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.

Biosimilars approvals by thirteen regulatory authorities: A cross-national comparison.

Biosimilars are biological medicines highly similar to a previously licensed reference product and their licensing is expected to improve access to biological therapies. This study aims to present an overview of biosimilars approval by thirteen regulatory authorities (RA). The study is a cross-national comparison of regulatory decisions involving biosimilars in Argentina, Australia, Brazil, Chile, Canada, Colombia, Europe, Hungary, Guatemala, Italy, Mexico, Peru and United States. We examined publicly available documents containing information regarding the approval of biosimilars and investigated the publication of public assessment reports for registration applications, guidelines for biosimilars licensing, and products approved. Data extraction was conducted by a network of researchers and regulatory experts. All the RA had issued guidance documents establishing the requirements for the licensing of biosimilars. However, only three RA had published public assessment reports for registration applications. In total, the investigated jurisdictions had from 19 to 78 biosimilars approved, most of them licensed from 2018 to 2020. In spite of the advance in the number of products in recent years, some challenges still persist. Limited access to information regarding the assessment of biosimilars by RA can affect confidence, which may ultimately impact adoption of these products in practice.

Identifying COVID-19 cases and extracting patient reported symptoms from Reddit using natural language processing.

We used social media data from "covid19positive" subreddit, from 03/2020 to 03/2022 to identify COVID-19 cases and extract their reported symptoms automatically using natural language processing (NLP). We trained a Bidirectional Encoder Representations from Transformers classification model with chunking to identify COVID-19 cases; also, we developed a novel QuadArm model, which incorporates Question-answering, dual-corpus expansion, Adaptive rotation clustering, and mapping, to extract symptoms. Our classification model achieved a 91.2% accuracy for the early period (03/2020-05/2020) and was applied to the Delta (07/2021-09/2021) and Omicron (12/2021-03/2022) periods for case identification. We identified 310, 8794, and 12,094 COVID-positive authors in the three periods, respectively. The top five common symptoms extracted in the early period were coughing (57%), fever (55%), loss of sense of smell (41%), headache (40%), and sore throat (40%). During the Delta period, these symptoms remained as the top five symptoms with percent authors reporting symptoms reduced to half or fewer than the early period. During the Omicron period, loss of sense of smell was reported less while sore throat was reported more. Our study demonstrated that NLP can be used to identify COVID-19 cases accurately and extracted symptoms efficiently.

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.

Comparative Risk of Angioedema With Sacubitril-Valsartan vs Renin-Angiotensin-Aldosterone Inhibitors.

BACKGROUND: Data on angioedema risk among sacubitril-valsartan (SV) users in real-world settings are limited. OBJECTIVES: We sought to evaluate the risk of angioedema among SV new users compared with angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor-blocker (ARB) new users separately. METHODS: We conducted a propensity score-matched cohort study, comparing SV new users (no use of SV, ACE inhibitor, ARB 6 months before) and SV new users with prior use (within 183 or 14 days) of ACE inhibitor or ARB (ACE inhibitor-SV and ARB-SV users; recent ACE inhibitor-SV and recent ARB-SV users, respectively) vs ACE inhibitor and ARB new users separately. RESULTS: Compared with ACE inhibitor, SV new (HR: 0.18; 95% CI: 0.11-0.29) and ACE inhibitor-SV users (HR: 0.31; 95% CI: 0.23-0.43) showed lower risk of angioedema. On the other hand, there was no difference in angioedema risk when SV new users (HR: 0.59; 95% CI: 0.35-1.01) or ARB-SV users (HR: 0.85; 95% CI: 0.58-1.26) were compared with ARB new users. Compared with SV new users, ACE inhibitor-SV users (HR: 1.62; 95% CI: 0.91-2.89) trended toward higher angioedema risk, which intensified when the ACE inhibitor to SV switch occurred within 14 days (recent ACE inhibitor-SV) (HR: 1.98; 95% CI: 1.11-3.53). Similarly, ARB-SV users (HR: 2.03; 95% CI: 1.16-3.54) experienced an increased risk compared with SV new users, which intensified for the more recent switchers (recent ARB-SV) (HR: 2.45; 95% CI: 1.36-4.43). CONCLUSIONS: We did not observe an increased risk of angioedema among SV new users compared with ACE inhibitor or ARB users. However, there was an increased risk of angioedema among SV users who recently switched from ACE inhibitor or ARB compared with SV new users.

