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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.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 for52 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.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]).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.

Background: Spironolactone is a mineralocorticoid receptor antagonist indicated for the management of heart failure with reduced ejection fraction (HFrEF). In a previous clinical trial, spironolactone significantly lowered the incidence of heart failure (HF) hospitalizations among HF patients with preserved ejection fraction (HFpEF). Real world utilization of spironolactone in HFrEF and HFpEF is unknown. Methods: We conducted a retrospective cohort study using data from FDA’s Sentinel System. We identified patients with HFrEF or HFpEF using diagnosis and procedure codes from a previously validated algorithm. We required patients to be continuously enrolled in the 183 days prior to HF diagnosis. Follow-up started on the day of HF diagnosis and ended at the earliest occurrence of a spironolactone dispensing, disenrollment, death, or end of data. We calculated the proportion of spironolactone utilization, and for those initiating treatment, we estimated the dose and duration of the first continuous treatment episode. Results: Among 2,009,529 HFrEF patients, 57.8% were male, and mean age was 73.8 ± 12.1 years. Among 9,257,514 HFpEF patients, 42.7% were male, and mean age was 73.0 ± 12.1 years. The proportion of spironolactone utilization following HFrEF diagnosis was 20.7% versus 7.6% after HFpEF. The median time (days) to initiation of spironolactone after HFrEF diagnosis was 90 (IQR: 19–385) versus 286 (IQR: 57–851) after HFpEF diagnosis. The median duration (days) of first treatment episode in HFrEF patients was 120 (IQR: 44–321) and 114 (IQR: 32–301) for HFpEF patients. The median dose was similar (25 mg/day) for both HF cohorts. Conclusion: Findings of low real-world utilization of spironolactone from our large, geographically, and demographically diverse multi-site study in the US are consistent with reports from smaller studies in the literature. Similar spironolactone dosing and duration were observed in both the HFpEF and HFrEF cohorts. Future research characterizing spironolactone treated and untreated HFpEF cohorts will be needed to identify treatment gaps.

Several commonly used immune-suppressing biologic drugs target proteins and cytokines involved in myeloma pathogenesis. Our objective was to determine whether targeted biologic disease-modifying antirheumatic drugs (DMARDs) are associated with risk of multiple myeloma (MM). We conducted a nested case-control study within a retrospective cohort of 56,886 commercially insured adults undergoing treatment for rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis between 2009 and 2015 using the Truven Health MarketScan Databases. MM cases (n = 287) were matched to up to 10 controls (n = 2,760) on age, sex and rheumatologic indication using incidence density sampling without replacement. Our exposures of interest were biologic DMARDs targeting tumor necrosis factor-alpha, interleukin 6, cytotoxic t-lymphocyte-associated protein-4 and depletion of B cells. Relative risks were estimated as adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. Cases and controls were similar with respect to use of prescription NSAIDs and concurrent conventional-synthetic DMARDs. Cases had slightly fewer etanercept users (4% vs. 7%) and slightly more tocilizumab users (1.4% vs. 0.4%). Compared to patients treated with only conventional-synthetic DMARDs, those receiving concomitant conventional-synthetic plus biologic DMARDs had lower risk of developing MM (OR = 0.48; 95% CI 0.30-0.88; p = 0.02). Risks differed by drug target with an inverse association observed with use of etanercept inhibiting tumor necrosis factor-alpha (OR = 0.55; 95% CI 0.30-1.02; p = 0.06) and a positive association with tocilizumab inhibiting interleukin-6 (OR = 4.33; 95% CI 1.33-14.19; p = 0.02) compared to biologic DMARD-naïve patients. Further investigation is warranted to understand the roles of drugs suppressing tumor necrosis factor-alpha and interleukin-6 in myeloma pathogenesis.

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post‐market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID‐19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID‐19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi‐pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID‐19, validated a diagnosis‐code based algorithm for identifying patients with COVID‐19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID‐19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID‐19 prevention and treatment.

The Sentinel System is a national electronic postmarketing resource established by the US Food and Drug Administration to support assessment of the safety and effectiveness of marketed medical products. It has built a large, multi-institutional, distributed data network that contains comprehensive electronic health data, covering about 700 million person-years of longitudinal observation time nationwide. With its sophisticated infrastructure and a large selection of flexible analytic tools, the Sentinel System permits rapid and secure analyses, while preserving patient privacy and health-system autonomy. The Sentinel System also offers enhanced capabilities, including accessing full-text medical records, supporting randomized clinical trials embedded in healthcare delivery systems, and facilitating effective collection of patient-reported data using mobile devices, among many other research programs. The nephrology research community can use the infrastructure, tools, and data that this national resource offers for evidence generation. This review summarizes the Sentinel System and its ability to rapidly generate high-quality, real-world evidence; discusses the program's experience in, and potential for, addressing gaps in kidney care; and outlines avenues for conducting research, leveraging this national resource in collaboration with Sentinel investigators.

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.

