frequently receive PIPs, and those who do are more likely to experience AHO. These results highlight the need to optimise medication in dementia patients, especially those with comorbidities.

Risk of Psychiatric Adverse Events Among Montelukast Users.

BACKGROUND: There have been conflicting results from observational studies regarding the risk of psychiatric adverse events (PAEs) with montelukast use. OBJECTIVE: To determine whether there are associations of depressive disorders, self-harm, and suicide with use of montelukast compared with inhaled corticosteroid (ICS) use. METHODS: Using data from the Sentinel Distributed Database from January 1, 2000, to September 30, 2015, patients (n = 457,377) exposed to montelukast or ICS, aged 6 years and older with a diagnosis of asthma, were matched 1:1 on propensity scores. Hazard ratios (HRs) and 95% CIs were estimated for each study outcome overall and by age, sex, psychiatric history, and pre-/post-2008 labeling updates using Cox proportional hazards regression models. RESULTS: Exposure to montelukast was associated with a lower risk of treated outpatient depressive disorder (HR, 0.91; 95% CI, 0.89-0.93). No increased risks of inpatient depressive disorder (HR, 1.06; 95% CI, 0.90-1.24), self-harm (HR, 0.92; 95% CI, 0.69-1.21), or self-harm using a modified algorithm (HR, 0.81; 95% CI, 0.63-1.05) were observed with montelukast use compared with ICS use. Most PAEs occurred in the roughly one-third of patients having a past psychiatric history. CONCLUSIONS: When compared with use of ICS, we did not find associations between montelukast use and hospitalizations for depression or self-harm events. Our findings should be interpreted considering the study's limitations. Psychiatric comorbidity was common, and most PAEs occurred in patients with a past psychiatric history.

Risk of Stroke and Bleeding in Atrial Fibrillation Treated with Apixaban Compared with Warfarin.

BACKGROUND: A previous FDA study reported a favorable benefit risk for apixaban compared with warfarin for stroke prevention in older non-valvular atrial fibrillation (NVAF) patients (≥ 65 years). However, it remains unclear whether this favorable benefit risk persists in other populations including younger users. We examined if a similar benefit risk was observed in the Sentinel System and if it varied by age group. OBJECTIVE: To examine the risk of ischemic stroke, gastrointestinal (GI) bleeding, and intracranial hemorrhage (ICH) in apixaban users compared with warfarin users in Sentinel Distributed Database (SDD). DESIGN AND PARTICIPANTS: A retrospective new user cohort study was conducted among patients, 21 years and older initiating apixaban and warfarin for NVAF, between December 28, 2012, and June 30, 2018, in the SDD. MAIN MEASURES: Cox proportional hazard regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI) for each outcome (ischemic stroke, GI bleeding, and ICH) in propensity score matched apixaban users compared with the warfarin users. Subgroup analyses by age (21-64, 65-74, and 75+ years) were conducted. KEY RESULTS: After matching, 55.3% and 58.4% (n = 55,038) of the apixaban and warfarin users were included in the main analysis. GI bleeding was the most common outcome. The HR (95% CI) for GI bleeding, ICH, and ischemic stroke in apixaban users compared with warfarin users were 0.57 (0.50-0.66), 0.53 (0.40-0.70), and 0.56 (0.45-0.71) respectively. The reduced risk of these outcomes in apixaban compared with warfarin users persisted across age groups. CONCLUSION: In NVAF patients of all ages initiating either apixaban or warfarin for stroke prevention in the Sentinel System, apixaban was associated with a decreased risk of GI bleeding, ICH, and ischemic stroke compared with warfarin. Among patients less than 65 years of age, apixaban use was associated with a decreased risk of GI bleeding and ischemic stroke.

Similar Breast Cancer Risk in Women Older Than 65 Years Initiating Glargine, Detemir, and NPH Insulins.