Social media for early characterization of pandemic symptoms: A qualitative analysis of patient-reported COVID-19 experiences.

BACKGROUND: Patients use social media forums to discuss their medical history and healthcare experiences, providing early insight into real-world patient experiences. We analyzed COVID-19 patient experiences from Reddit social media posts. METHODS: We extracted Reddit Application Programming Interface data for the subreddit/COVID-19 positive from March to August 2020 and selected users tagged as "Tested Positive" or "Tested Positive- Me" flair and who posted at least thirty times in any calendar month, excluding users who explicitly stated location outside of the U.S. For tested-positive patients (users), we created and reviewed individual case profiles summarizing their COVID-19 symptoms, testing, and medications or treatments. Data were imported to Nvivo qualitative analysis software and qualitative coding was conducted. FINDING: There were 31 759 posts and comments from 720 users in March to May 2020 (Q1) and 40 446 posts and comments from 1649 users from June to August 2020 (Q2). Final count of "Tested Positive" was 1296 users (280 in Q1 and 1016 in Q2). Across both quarters, frequently reported symptoms included sore throat, headaches, fevers, or chills. Loss of sense of smell or taste were reported by users in early March, prior to the inclusion of this symptom to the CDC list in April and GI-related symptoms and fatigue were reported in the March to May data, before they were added as a COVID-19 associated symptom in July 2020. Users also reported in-depth descriptions of their symptoms, motivations for testing, and long-term impacts such as post-viral fatigue. INTERPRETATION: Social media data can potentially serve as an early surveillance data source in a pandemic and offer preliminary insights into patient disease experiences.

A cohort study to assess risk of cutaneous small vessel vasculitis among users of different oral anticoagulants.

PURPOSE: Cutaneous small vessel vasculitis (CSVV) was identified as a safety signal among patients treated with direct oral anticoagulants (DOAC). This study aimed to determine if CSVV risk differed among patients with atrial fibrillation (Afib) who newly initiated warfarin or a DOAC. METHODS: We identified enrollees aged ≥21 years diagnosed with Afib who newly initiated rivaroxaban, dabigatran, apixaban, and warfarin in the Sentinel Distributed Database from October 19, 2010 to February 29, 2020. We selected and followed patients who did not have evidence of the following in the 183 days prior to initiating treatment: CSVV diagnosis, dispensing of other study drugs, select autoimmune diseases or autoimmune medications, cancer diagnoses or chemotherapeutic treatment, kidney dialysis or transplant, alternative anticoagulation indications, or an institutional (nursing home, hospice, hospital) stay on the treatment initiation date (index date) until CSVV outcome or pre-specified censoring. We conducted 1:1 propensity score matching in six comparisons. RESULTS: CSVV incidence rates for DOACs and warfarin ranged from 3.3 to 5.6 per 10 000-person years in our matched Afib population. The adjusted CSVV hazard ratio (HR) and 95% confidence interval (CI) was 0.94 (0.64, 1.39) for rivaroxaban versus warfarin; 1.17 (0.67, 2.06) for dabigatran vs. warfarin; 0.85 (0.62, 1.16) for apixaban vs. warfarin; 0.86 (0.49, 1.50) for rivaroxaban vs. dabigatran; 0.99 (0.68, 1.45) for rivaroxaban versus apixaban; and 1.70 (0.90, 3.21) for dabigatran versus apixaban. CONCLUSION: We did not find significant evidence of differential CSVV risk in pair-wise comparisons of DOACs and warfarin.

Risk of Covid-19-Related Hospitalization and More Severe Outcomes in Medicare Beneficiaries Treated with Renin-Angiotensin-Aldosterone System Inhibitors for Hypertension.

BACKGROUND: There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. OBJECTIVE: To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. DESIGN: Observational case-control study. PARTICIPANTS: Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. MAIN MEASURES: Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. RESULTS: A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5-12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92-0.98; OR for ARBs 0.94, 95% CI 0.90-0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04-1.14), ARBs (OR 1.10, 95% CI 1.05-1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03-1.19). CONCLUSIONS: ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding.

