Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis.

BACKGROUND: Antitumor necrosis factor (anti-TNF) inhibitors are first-line treatment among patients with ulcerative colitis (UC). With time, patients tend to lose response or become intolerant, necessitating switching to small cell biologics such as tofacitinib or vedolizumab. In this real-world study of a large, geographically diverse US population of TNF-experienced patients with UC, we evaluated the effectiveness and safety of newly initiating treatment with tofacitinib vs vedolizumab. METHODS: We conducted a cohort study using secondary data from a large US insurer (Anthem, Inc.). Our cohort included patients with UC newly initiating treatment with tofacitinib or vedolizumab. Patients were required to have evidence of treatment with anti-TNF inhibitors in the 6 months prior to cohort entry. The primary outcome was treatment persistence >52 weeks. Additionally, we evaluated the following secondary outcomes as additional measures of effectiveness and safety: (1) all-cause hospitalization; (2) total abdominal colectomy; (3) hospitalization for infection; (4) hospitalization for malignancy; (5) hospitalization for cardiac events; and (6) hospitalization for thromboembolic events. We used fine stratification by propensity scores to control for confounding by demographics, clinical factors, and treatment history at baseline. RESULTS: Our primary cohort included 168 new users of tofacitinib and 568 new users of vedolizumab. Tofacitinib was associated with lower treatment persistence (adjusted risked ratio, 0.77; 95% CI, 0.60 -0.99). Differences in secondary measures of effectiveness or safety between tofacitinib initiators vs vedolizumab initiators were not statistically significant (all-cause hospitalization, adjusted hazard ratio, 1.23; 95% CI, 0.83-1.84; total abdominal colectomy, adjusted HR, 1.79; 95% CI, 0.93-3.44;and hospitalization for any infection, adjusted HR, 1.94; 95% CI, 0.83-4.52). DISCUSSION: Ulcerative colitis patients with prior anti-TNF experience initiating tofacitinib demonstrated lower treatment persistence compared with those initiating vedolizumab. This finding is in contrast to other recent studies suggesting superior effectiveness of tofacitinib. Ultimately, head-to-head randomized, controlled trials that focus on directly measured end points may be needed to best inform clinical practice.

Anti-TNF-experienced patients with UC initiating vedolizumab demonstrated higher treatment persistence compared with those initiating tofacitinib in this real-world evaluation of comparative effectiveness. Ultimately, head-to-head randomized trials that focus on directly measured end points are needed to best inform clinical practice.

Corticosteroids but not Anti-TNF Are Associated With Increased COVID-19 Complications in Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Immunosuppressed individuals are at higher risk for COVID-19 complications, yet data in patients with inflammatory bowel disease (IBD) are limited. We evaluated the risk of COVID-19- severe sequelae by medication utilization in a large cohort of patients with IBD. METHODS: We conducted a retrospective cohort study utilizing insurance claims data between August 31, 2019, and August 31, 2021.We included IBD patients identified by diagnosis and treatment codes. Use of IBD medications was defined in the 90 days prior to cohort entry. Study outcomes included COVID-19 hospitalization, mechanical ventilation, and inpatient death. Patients were followed until the outcome of interest, outpatient death, disenrollment, or end of study period. Due to the aggregate nature of available data, we were unable to perform multivariate analyses. RESULTS: We included 102 986 patients (48 728 CD, 47 592 UC) with a mean age of 53 years; 55% were female. Overall, 412 (0.4%) patients were hospitalized with COVID-19. The incidence of hospitalization was higher in those on corticosteroids (0.6% vs 0.3%; P < .0001; 13.6 per 1000 person-years; 95% confidence interval [CI], 10.8-16.9) and lower in those receiving anti-tumor necrosis factor α therapy (0.2% vs 0.5%; P < .0001; 3.9 per 1000 person-years; 95% CI, 2.7-5.4). Older age was associated with increased hospitalization with COVID-19. Overall, 71 (0.07%) patients required mechanical ventilation and 52 (0.05%) died at the hospital with COVID-19. The proportion requiring mechanical ventilation (1.9% vs 0.05%; P < .0001; 3.9 per 1000 person-years; 95% CI, 2.5-5.9) was higher among users of corticosteroids. CONCLUSIONS: Among patients with IBD, those on corticosteroids had more hospitalizations and mechanical ventilation with COVID-19. Anti-tumor necrosis factor α therapy was associated with a decreased risk of hospitalization. These findings reinforce previous guidance to taper and/or discontinue corticosteroids in IBD.