PURPOSE Studies examining the association between use of oseltamivir and neuropsychiatric events (including suicide) among children have had mixed findings and have been limited by small sample size, reliance on older data, and potential confounding. We undertook an analysis that addresses these limitations. METHODS Using a national administrative claims database and a case-crossover design that minimized confounding, we analyzed data from 5 contemporary influenza seasons (2009–2013) for individuals aged 1 to 18 years and ascertained oseltamivir exposure from pharmacy dispensing. RESULTS We identified 21,407 suicide-related events during this study period, 251 of which were in oseltamivir-exposed children. In case-crossover analysis, we did not find any significant association with suicide either for oseltamivir exposure (odds ratio = 0.64; 95% CI, 0.39–1.00; P = .05) or for influenza diagnosis alone (odds ratio = 0.63; 95% CI, 0.34–1.08; P = .10). CONCLUSION Our findings suggest that oseltamivir does not increase risk of suicide in the pediatric population.

STUDY OBJECTIVE Bevacizumab is used in the treatment of recurrent glioblastoma, but evidence is limited on the incidence of thromboembolic complications regarding the use of this drug in real-world settings. We evaluated the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) associated with the use of bevacizumab among adults diagnosed with high-grade gliomas in a commercially insured U.S. POPULATION DESIGN Nested case-control study. DATA SOURCE Truven Health MarketScan Commercial and Medicare Supplemental health claims databases (2009-2015). PATIENTS A total of 2157 patients with high-grade gliomas who underwent incident (first-time) craniotomy, radiation, and concurrent temozolomide treatment between 2009 and 2015 were identified. Overall, 25 cases of ATE and 99 cases of VTE were each identified in this cohort, and each case was matched to up to 10 controls (170 for ATE and 819 for VTE) based on sex, age, quarter year of index time, and follow-up duration by using incidence density sampling without replacement from the overall cohort. Controls were at risk for the outcome of interest (ATE or VTE) at the time of case occurrence and survived at least as long as their referent case. MEASUREMENTS AND MAIN RESULTS Exposure to bevacizumab was determined during inpatient or outpatient encounters between the index date (date of the incident craniotomy) and the ATE or VTE event or corresponding matched control date. Multivariable conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of ATE and VTE separately. A higher proportion of patients with ATE received bevacizumab compared with controls (28% vs 17%; adjusted OR 1.51, 95% CI 0.54-4.24), but this excess in odds was not statistically significant. Similarly, bevacizumab was not significantly associated with VTE (13% vs 9%; adjusted OR 1.40, 95% CI 0.71-2.75). CONCLUSION We found no significant association between the use of bevacizumab and the occurrence of thromboembolic events in patients with high-grade gliomas, although our study was limited by the small number of ATE events. Because the potential for complications from arterial thrombosis cannot be completely ruled out, further research is needed to confirm the thromboembolic safety of bevacizumab in a larger sample of patients with high-grade gliomas.

Purpose To determine the risk of fractures associated with sodium-glucose co-transporter 2 inhibitors (SGLT2i) compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Methods We conducted a retrospective cohort study using data from the Truven Health MarketScan (2009-2015) databases. Our cohort included patients newly initiating treatment with SGLT2i or DPP-4i between 1 April 2013 and 31 March 2015 that were matched 1:1 using high dimensional propensity scores. Patients were followed up in an as-treated approach starting from initiation of treatment until the earliest of any fracture, treatment discontinuation, disenrollment, or end of data (31 December 2015). Risk of fractures was determined at any time during the follow-up, early in therapy (1-14 days of the follow-up), and later in therapy (15 days and beyond). Cox proportional hazards models were used to determine hazard ratios and robust 95% confidence intervals (95% CI). Results After matching, our cohort included 30 549 patients in each treatment group. Over a median follow-up of 219 days, there were 745 fractures overall. The most common site for fractures was the foot (32.7%). The effect estimates for fracture risk occurring at any time during follow-up, early in therapy, and later in therapy were HR 1.11 [95% CI 0.96-1.28], HR 1.82 [95% CI 0.99-3.32], and HR 1.07 [95% CI 0.92-1.24], respectively. Conclusion There is a possible increase in risk for fractures early in therapy with SGLT2i. Beyond this initial period, SGLT2is had no apparent effect on the incidence of fractures.