OBJECTIVE: To assess whether initiation of insulin glargine (glargine), compared with initiation of NPH or insulin detemir (detemir), was associated with an increased risk of breast cancer in women with diabetes. RESEARCH DESIGN AND METHODS: This was a retrospective new-user cohort study of female Medicare beneficiaries aged ≥65 years initiating glargine (203,159), detemir (67,012), or NPH (47,388) from September 2006 to September 2015, with follow-up through May 2017. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for incidence of breast cancer according to ever use, cumulative duration of use, cumulative dose of insulin, length of follow-up time, and a combination of dose and length of follow-up time. RESULTS: Ever use of glargine was not associated with an increased risk of breast cancer compared with NPH (HR 0.97; 95% CI 0.88-1.06) or detemir (HR 0.98; 95% CI 0.92-1.05). No increased risk was seen with glargine use compared with either NPH or detemir by duration of insulin use, length of follow-up, or cumulative dose of insulin. No increased risk of breast cancer was observed in medium- or high-dose glargine users compared with low-dose users. CONCLUSIONS: Overall, glargine use was not associated with an increased risk of breast cancer compared with NPH or detemir in female Medicare beneficiaries.

Trends and Patterns of Testosterone Therapy among U.S. Male Medicare Beneficiaries, 1999 to 2014.

PURPOSE: We explored the Medicare database (1999 to 2014) to provide a comprehensive assessment of testosterone therapy patterns in the older U.S. male population. MATERIALS AND METHODS: We estimated annual age-standardized incidence (new users) and prevalence (existing users) of testosterone therapy according to demographic characteristics, comorbidities and potential indications. RESULTS: There were 392,698 incident testosterone therapy users during 88 million person-years. Testosterone therapy users were predominantly younger, white nonHispanic, and located in South and West U.S. Census regions. On average testosterone therapy use increased dramatically during 2007 to 2014 (average annual percent change 15.5%), despite a decrease in 2014. In 2014 the most common recorded potential indications for any testosterone therapy were hypogonadism (48%), fatigue (18%), erectile dysfunction (15%), depression (4%) and psychosexual dysfunction (1%). Laboratory tests to measure circulating testosterone concentrations for testosterone therapy were infrequent with 35% having had at least 1 testosterone test in the 120 days preceding testosterone therapy, 4% the recommended 2 pre-testosterone therapy tests, and 16% at least 1 pre-testosterone therapy test and at least 1 post-testosterone therapy test. CONCLUSIONS: Testosterone therapy remains common in the older U.S. male population, despite a recent decrease. Although testosterone therapy prescriptions are predominantly for hypogonadism, a substantial proportion appear to be for less specific conditions. Testosterone tests among men prescribed testosterone therapy appear to be infrequent.

Oophorectomy and risk of non-alcoholic fatty liver disease and primary liver cancer in the Clinical Practice Research Datalink.

Incidence of non-alcoholic fatty liver disease (NAFLD) and liver cancer are 2-3 times higher in males than females. Hormonal mechanisms are hypothesized, with studies suggesting that oophorectomy may increase risk, but population-based evidence is limited. Thus, we conducted a study within the Clinical Practice Research Datalink, with controls matched to cases of NAFLD (n = 10,082 cases/40,344 controls) and liver cancer (n = 767 cases/3068 controls). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Effect measure modification by menopausal hormone therapy (MHT) was examined, using likelihood ratio tests and relative excess risk due to interaction (RERI). Oophorectomy was associated with a 29% elevated NAFLD risk (OR = 1.29, 95% CI 1.18-1.43), which was more pronounced in women without diabetes (OR = 1.41, 95% CI 1.27-1.57) and in women who had oophorectomy prior to age 50 (OR = 1.37, 95% CI 1.22-1.52). Compared to women without oophorectomy or MHT use, oophorectomy and MHT were each associated with over 50% elevated risk of NAFLD. However, the combination of oophorectomy and MHT showed evidence of a negative interaction on the multiplicative (p = 0.003) and additive scales (RERI = - 0.28, 95% CI - 0.60 to 0.03, p = 0.08). Oophorectomy, overall, was not associated with elevated liver cancer risk (OR = 1.16, 95% CI 0.79-1.69). These findings suggest that oophorectomy may increase the risk of NAFLD, but not liver cancer.