Risk of admission to hospital with arterial or venous thromboembolism among patients diagnosed in the ambulatory setting with covid-19 compared with influenza: retrospective cohort study.

Objective: To measure the 90 day risk of arterial thromboembolism and venous thromboembolism among patients diagnosed with covid-19 in the ambulatory (ie, outpatient, emergency department, or institutional) setting during periods before and during covid-19 vaccine availability and compare results to patients with ambulatory diagnosed influenza. Design: Retrospective cohort study. Setting: Four integrated health systems and two national health insurers in the US Food and Drug Administration's Sentinel System. Participants: Patients with ambulatory diagnosed covid-19 when vaccines were unavailable in the US (period 1, 1 April-30 November 2020; n=272 065) and when vaccines were available in the US (period 2, 1 December 2020-31 May 2021; n=342 103), and patients with ambulatory diagnosed influenza (1 October 2018-30 April 2019; n=118 618). Main outcome measures: Arterial thromboembolism (hospital diagnosis of acute myocardial infarction or ischemic stroke) and venous thromboembolism (hospital diagnosis of acute deep venous thrombosis or pulmonary embolism) within 90 days after ambulatory covid-19 or influenza diagnosis. We developed propensity scores to account for differences between the cohorts and used weighted Cox regression to estimate adjusted hazard ratios of outcomes with 95% confidence intervals for covid-19 during periods 1 and 2 versus influenza. Results: 90 day absolute risk of arterial thromboembolism with covid-19 was 1.01% (95% confidence interval 0.97% to 1.05%) during period 1, 1.06% (1.03% to 1.10%) during period 2, and with influenza was 0.45% (0.41% to 0.49%). The risk of arterial thromboembolism was higher for patients with covid-19 during period 1 (adjusted hazard ratio 1.53 (95% confidence interval 1.38 to 1.69)) and period 2 (1.69 (1.53 to 1.86)) than for patients with influenza. 90 day absolute risk of venous thromboembolism with covid-19 was 0.73% (0.70% to 0.77%) during period 1, 0.88% (0.84 to 0.91%) during period 2, and with influenza was 0.18% (0.16% to 0.21%). Risk of venous thromboembolism was higher with covid-19 during period 1 (adjusted hazard ratio 2.86 (2.46 to 3.32)) and period 2 (3.56 (3.08 to 4.12)) than with influenza. Conclusions: Patients diagnosed with covid-19 in the ambulatory setting had a higher 90 day risk of admission to hospital with arterial thromboembolism and venous thromboembolism both before and after covid-19 vaccine availability compared with patients with influenza.

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.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

INTRODUCTION: Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. METHODS: We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. RESULTS: Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). DISCUSSION: This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Association of COVID-19 vs Influenza With Risk of Arterial and Venous Thrombotic Events Among Hospitalized Patients.