Aims To determine the risk of mycotic infections associated with the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in a real-world setting. Methods We conducted a prescription sequence symmetry analysis using data from Truven Health MarketScan (2009-2015). We selected continuously enrolled patients newly initiating both an SGLT2i and an antifungal between 1 April 2013 and 31 December 2015 within time periods of 30, 60, 90, 180 or 365 days of each other. Adjusted sequence ratios (ASR) were calculated for each time period as the ratio of patients initiating SGLT2i first over those initiating an antifungal first adjusted for time trends in prescribing. Analyses were stratified by sex and type of SGLT2i. Results There were 23 276 patients who newly initiated both SGLT2i and an antifungal in our study period. These patients were further classified into those initiating the two drugs within 365 (n = 17 504), 180 (n = 11 873), 90 (n = 7697), 60 (n = 5856) or 30 (n = 3650) days of each other. Increased risks of mycotic infections were present across all time periods, with the strongest effect observed in the 90-day interval [ASR 1.53 (confidence interval, CI 1.43-1.60)]. Findings differed by sex [90-day ASR females: 1.65 (CI 1.56-1.74); males 1.25 (CI 1.14-1.36)] and by SGLT2i [90-day ASR canagliflozin 1.57 (CI 1.49-1.66); non-canagliflozin 1.42 (CI 1.31-1.55)]. Conclusion Initiation of SGLT2i was associated with an increased risk for mycotic infections. Findings from this commercially insured population in the real world are consistent with evidence available from clinical trials.

Aim To determine the risk of amputations associated with sodium-glucose co-transporter-2 inhibitors (SGLT2i) relative to dipeptidyl peptidase-4 inhibitors (DPP4i). Materials and methods We conducted an active comparator, new user cohort study using data from the Truven Health MarketScan (2009-2015) databases. Patients aged ≥18 years newly initiating SGLT2i or DPP4i between April 1, 2013 and March 31, 2015 were included. Patients were matched 1:1 on high dimensional propensity scores and followed until the earliest of any amputation, treatment discontinuation, disenrollment or end of study period (December 31, 2015). Cox proportional hazards models were used to estimate hazard ratios (HR) and robust 95% confidence intervals (CI) for amputation risk. Results There were 30 216 comparable patients in each arm after matching. Over a median follow-up of 0.6 years, there were 60 amputations (SGLT2i: 36; DPP4i: 24), most at the level of partial foot (75%) and associated with diabetes-related vascular disease (66.7%). The incidence of amputations was higher among SGLT2i patients (1.62 vs. 1.15 per 1000 person-years) with a HR of 1.38 (CI: 0.83-2.31). In subgroup analyses, risk differed by type of SGLT2i: canagliflozin, HR 1.15 (CI: 0.63-2.09); dapagliflozin or empagliflozin, HR 2.25 (CI: 0.78-6.47). Conclusion All SGLT2i had an elevated, though not statistically significant, risk for amputations.

Based on limited evidence, the U.S. Food and Drug Administration (FDA) issued a black box warning for the use of tumor necrosis factor-alpha inhibitors (TNFIs) and risk of non-Hodgkin lymphoma (NHL). Our objective was to determine the risk of NHL associated with TNFI use by duration and type of anti-TNF agent. We performed a nested case-control study within a retrospective cohort of adults with rheumatologic conditions from a U.S. commercial health insurance database between 2009 and 2015. Use of TNFIs (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol) and conventional-synthetic disease-modifying antirheumatic drugs (csDMARDs) was identified, and conditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL. From a retrospective cohort of 55,446 adult patients, 101 NHL cases and 984 controls matched on age, gender and rheumatologic indication were included. Compared to controls, NHL cases had greater TNFI use (33% vs. 20%) but were similar in csDMARD use (70% vs. 71%). TNFI ever-use was associated with nearly two-fold increased risk of NHL (OR = 1.93; 95% CI: 1.16-3.20) with suggestion of increasing risk with duration (P-trend = 0.05). TNF fusion protein (etanercept) was associated with increased NHL risk (OR = 2.73; 95% CI: 1.40-5.33), whereas risk with anti-TNF monoclonal antibodies was not statistically significant (OR = 1.77; 95% CI: 0.87-3.58). In sensitivity analyses evaluating confounding by rheumatologic disease severity, channeling bias was not likely to account for our results. Our findings support the FDA black box warning for NHL. Continued surveillance and awareness of this rare but serious adverse outcome are warranted with new TNFIs and biosimilar products forthcoming.

Supplemental Digital Content is available in the text, Despite near universal health coverage under Medicare, racial disparities persist in the treatment of diffuse large B-cell lymphoma (DLBCL) among older patients in the United States. Studies evaluating DLBCL outcomes often treat socioeconomic status (SES) measures as confounders, potentially introducing biases when SES factors are mediators of disparities in cancer treatment. To examine differences in DLBCL treatment, we performed causal mediation analyses of SES measures, including: metropolitan statistical area (MSA) of residence; census-tract poverty level; and private Medicare supplementation using the Surveillance, Epidemiology and End Results-Medicare linked database between 2001 and 2011. In this retrospective cohort study of DLBCL patients ages 66+ years, we conducted a series of multivariable logistic regression analyses estimating odds ratios (OR) and 95% confidence intervals (CI) relating chemo- and/or immuno-therapy treatment and each SES measure, comparing non-Hispanic (NH)-black, Hispanic/Latino, and Asian/Pacific Islander (API) to NH-white patients. Compared to NH-white patients, racial/ethnic minority patients had lower odds of receiving chemo- and/or immuno-therapy treatment (NH-black: OR 0.84, 95% CI 0.65, 1.08; API: OR 0.80, 95% CI 0.64, 1.01; Hispanic/Latino: OR 0.78, 95% CI 0.64, 0.96) and higher odds of lacking private Medicare supplementation and residence within an urban MSA and poor census tracts. Adjustment for SES measures as confounders nullified observed racial differences. In causal mediation analyses, between 31% and 38% of race/ethnicity differences were mediated by having private Medicare supplementation. Providing equitable access to Medicare supplementation may reduce disparities in receipt of chemo- and/or immuno-therapy treatment in older DLBCL patients.