Risk of Severe Abnormal Uterine Bleeding Associated with Rivaroxaban Compared with Apixaban, Dabigatran and Warfarin.

INTRODUCTION: There have been reports of clinically relevant uterine bleeding events among women of reproductive age exposed to rivaroxaban. OBJECTIVE: The aim of this study was to compare the risk of severe abnormal uterine bleeding (SAUB) resulting in transfusion or surgical intervention among women on rivaroxaban versus apixaban, dabigatran and warfarin. METHODS: We conducted a retrospective cohort study in the FDA's Sentinel System (10/2010-09/2015) among females aged 18+ years with venous thromboembolism (VTE), or atrial flutter/fibrillation (AF) who newly initiated a direct oral anticoagulant (DOAC; rivaroxaban, apixaban, dabigatran) or warfarin. We followed women from dispensing date until the earliest of transfusion or surgery following vaginal bleeding, disenrollment, exposure or study end date, or recorded death. We estimated hazard ratios (HRs) using Cox proportional hazards regression via propensity score stratification. Four pairwise comparisons were conducted for each intervention. RESULTS: Overall, there was an increased risk of surgical intervention with rivaroxaban when compared with dabigatran (HR 1.19; 95% CI 1.03-1.38), apixaban (1.23; 1.04-1.47), and warfarin (1.34; 1.22-1.47). No difference in risk for surgical intervention was observed for dabigatran-apixaban comparisons. Increased risk of transfusion was observed for rivaroxaban compared with dabigatran (1.49; 1.03-2.17) only. For patients with no gynecological history, rivaroxaban was associated with risk of surgical intervention compared with dabigatran (1.22; 1.05-1.42), apixaban (1.25; 1.04-1.49), and warfarin (1.36; 1.23-1.50). CONCLUSION: Our study found increased SAUB risk with rivaroxaban use compared with other DOACs or warfarin. Increased risk with rivaroxaban was present among women without underlying gynecological conditions. Women on anticoagulant therapy should be aware of a risk of SAUB.

A Boxed Warning for Montelukast: The FDA Perspective.

The U.S. Food and Drug Administration (FDA) became aware of postmarketing reports of neuropsychiatric adverse events with Singulair (montelukast) use in 2007. Over the years, the FDA has conducted reviews of the clinical trial safety data, focused analyses of postmarketing reports, and reviews of the published literature. These activities have resulted in successive labeling updates and public communications. However, there has been continued concern among stakeholders about the risk of neuropsychiatric events and the lack of awareness among prescribers and patients/caregivers. On the basis of these concerns, the FDA embarked on another comprehensive review and also conducted a new observational study using claims data in the Sentinel Distributed Database. In September 2019, the FDA held a public Advisory Committee meeting to discuss its review and solicit recommendations from the panel regarding labeling and communication strategies. After careful consideration of the available data and feedback received during the FDA Advisory Committee meeting, the FDA required a boxed warning and a revision specifically for the allergic rhinitis indication to reserve use of montelukast to patients who have an inadequate response or intolerance to alternative therapies. Based on benefit-risk considerations, the asthma indication was not changed. To provide insight into the process and rationale for the required labeling changes, we provide an overview of the decision-making framework we used.

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.

A General Propensity Score for Signal Identification Using Tree-Based Scan Statistics.

The tree-based scan statistic (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) is a data-mining method that adjusts for multiple testing of correlated hypotheses when screening thousands of potential adverse events for signal identification. Simulation has demonstrated the promise of TreeScan with a propensity score (PS)-matched cohort design. However, it is unclear which variables to include in a PS for applied signal identification studies to simultaneously adjust for confounding across potential outcomes. We selected 4 pairs of medications with well-understood safety profiles. For each pair, we evaluated 5 candidate PSs with different combinations of 1) predefined general covariates (comorbidity, frailty, utilization), 2) empirically selected (data-driven) covariates, and 3) covariates tailored to the drug pair. For each pair, statistical alerting patterns were similar with alternative PSs (≤11 alerts in 7,996 outcomes scanned). Inclusion of covariates tailored to exposure did not appreciably affect screening results. Inclusion of empirically selected covariates can provide better proxy coverage for confounders but can also decrease statistical power. Unlike tailored covariates, empirical and predefined general covariates can be applied "out of the box" for signal identification. The choice of PS depends on the level of concern about residual confounding versus loss of power. Potential signals should be followed by pharmacoepidemiologic assessment where confounding control is tailored to the specific outcome(s) under investigation.