Importance: The incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 remains unclear. Objective: To measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability vs patients hospitalized with influenza. Design, Setting, and Participants: Retrospective cohort study of 41 443 patients hospitalized with COVID-19 before vaccine availability (April-November 2020), 44 194 patients hospitalized with COVID-19 during vaccine availability (December 2020-May 2021), and 8269 patients hospitalized with influenza (October 2018-April 2019) in the US Food and Drug Administration Sentinel System (data from 2 national health insurers and 4 regional integrated health systems). Exposures: COVID-19 or influenza (identified by hospital diagnosis or nucleic acid test). Main Outcomes and Measures: Hospital diagnosis of arterial thromboembolism (acute myocardial infarction or ischemic stroke) and venous thromboembolism (deep vein thrombosis or pulmonary embolism) within 90 days. Outcomes were ascertained through July 2019 for patients with influenza and through August 2021 for patients with COVID-19. Propensity scores with fine stratification were developed to account for differences between the influenza and COVID-19 cohorts. Weighted Cox regression was used to estimate the adjusted hazard ratios (HRs) for outcomes during each COVID-19 vaccine availability period vs the influenza period. Results: A total of 85 637 patients with COVID-19 (mean age, 72 [SD, 13.0] years; 50.5% were male) and 8269 with influenza (mean age, 72 [SD, 13.3] years; 45.0% were male) were included. The 90-day absolute risk of arterial thromboembolism was 14.4% (95% CI, 13.6%-15.2%) in patients with influenza vs 15.8% (95% CI, 15.5%-16.2%) in patients with COVID-19 before vaccine availability (risk difference, 1.4% [95% CI, 1.0%-2.3%]) and 16.3% (95% CI, 16.0%-16.6%) in patients with COVID-19 during vaccine availability (risk difference, 1.9% [95% CI, 1.1%-2.7%]). Compared with patients with influenza, the risk of arterial thromboembolism was not significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.04 [95% CI, 0.97-1.11]) or during vaccine availability (adjusted HR, 1.07 [95% CI, 1.00-1.14]). The 90-day absolute risk of venous thromboembolism was 5.3% (95% CI, 4.9%-5.8%) in patients with influenza vs 9.5% (95% CI, 9.2%-9.7%) in patients with COVID-19 before vaccine availability (risk difference, 4.1% [95% CI, 3.6%-4.7%]) and 10.9% (95% CI, 10.6%-11.1%) in patients with COVID-19 during vaccine availability (risk difference, 5.5% [95% CI, 5.0%-6.1%]). Compared with patients with influenza, the risk of venous thromboembolism was significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.60 [95% CI, 1.43-1.79]) and during vaccine availability (adjusted HR, 1.89 [95% CI, 1.68-2.12]). Conclusions and Relevance: Based on data from a US public health surveillance system, hospitalization with COVID-19 before and during vaccine availability, vs hospitalization with influenza in 2018-2019, was significantly associated with a higher risk of venous thromboembolism within 90 days, but there was no significant difference in the risk of arterial thromboembolism within 90 days.

Validation of diagnosis codes to identify hospitalized COVID-19 patients in health care claims data.

PURPOSE: Health plan claims may provide complete longitudinal data for timely, real-world population-level COVID-19 assessment. However, these data often lack laboratory results, the standard for COVID-19 diagnosis. METHODS: We assessed the validity of ICD-10-CM diagnosis codes for identifying patients hospitalized with COVID-19 in U.S. claims databases, compared to linked laboratory results, among six Food and Drug Administration Sentinel System data partners (two large national insurers, four integrated delivery systems) from February 20-October 17, 2020. We identified patients hospitalized with COVID-19 according to five ICD-10-CM diagnosis code-based algorithms, which included combinations of codes U07.1, B97.29, general coronavirus codes, and diagnosis codes for severe symptoms. We calculated the positive predictive value (PPV) and sensitivity of each algorithm relative to laboratory test results. We stratified results by data source type and across three time periods: February 20-March 31 (Time A), April 1-30 (Time B), May 1-October 17 (Time C). RESULTS: The five algorithms identified between 34 806 and 47 293 patients across the study periods; 23% with known laboratory results contributed to PPV calculations. PPVs were high and similar across algorithms. PPV of U07.1 alone was stable around 93% for integrated delivery systems, but declined over time from 93% to 70% among national insurers. Overall PPV of U07.1 across all data partners was 94.1% (95% CI, 92.3%-95.5%) in Time A and 81.2% (95% CI, 80.1%-82.2%) in Time C. Sensitivity was consistent across algorithms and over time, at 94.9% (95% CI, 94.2%-95.5%). CONCLUSION: Our results support the use of code U07.1 to identify hospitalized COVID-19 patients in U.S. claims data.

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.

Validation of an electronic algorithm for Hodgkin and non-Hodgkin lymphoma in ICD-10-CM.