Study objective To evaluate the risk of arrhythmias associated with inhaled anticholinergic (IAC) use in young patients with asthma. Design Population-based nested case-control study. Database IMS LifeLink Health Plan Claims Database. Patients Patients 5-24 years of age who were diagnosed with asthma and were new users of asthma controller medications were identified between July 1997 and April 2010. Cases were newly diagnosed with arrhythmia and were matched with up to 10 controls based on age, gender, geographic region, and quarter and year of first controller medication dispensing. Measurements and main results Exposure to IACs was determined in the 180 days prior to the event date, defined as date of arrhythmia claim. Active use was defined as sufficient days' supply of a prescription to extend through the event date. Among 283,429 patients with asthma, 7656 cases were matched to 76,304 controls. Most of those included were female (58.8%) and 12 years or older (73.3%). Active exposure of IACs was observed in 0.69% of cases and 0.18% of controls. Active use was associated with a 1.56-fold increase in arrhythmia risk compared with nonactive users or nonusers (adjusted odds ratio [ORadj ] 1.56, 95% confidence interval [CI] 1.08-2.25]). Risk was highest among active users of ipratropium (ORadj 1.59, 95% CI 1.08-2.33). Active high-dose users of IACs (more than 0.114 mg of ipratropium equivalents) had a 69% increase in risk (ORadj 1.69, 95% CI 1.10-2.59), whereas the added risk for active users receiving low-dose IACs (0.114 mg of ipratropium equivalents or less) was not statistically significant (ORadj 1.22, 95% CI 0.53-2.65). Conclusion Use of ipratropium bromide was associated with an increased risk of arrhythmias in 12-24-year-old patients with asthma.

Objective Self-injectable TNF inhibitors are increasingly used early in the chronic treatment of moderate to severe rheumatologic conditions. We estimated medication adherence/persistence over time following initiation in young adult and older adult patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis. Methods We conducted a retrospective cohort study of patients aged 18+ years newly initiating etanercept, adalimumab, certolizumab pegol, or golimumab using the Truven Health MarketScan Database between 2009 and 2013. Pharmacy dispensing data were used to calculate 12-month medication possession ratios (MPR) and determine adherence (MPR ≥ 0.80) for up to 3 years after starting therapy. Persistence over each 12-month interval was defined as not having a ≥92-day treatment gap. Multivariable generalized estimating equation models were used to calculate odds ratios (OR) and robust 95% confidence intervals (CI) for associations between patient characteristics and repeated adherence/persistence measures over time. Results Among 53,477 new users, 14% were young adults (18–34 years), 49% middle-aged (35–54 years), and 37% older adults (55+ years). Overall, 37% of patients were adherent and 83% were persistent in the first year of therapy. The lowest adherence (17%) and persistence (70%) were observed among young adult patients by Year +3. Compared to older adults, middle-aged (OR = 0.73, 95% CI: 0.71–0.76) and young adults (OR = 0.50, 95% CI: 0.47–0.53) were less likely to be adherent. Higher Charlson comorbidity scores, hospitalizations, and emergency department visits were associated with non-adherence/non-persistence. Conclusions We observed low adherence to self-administered TNF inhibitors but most patients remained persistent over time. Further efforts to improve adherence in young adults and patients with greater comorbidity are needed.