Risk of serious spinal adverse events associated with epidural corticosteroid injections in the Medicare population.

BACKGROUND: Epidural corticosteroid injections (ESIs) are widely performed and have an unquantified risk of serious spinal adverse events (SSAEs). We sought to determine the rate of SSAEs following ESI and to compare the rates by spinal level, injection approach and corticosteroid formulation. METHODS: We included patients enrolled in Medicare parts A and B who had an ESI between 1 January 2009 and 30 September 2015. We identified potential cases as patients with spine-related diagnoses within 3 days after the first eligible ESI. Event categorization as probable, possible or non-case was based on review of medical records. The rates of probable and possible cases were expressed per 1 000 000 patients overall, and by spinal level, injection approach and corticosteroid formulation. A score test was used to compare these rates. RESULTS: We identified 1 355 957 eligible ESIs during the study period. Of the 110 potential cases, 43 were selected for medical record review and 11 were categorized as probable, yielding a rate of 8.1 per 1 000 000 patients (95% CI 4.5 to 14.5). Risk of SSAEs was statistically higher with cervical/thoracic injections (29.4, 95% CI 12.5 to 68.8) compared with lumbar/sacral injections (5.1, 95% CI 2.3 to 11.0) (p value 0.001). Event rates for lumbar/sacral non-transforaminal injections was 8.8 (95% CI 4.0 to 19.1). Event rates for particulate (7.5, 95% CI 3.9 to 14.2) and non-particulate formulations (13.1, 95% CI 3.6 to 47.9) appeared similar (p value 0.47). CONCLUSION: Between 2009 and 2015, rates of SSAEs following ESI in the Medicare population were low. Patients receiving cervical/thoracic ESIs were at higher risk of SSAE than those receiving lumbar/sacral ESIs. Event rates were similar for each corticosteroid formulation.

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.

Complementary Use of U.S. FDA's Adverse Event Reporting System and Sentinel System to Characterize Direct Oral Anticoagulants-Associated Cutaneous Small Vessel Vasculitis.

BACKGROUND: Cutaneous small vessel vasculitis (CSVV) has been reported after exposure to direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban. OBJECTIVE: We used the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to describe clinical characteristics associated with CSVV among DOAC-exposed patients. Furthermore, we characterized this signal in the Sentinel System to relate the clinical data from the individual FAERS cases to population-based electronic healthcare data. METHODS: We queried FAERS for all cases of CSVV associated with DOACs from U.S. approval date of each DOAC through March 16, 2018. Within the Sentinel System, we identified incident CSVV cases using ICD-9 and ICD-10 diagnosis codes among adults aged ≥ 30 years who received a DOAC in the prior 90 days between January 1, 2010, and June 30, 2018. We excluded patients with evidence of select autoimmune diagnoses in the 183 days prior to their CSVV diagnoses and reported patient characteristics in the 183-day period prior to CSVV diagnoses. RESULTS: In FAERS, we identified 50 cases of CSVV reported with rivaroxaban (n=26), apixaban (n=14), dabigatran (n=9), and edoxaban (n=1). Approximately 50% of the cases reported time to onset within 10 days after DOAC exposure. When specified, the predominant type of CSVV reported was leukocytoclastic vasculitis (n=31), followed by Henoch-Schonlein purpura (n=4). Hospitalization occurred in most of the cases (n=37). Switching of the offending agent after the development of CSVV was reported (n=26). Three rivaroxaban (n=3) cases and one dabigatran case (n=1) reported positive rechallenge. In the Sentinel system, we identified 3659 CSVV cases with prior DOAC exposure, with 85% of events occurring within 10 days. CONCLUSIONS: The assessment of FAERS cases, combined with the temporal clustering of the Sentinel System cases suggest a possible causal relationship of DOACs and CSVV. Future efforts should characterize the risk of CSVV among the various DOAC users.