PURPOSE: Lymphoma is a health outcome of interest for drug safety studies. Studies using administrative claims data require the accurate identification of lymphoma cases. We developed and validated an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM)-based algorithm to identify lymphoma in healthcare claims data. METHODS: We developed a three-component algorithm to identify patients aged ≥15 years who were newly diagnosed with Hodgkin (HL) or non-Hodgkin (NHL) lymphoma from January 2016 through July 2018 among members of four Data Partners within the FDA's Sentinel System. The algorithm identified potential cases as patients with ≥2 ICD-10-CM lymphoma diagnosis codes on different dates within 183 days; ≥1 procedure code for a diagnostic procedure (e.g., biopsy, flow cytometry) and ≥1 procedure code for a relevant imaging study within 90 days of the first lymphoma diagnosis code. Cases identified by the algorithm were adjudicated via chart review and a positive predictive value (PPV) was calculated. RESULTS: We identified 8723 potential lymphoma cases via the algorithm and randomly sampled 213 for validation. We retrieved 138 charts (65%) and adjudicated 134 (63%). The overall PPV was 77% (95% confidence interval: 69%-84%). Most cases also had subtype information available, with 88% of cases identified as NHL and 11% as HL. CONCLUSIONS: Seventy-seven percent of lymphoma cases identified by an algorithm based on ICD-10-CM diagnosis and procedure codes and applied to claims data were true cases. This novel algorithm represents an efficient, cost-effective way to target an important health outcome of interest for large-scale drug safety and public health surveillance studies.

Translating claims-based CHA2 DS2 -VaSc and HAS-BLED to ICD-10-CM: Impacts of mapping strategies.

PURPOSE: The CHA2 DS2 -VaSc and HAS-BLED risk scores are commonly used in the studies of oral anticoagulants (OACs). The best ways to map these scores to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes is unclear, as is how they perform in various types of OAC users. We aimed to assess the distributions of CHA2 DS2 -VaSc and HAS-BLED scores and C-statistics for outcome prediction in the ICD-10-CM era using different mapping strategies. METHODS: We compared the distributions of CHA2 DS2 -VaSc and HAS-BLED scores from various mapping strategies in atrial fibrillation patients before, during, and after ICD-10-CM transition. We estimated the C-statistics predicting the 90-day risk of hospitalized stroke (for CHA2 DS2 -VaSc) or hospitalized bleeding (for HAS-BLED) in patients identified at least 6 months after the ICD-10-CM transition, overall and by anticoagulant type. RESULTS: Forward-backward mapping produced higher CHA2 DS2 -VaSc and HAS-BLED scores in the ICD-10-CM era compared to the ICD-9-CM era: the mean difference was 0.074 (95% confidence interval 0.064-0.085) for CHA2 DS2 -VaSc and 0.055 (0.048-0.062) for HAS-BLED. Both scores had higher C-statistics in patients taking no OACs (0.697 [0.677-0.717] for CHA2 DS2 -VaSc; 0.719 [0.702-0.737] for HAS-BLED) or direct OACs (0.695 [0.654-0.735] for CHA2 DS2 -VaSc; 0.700 [0.673-0.728] for HAS-BLED) than those taking warfarin (0.655 [0.613-0.697] for CHA2 DS2 -VaSc; 0.663 [0.6320.695] for HAS-BLED). CONCLUSIONS: Existing mapping strategies generally preserved the distributions of CHA2 DS2 -VaSc and HAS-BLED scores after ICD-10-CM transition. Both scores performed better in patients on no OACs or direct OACs than patients on warfarin.

Quantifying how small variations in design elements affect risk in an incident cohort study in claims.