INTRODUCTION Bevacizumab, an angiogenesis inhibitor targeting vascular endothelial growth factor A, is used for the treatment of recurrent glioblastoma, the most common primary brain malignancy in adults. Multiple studies demonstrate the efficacy of bevacizumab on progression-free and overall survival of patients with recurrent glioblastoma. However, real world safety data of bevacizumab in patients with glioblastoma is limited on serious adverse outcomes including arterial and venous thrombosis. Our study aimed to evaluate the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) in a population-based sample of adult patients with high grade gliomas. METHOD We conducted a nested case-control study within a retrospective cohort of patients receiving treatment for high grade gliomas under the protocol by Stupp, et al. (radiotherapy plus concomitant/adjuvant temezolomide). Patients were sampled from the Truven Health MarketScan® Research Database, containing administrative health claims data of over 40 million commercially insured enrollees and their dependents, between 2009 and 2015. A validated algorithm was used to identify patients with high grade gliomas that underwent craniotomy (index time) with external beam radiation and temozolomide-based treatment occurring within 91 days (cohort entry time). Patients were excluded if they received craniotomy, radiation, temozolomide or bevacizumab during year prior to surgery or had one of our outcomes of interest (ATE or VTE) during the cohort ascertainment period (between index and cohort entry dates). Patients were required to have continuous health plan enrollment during the 12-month baseline and follow up periods (unless died). Surgical procedures and chemotherapy treatments were identified using diagnostic and procedural medical and pharmacy claims data. These data sources were also used to identify VTE risk factors, including medical conditions, procedures and medication use, and to calculate modified Charlson comorbidity index scores at baseline. Cases of ATE and VTE were each identified in the overall cohort using a validated algorithm for administrative claims data. For ATE and VTE separately, each case was matched to up to ten controls on sex, age group, index time and follow-up duration using incidence density sampling with replacement. Exposure to bevacizumab was characterized as any use (yes vs. no) and recent use (last bevacizumab infusion within 30 days prior event or control censoring). We estimated relative risk of ATE and VTE associated with bevacizumab in separate models using conditional logistic regression models to calculate adjusted odds ratios (aOR) and 95% confidence interval (CI). All multivariable models were adjusted for sex, age, and comorbidity index scores; models for risk of VTE were also adjusted for number of baseline VTE risk factors and VTE prophylaxis received. RESULTS Our final study cohort included 2157 patients undergoing treatment for high grade gliomas. We identified 25 ATE cases and 99 VTE cases and matched incidence density-sampled controls (n=170 for ATE; n=819 for VTE) for our nested case-control analysis. A higher proportion of ATE cases received bevacizumab during follow up compared to the controls (28% vs. 17%). In multivariable analyses, no statistically significant increase in ATE risk was observed with bevacizumab overall (aOR 1.51, 95% CI 0.54-4.24), although confidence intervals were wide given the few events observed. Compared to controls in the VTE analysis, cases had a slightly higher proportion of baseline VTE risk factors (2 or more: 17% vs. 13%) and treatment with bevacizumab (13% vs. 9%). However, we found no significant increased risk of VTE associated with bevacizumab overall (aOR 1.40, 95% CI 0.71-2.75) or recent infusion of bevacizumab (aOR 1.40, 95% CI 0.65-3.01). CONCLUSIONS Our findings from this large retrospective cohort of patients undergoing treatment for high grade glioma provide little evidence in support of the increased risk of ATE and VTE reported with use of bevacizumab in other cancer sites. Our study was limited by an overall small number of ATE events observed, and further research is needed to confirm safety of bevacizumab with respect to arterial thrombosis. These population-based estimates show no significant increase in risk of VTE associated with bevacizumab and suggest its safe use in the treatment of high grade gliomas. Disclosures Lee: AbbVie Inc.: Research Funding. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

INTRODUCTION: Biologic disease-modifying antirheumatic drugs (DMARDs) are used more frequently and earlier in the course of rheumatologic conditions in a treat-to-target approach. These medications act on proteins and cytokines with potential pro- and anti-malignancy roles, including tumor necrosis factor-alpha (TNF), human interleukin (IL) receptors and B- and T-cell functions. There is concern for hematologic malignancy with some but not all biologic DMARDs. Little is known about possible associations between these medications and development of multiple myeloma (MM). Our purpose was to determine risk of MM in relation to biologic DMARD treatment, duration of use and by biologic target in a large cohort of patients with rheumatologic conditions. METHODS: We conducted a nested case-control study within a cohort of adults undergoing active treatment for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Patients were sampled from a population of commercially-insured U.S. health plan enrollees in the Truven Health MarketScan Research Database between 2009 and 2015. MM cases were ascertained using validated algorithms for administrative data. Up to ten controls from the overall cohort were matched to each MM case on age, sex and rheumatologic indication using incidence density sampling with replacement. Index date was defined as the date of MM diagnosis for a case and corresponding time at-risk for matched controls. Exposure was defined as both treatment and duration of biologic DMARD use including TNF inhibitor (etanercept, infliximab, adalimumab, golimumab, certolizumab pegol), IL-6 receptor antagonist (tocilizumab), T-cell targeted (abatacept) and B-cell depleting (rituximab) agents and were determined from health claims and pharmacy dispensing data. Data on rheumatologic indication, comorbid conditions and treatment with prescription nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and conventional synthetic DMARDs (hydroxychloroquine, sulfasalazine, methotrexate, leflunomide) were documented in the 12 month baseline period and during follow up as potential confounders. An exposure lag time of 365 days was used to minimize protopathic bias. Multivariable conditional logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of MM associated with biologic DMARDs. RESULTS: From a retrospective cohort of 56866 adult patients with rheumatologic conditions, 287 MM cases and 2760 matched controls were identified. Compared to controls, a higher proportion of cases had Charlson comorbidity scores of 2 or greater (24% vs 18%) and used oral corticosteroids during follow up (67% vs 61%). Cases and controls were similar with respect to use of prescription NSAIDs (56% vs 59%) and use of conventional DMARDs (63% vs 67%). Use of biologic DMARDs overall was similar between cases and controls (14% vs 15%), although cases had a slightly lower proportion of etanercept users (5% vs 7%) and a slightly higher proportion of tocilizumab users (1.4% vs 0.4%). Biologic DMARD users were younger, more likely to have psoriatic arthritis or ankylosing spondylitis, lower comorbidity and greater use of concomitant NSAIDs and oral corticosteroids. Risk of MM was neither associated with biologic DMARD use overall (OR 0.84; 95% CI 0.57, 1.26; P=0.40) nor with longer duration of biologic DMARD use (>2.5 years: OR 0.72; 95% CI 0.34, 1.52; P=0.39). However, compared to patients treated with only conventional DMARDs, those receiving concomitant conventional plus biologic DMARDs had a 48% lower risk of developing MM (OR 0.52; 95% CI 0.30, 0.88; P=0.02). Associations with MM appeared to differ by specific biologic DMARD agent with estimates suggesting a lowered risk of MM with use of etanercept (OR 0.55; 95% CI 0.30, 1.02; P=0.06) and greater risk with use of tocilizumab (OR 4.33; 95% CI 1.33, 14.19; P=0.02) that was statistically significant, although confidence intervals were wide. CONCLUSIONS: The potential influence of biologic DMARDs on multiple myeloma is complex. We found that immune suppression with conventional plus biologic DMARDs is inversely associated with MM risk in patients with rheumatologic conditions, but this association differed by biologic drug target. Further research is needed to understand the roles of DMARDs targeting TNF and IL-6 in relation to subsequent myeloma pathogenesis. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Background Antibiotics are recommended prior to certain dental procedures (“antibiotic prophylaxis”) in patients with select comorbidities to prevent serious distant site infections. Our objective was to assess the appropriateness of antibiotic prophylaxis by dentists using Truven, a national integrated medical, dental, and prescription (Rx) claims database of 350 commercial plans. Methods Cross-sectional study of 8.7 million adult dental visits in 2015. Antibiotic prophylaxis was defined as Rx with Results In 2015, 30,726 antibiotics were prescribed for dental infection prophylaxis for 21,986 patients (mean age=58.6 + 15.0 years; 55.9% female). Amoxicillin (68.5%) and clindamycin (14.7%) were most common. 29,879 dental visits were associated with 69,639 dental codes ([CDTs]; range 1–14 CDTs/visit). Most dental visits were diagnostic (65.9% of visits with >1 diagnostic CDT), preventative (53.0%), and restorative (11.2%). 98.4% of dental visits had an appropriate CDT for antibiotic prophylaxis. Comorbidities include orthopedic implants (45.4%) and cardiac diagnoses at the highest risk of infective endocarditis (22.2%). Per guidelines, 78.0% of dental visits with antibiotic prophylaxis were inappropriate. Amoxicillin was more likely to be inappropriate than other agents (OR=1.65; 95% CI: 1.55–1.76). Orthopedic implants (OR=3.35; 95% CI: 3.14–3.56), tooth implant procedures (OR=3.30; 95% CI: 2.48–4.39), females (OR=1.35; 95% CI: 1.27–1.43) and the western US (OR=1.22; 95% CI: 1.09–1.36) were associated with inappropriate prescribing. Conclusion Antibiotic prophylaxis is prescribed for indicated dental procedures, but is not appropriately limited to patients with cardiac diagnoses per guidelines. Implementing antimicrobial stewardship efforts in dental practices may be an opportunity to improve antibiotic prescribing for infection prophylaxis. Disclosures J. C. McGregor, Merck: Grant Investigator, Research grant.

Purpose The purpose of this study was to examine use of granulocyte colony-stimulating factors (G-CSF) in relation to risk of myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in a population-based cohort of elderly patients with non-Hodgkin lymphoma (NHL). Methods We conducted a retrospective cohort study of adults ages 66 years and older diagnosed with first primary NHL between 2001 and 2011 using the Surveillance Epidemiology and End Results (SEER)-Medicare linked database. Patients were included if they were alive and without documented secondary primary cancer at three months post-diagnosis. Using a validated algorithm with Medicare claims and SEER records, we identified MDS/AML cases, primary NHL treatment received (i.e., chemo-immunotherapy and radiation) and type and number of doses of G-CSF received (i.e., filgrastim and/or pegfilgrastim). We determined the risk of developing MDS/AML at 12 months or longer after NHL diagnosis. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for MDS/AML risk associated with G-CSF use in cause-specific Cox proportional hazards models, stratified by treatment to account for confounding by indication. Results A total of 18,245 patients were included with a mean age of 76 years and median follow up of 3.5 years. Most patients were diagnosed with diffuse large B-cell lymphoma (34%) and follicular lymphoma (22%). Fifty-six percent of all patients received chemo-immunotherapy, among whom most received rituximab-based chemotherapy (74%) or monotherapy (18%). G-CSF was most commonly used among those who received rituximab plus chemotherapy (77%). Subsequent MDS/AML was observed in 666 (3.7%) patients. Overall, we found a modest increased risk of MDS/AML with any use of G-CSF (HR=1.28, 95% CI 1.01-1.62); although, a linear trend was observed with increasing number of G-CSF doses (P Conclusions In this study of elderly NHL patients, we observed a higher MDS/AML risk among those receiving chemo-immunotherapy and G-CSF that was specific to higher number of filgrastim doses but not pegfilgrastim. The benefits of preventing complications from therapy-related neutropenia in patients receiving highly myeloablative treatments likely outweigh the risk of this rare but serious second primary cancer. Understanding differential risk by type of agent warrants further study with the increasing use of G-CSF and FDA-approved biosimilar products (filgrastim-sndz) newly available. Citation Format: Kellyn M. Moran, Zhaoju Wu, Sruthi Adimadhyam, Todd A. Lee, Brian C. Chiu, Gregory S. Calip. Myelodysplastic syndrome and acute myeloid leukemia following use of chemo-immunotherapy and granulocyte colony-stimulating factors among elderly non-Hodgkin lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4225.