BACKGROUND: Epidemiological study reporting is improving but is not transparent enough for easy evaluation or replication. One barrier is insufficient details about design elements in published studies. METHODS: Using a previously conducted drug safety evaluation in claims as a test case, we investigated the impact of small changes in five key design elements on risk estimation. These elements are index day of incident exposure's determination of look-back or follow-up periods, exposure duration algorithms, heparin exposure exclusion, propensity score model variables, and Cox proportional hazard model stratification. We covaried these elements using a fractional factorial design, resulting in 24 risk estimates for one outcome. We repeated eight of these combinations for two additional outcomes. We measured design effects on cohort sizes, follow-up time, and risk estimates. RESULTS: Small changes in specifications of index day and exposure algorithm affected the risk estimation process the most. They affected cohort size on average by 8 to 10%, follow-up time by up to 31%, and magnitude of log hazard ratios by up to 0.22. Other elements affected cohort before matching or risk estimate's precision but not its magnitude. Any change in design substantially altered the matched control-group subjects in 1:1 matching. CONCLUSIONS: Exposure-related design elements require attention from investigators initiating, evaluating, or wishing to replicate a study or from analysts standardizing definitions. The methods we developed, using factorial design and mapping design effect on causal estimation process, are applicable to planning of sensitivity analyses in similar studies.

Evaluation of the US Food and Drug Administration Sentinel Analysis Tools Using a Comparator with a Different Indication: Comparing the Rates of Gastrointestinal Bleeding in Warfarin and Statin Users.

BACKGROUND: The US Food and Drug Administration's Sentinel System was established to monitor safety of regulated medical products. Sentinel investigators identified known associations between drugs and adverse events to test reusable analytic tools developed for Sentinel. This test case used a comparator with a different indication. OBJECTIVE: We tested the ability of Sentinel's reusable analytic tools to identify the known association between warfarin and gastrointestinal bleeding (GIB). Statins, expected to have no effect on GIB, were the comparator. We further explored the impact of analytic features, including matching ratio and stratifying Cox regression analyses, on matched pairs. METHODS: This evaluation included data from 14 Sentinel Data Partners. New users of warfarin and statins, aged 18 years and older, who had not received other anticoagulants or had recent GIB were matched on propensity score using 1:1 and 1:n variable ratio matching, matching statin users with warfarin users to estimate the average treatment effect in warfarin-treated patients. We compared the risk of GIB using Cox proportional hazards regression, following patients for the duration of their observed continuous treatment or until a GIB. For the 1:1 matched cohort, we conducted analyses with and without stratification on matched pair. The variable ratio matched cohort analysis was stratified on the matched set. RESULTS: We identified 141,398 new users of warfarin and 2,275,694 new users of statins. In analyses stratified on matched pair/set, the hazard ratios (HR) for GIB in warfarin users compared with statin users were 2.78 (95% confidence interval [CI] 2.36-3.28) in the 1:1 matched cohort and 3.10 (95% CI 2.76-3.49) in the variable ratio matched cohort. The HR was lower in the analysis of the 1:1 matched cohort not stratified by matched pair (2.22, 95% CI 1.97-2.49), and highest early in treatment. Follow-up for warfarin users tended to be shorter than for statin users. CONCLUSIONS: This study identified the expected GIB risk with warfarin compared with statins using an analytic tool developed for Sentinel. Our findings suggest that comparators with different indications may be useful in surveillance in select circumstances. Finally, in the presence of differential censoring, stratification by matched pair may reduce the potential for bias in Cox regression analyses.

Erratum: "A Case-Control Study of Maternal Polybrominated Diphenyl Ether (PBDE) Exposure and Cryptorchidism in Canadian Populations".

[This corrects the article DOI: 10.1289/EHP522.].

Malignant Endometrial Polyps in Uterine Serous Carcinoma: The Prognostic Value of Polyp Size and Lymphovascular Invasion.

OBJECTIVES: Uterine serous carcinoma (USC) involving an endometrial polyp and concurrent extrauterine disease is associated with poor prognosis. We examined the clinicopathological profiles of patients with stage 1A USC with and without polyp involvement and the role of polyp size and lymphovascular invasion (LVI) as prognostic indicators for extrauterine disease in patients with early USC. METHODS/MATERIALS: From 2002 to 2014, 242 patients with pure USC were identified. Fisher exact test was used for categorical variables. The student t test was used for means. Logistic regression was used to compute the odds ratio for continuous and categorical variables. RESULTS: Among stage 1A patients, the odds ratio of developing extrauterine disease for every 1 cm increase in polyp size is 1.368 (95% confidence interval, 1.034-1.810). Polyp size is only significantly associated with advanced stage disease for patients with myometrial invasion. A higher percent of LVI was found in stage 4 patients (31%). There is no survival or recurrence difference for stage 1 patients regardless of treatment or observation. CONCLUSIONS: Polyp size does not predict extrauterine disease for USC patients with disease in polyp only or disease in polyp and endometrium. Further study is needed to investigate whether presence of LVI is a prognostic factor.