Introduction Individuals with multiple myeloma (MM) are at a greater risk of thrombotic complications than those with other cancers. Cancer-related venous thromboembolism (VTE) including pulmonary embolism and deep vein thrombosis is associated with increased morbidity and mortality. Both incidence of MM and VTE differ by race/ethnicity. Blacks have a higher incidence of MM compared to Whites, whereas Asian/Pacific Islanders (API) and Hispanics have a lower incidence. In the general population, the risk of VTE and prevalence of its associated risk factors are higher in Blacks. The hypercoagulable state induced by MM and its treatment could further modify any pre-existing VTE risk in different racial/ethnic groups. Our objective was to describe the incidence of VTE following diagnosis and treatment of MM by race/ethnicity. Methods We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) - Medicare linked database. Individuals 66 years or older with myeloma as their first primary malignancy diagnosed between 2001 - 2011 were identified. These individuals were required to have age related eligibility for Medicare, continuous enrollment in the 12 months period prior and post myeloma diagnosis, and Medicare as their primary payer. Using SEER registries and administrative claims, we collected data on race/ethnicity, cancer characteristics and treatment, and chronic comorbidities. VTE events were defined as having an inpatient hospitalization or 2+ outpatient visits with ICD-9 diagnosis codes 415.1x, 451.xx, and 453.xx. Long-term risk of VTE was assessed by determining the annualized incidence of VTE at 12, 24, and 36 months following MM diagnosis. In each 12-month period, MM patients were followed from diagnosis until the earliest of the following: a VTE event, death, or end of 12-month period since diagnosis. Additionally, we calculated VTE incidence rates in the 12-month period following stem cell transplantation for those that received it. Overall and race-specific crude incidence rates with 95% confidence intervals (CIs) were calculated in each period using person-time contributed per observation period. Poisson regression was used to compare age- and gender-adjusted incidence rate ratios (IRRs) and 95% CIs comparing different racial/ethnic groups with White patients. Results In a final analytic cohort of 9,480 patients, most were White (73%) and fewer patients were Black (15%), Hispanic (6%) or API (4%). The median age at diagnosis was 77 years (interquartile range [IQR]: 71-82). Half the cohort (51%) were women, 28% had diabetes and 21% had a history of heart failure at diagnosis. Overall, the median time to first VTE event post-MM diagnosis was 140 days (IQR: 46-409). More patients that developed VTE were female, Black, younger at MM diagnosis, and treated with stem cell transplantation. The overall incidence rate of VTE during the first 12 months following the diagnosis of MM was 170 per 1,000 person-years (95% CI 160-180). Adjusting for age and gender, Blacks had a higher incidence of VTE compared to Whites (IRR 1.24; 95% CI 1.07-1.44) and APIs had a lower incidence (IRR 0.55; 95% CI 0.37-0.81). In the second post-diagnosis year, there were 6,257 individuals remaining that contributed 5,443 person-years. Overall, the incidence rate was 82 per 1,000 person-years (95% CI 75-90). Incidence was greater in Blacks vs. Whites (adjusted IRR 1.25; 95% CI 0.98-1.59). Consistent with findings from the first analysis period, APIs continued to have lower incidence vs. Whites (adjusted IRR 0.44; 95% CI 0.22-0.89). In the third post-diagnosis year, the overall incidence rate was 80 per 1,000 person-years (95% CI 72-89) and any racial disparities observed in age and gender adjusted IRRs were no longer significant. For patients in the first year following stem cell transplantation, annualized incidence rates of VTE were elevated (overall incidence rate of 148, 95% CI 117-188). Conclusion In this large population-based cohort of older MM patients, we observed racial disparities in the incidence of VTE within the first 24 months of diagnosis. A risk-adapted method of VTE prophylaxis should be considered. Understanding risk factors and groups vulnerable to development of thromboembolic events can help guide clinical decision making regarding VTE prophylaxis. Disclosures No relevant conflicts of interest to declare.