A Case-Control Study of Maternal Polybrominated Diphenyl Ether (PBDE) Exposure and Cryptorchidism in Canadian Populations.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are flame retardants found in North American household products during the past four decades. These chemicals leach out in dust as products age, exposing individuals daily through inhalation and ingestion. Animal studies suggest that PBDEs disrupt sex hormones and adversely affect development of the reproductive system. OBJECTIVES: In the present study, we examined whether there is a link between maternal hair PBDE concentrations and the risk of cryptorchidism (undescended testes) in male infants; testis descent is known to be dependent on androgens. METHODS: Full-term male infants were recruited through clinics in Montreal, Toronto, and London, Canada. Boys with cryptorchidism at 3-18 months of age (n=137) were identified by pediatric urologists and surgeons; similar-aged controls (n=158) had no genitourinary abnormalities as assessed by pediatricians. Eight BDE congeners (BDE-28, -47, -99, -100, -153, -154, -183, -209) were measured by GC-MS (gas chromatography-mass spectrometry) in maternal hair samples collected at the time of recruitment. RESULTS: The ∑PBDE geometric mean for maternal hair was 45.35 pg/mg for controls and 50.27 pg/mg for cases; the concentrations of three BDEs (BDE-99, -100, and -154) were significantly higher in cases than controls in unadjusted models. In adjusted models, every 10-fold increase in the concentration of maternal hair BDE-99 [OR=2.53 (95% CI: 1.29, 4.95) or BDE-100 [OR=2.45 (95% CI: 1.31, 4.56)] was associated with more than a doubling in the risk of cryptorchidism. BDE-154 [OR=1.88 (95% CI: 1.08, 3.28) was also significant. CONCLUSIONS: Our results suggest that maternal exposure to BDE-99, -100, and -154 may be associated with abnormal migration of testes in the male fetus. This may be due to the anti-androgenic properties of the PBDEs. https://doi.org/10.1289/EHP522.

The risk of nerve injury during anatomical and reverse total shoulder arthroplasty: an intraoperative neuromonitoring study.

BACKGROUND: This study compared the incidence and pattern of potential nerve injuries between reverse shoulder (RSA) and total shoulder arthroplasty (TSA) using intraoperative neuromonitoring. Our hypothesis was that RSA has a greater risk of nerve injury than TSA due to arm lengthening. METHODS: We reviewed 36 consecutive patients who underwent RSA (n = 12) or TSA (n = 24) with intraoperative neuromonitoring. The number of nerve alerts was recorded for each stage of surgery. Neurologic function was assessed preoperatively and postoperatively at routine follow-up visits. Predictive factors for increased intraoperative nerve alerts and clinically detectable neurologic deficits were determined. RESULTS: There were nearly 5 times as many postreduction nerve alerts per patient in the RSA cohort compared with the TSA cohort (2.17 vs. 0.46). There were 17 unresolved nerve alerts postoperatively, with only 2 clinically detectable nerve injuries, which fully resolved by 6 months postoperatively. A preoperative decrease in active forward flexion and the diagnosis of rotator cuff arthropathy were independent predictors of intraoperative nerve alerts. CONCLUSION: RSA has a higher incidence of intraoperative nerve alerts than TSA during the postreduction stage due to arm lengthening. Decreased preoperative active forward flexion and the diagnosis of rotator cuff arthropathy are predictors of more nerve alerts. The clinical utility of routine intraoperative nerve monitoring remains in question given the high level of nerve alerts and lack of persistent postoperative neurologic deficits.