Purpose Clinical trials for treatment of diffuse large B-cell lymphoma (DLBCL) exclude the very elderly, ages 80 years and older. Treatment differences by race/ethnicity in very elderly DLBCL patients may result from disparities in health care access and other socioeconomic factors, but it remains unclear whether disparities in treatment lead to poorer survival. Our purpose was to (1) examine differences in utilization of chemotherapy and immunotherapy for DLBCL in very elderly patients and (2) characterize the comparative effectiveness of these treatments for all-cause and cancer-specific mortality in this population. Patients and Methods We conducted a retrospective cohort study of very elderly patients ages 80 years and older diagnosed with first primary DLBCL between 2001-2011 from the Surveillance Epidemiology and End Results (SEER)-Medicare linked database. Patients were included if they had at least 12 months of continuous enrollment on Medicare Parts A and B prior to and following diagnosis. Using SEER-Medicare administrative claims, we determined types of primary DLBCL treatment (e.g., observation, radiation, chemotherapy and immunotherapy). We also collected information on cancer stage, clinical characteristics, comorbid conditions and census tract level sociodemographic data. We used multivariable logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for likelihood of being treated with chemotherapy/immunotherapy. We examined possible differences in risk of all-cause and cancer-specific mortality by race and ethnicity using Cox proportional hazards models to account for differences in treatment. We also estimated hazard ratios (HR) and 95% CIs to determine the comparative effectiveness of rituximab-based combination chemotherapy for these mortality endpoints by racial/ethnic group. Results Among 4,404 very elderly DLBCL patients, the median age was 84 years (interquartile range: 82-87) and more patients included in the analysis were female (59%), non-Hispanic White (86%) and slightly more advanced stage at diagnosis (Ann Arbor stages III-IV, 51%). Forty five percent of patients received infused chemotherapy and/or immunotherapy. Of those treated patients, 77% received rituximab plus combination chemotherapy, either CHOP or CVP. Greater proportions of Black (63%) and Hispanic (63%) patients were not treated with chemotherapy/immunotherapy compared to White patients (54%). The observed treatment disparities were not significant after accounting for sociodemographic variables including Medicare supplementation and census tract poverty level (Black vs. White: OR=0.72, 95% CI 0.43-1.22; Hispanic vs. White: OR=1.04, 95% CI 0.72-1.49). No differences were observed in all-cause or cancer-specific mortality by race/ethnicity. When analyzing the comparative effectiveness of rituximab combination therapy in these populations, the benefit of treatment in all-cause mortality was equal or greater in Black (HR=0.28, 95% CI 0.16-0.50) and Hispanic (HR=0.22, 95% CI 0.15-0.34) patients compared to White patients (HR=0.33, 95% CI 0.30, 0.36); similar results were found for reduced cancer-specific mortality in Black (HR=0.14, 95% CI 0.07-0.31), Hispanic (HR=0.20, 95% CI 0.12-0.34) and White patients (HR=0.28, 95% CI 0.25-0.32). Conclusions In this population-based sample of very elderly Medicare beneficiaries with DLBCL, we observed low rates of treatment with systemic therapy. Racial/ethnic differences in treatment utilization were explained by socioeconomic factors. When accounting for these factors, we demonstrated no differences in risk of all-cause or cancer-specific mortality by race/ethnicity and similar effectiveness of treatment across racial/ethnic groups. Determining barriers to access for highly effective DLBCL therapies in the very elderly, particularly for racial and ethnic minorities, is of public health importance. Disclosures Smith: Gilead: Consultancy; Juno: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Pharmacyclics: Consultancy; Celgene: Consultancy; Portola: Consultancy; AbbVie: Consultancy; TGTX: Consultancy; Amgen: Other: Educational lecture to sales force.

Background Maintenance of problem lists in electronic medical records is required for the meaningful use incentive and by the Joint Commission. Linking indication with prescribed medications using computerized physician order entry (CPOE) can improve problem list documentation. Prescribing of antihypertensive medications is an excellent target for interventions to improve indication-based prescribing because antihypertensive medications often have multiple indications and are frequently prescribed. Objective To measure the accuracy and completeness of electronic problem list additions using indication-based prescribing of antihypertensives. Design Clinical decision support (CDS) was implemented so that orders of antihypertensives prompted ordering physicians to select from problem list additions indicated by that medication. An observational analysis of 1000 alerts was performed to determine the accuracy of physicians' selections. Results At least one accurate problem was placed 57.5% of the time. Inaccurate problems were placed 4.8% of the time. Accuracy was lower in medications with multiple indications and the likelihood of omitted problems was higher compared to medications whose only indication was hypertension. Attending physicians outperformed other clinicians. There was somewhat lower accuracy for inpatients compared to outpatients. Conclusion CDS using indication-based prescribing of antihypertensives produced accurate problem placement roughly two-thirds of time with fewer than 5% inaccurate problems placed. Performance of alerts was sensitive to the number of potential indications of the medication and attendings vs. other clinicians prescribing. Indication-based prescribing during CPOE can be used for problem list maintenance, but requires optimization.