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Background Little is known about the relationship between coronavirus disease 2019 (COVID-19) severity and subsequent risk of experiencing a cardiovascular event (CVE) after COVID-19 recovery. We evaluated this relationship in a large cohort of United States adults. Methods Using a claims database, we performed a retrospective cohort study of adults diagnosed with COVID-19 between 1 April 2020 and 31 May 2021. We evaluated the association between COVID-19 severity and risk of CVE >30 days after COVID-19 diagnosis using inverse probability of treatment–weighted competing risks regression. Severity was based on level of care required for COVID-19 treatment: intensive care unit (ICU) admission, non-ICU hospitalization, or outpatient care only. Results A total of 1 357 518 COVID-19 patients were included (2% ICU, 3% non-ICU hospitalization, and 95% outpatient only). Compared to outpatients, there was an increased risk of any CVE for patients requiring ICU admission (adjusted hazard ratio [aHR], 1.80 [95% confidence interval {CI}, 1.71–1.89]) or non-ICU hospitalization (aHR, 1.28 [95% CI, 1.24–1.33]). Risk of subsequent hospitalization for CVE was even higher (aHRs, 3.47 [95% CI, 3.20–3.76] for ICU and 1.96 [95% CI, 1.85–2.09] for non-ICU hospitalized vs outpatient only). Conclusions COVID-19 patients hospitalized or requiring critical care had a significantly higher risk of experiencing and being hospitalized for post–COVID-19 CVE than patients with milder COVID-19 who were managed solely in the outpatient setting, even after adjusting for differences between these groups. These findings underscore the continued importance of preventing severe acute respiratory syndrome coronavirus 2 infection from progressing to severe illness to reduce potential long-term cardiovascular complications.

ObjectivesTo quantify healthcare resource utilisation (HCRU) and costs to the National Health Service (NHS) associated with acute COVID-19 in adults in England.DesignPopulation-based retrospective cohort study, using Clinical Practice Research Datalink (CPRD) Aurum primary care electronic medical records linked when available to Hospital Episode Statistics (HES) secondary care administrative data.SettingPatients registered to primary care practices in England.Population1,706,368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13,105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1,693,263 within the primary care cohort indexed between August 2020 and January 2022.Main outcome measuresPrimary and secondary care HCRU and associated costs during the acute phase of COVID-19 (≤4 weeks following positive test), stratified by age group, risk of severe COVID-19 and immunocompromised status.ResultsAmong the hospitalised cohort, average total length of stay, as well as in critical care wards, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75 – 84 (£8,942) and ≧85 years (£8,835) than in those aged ConclusionsCOVID-19 related hospitalisations in older adults, particularly critical care admissions, were the primary drivers of high resource use of COVID-19 in England. These findings may inform health policy decisions and resource allocation in the prevention and management of COVID-19.

ObjectiveTo create case definitions for confirmed COVID diagnoses, COVID vaccination status, and three separate definitions of high risk of severe COVID, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID epidemiology in England.DesignRetrospective cohort studySettingElectronic healthcare records from primary care (Clinical Practice Research Datalink, or CPRD) linked to secondary care data (Hospital Episode Statistics, or HES) data covering 24% of the population in EnglandParticipants2,271,072 persons aged 1 year and older diagnosed with COVID in CPRD Aurum between August 1, 2020 through January 31, 2022.Main Outcome MeasuresAge, sex, and regional distribution of COVID cases and COVID vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalized for COVID (primary diagnosis code of ICD-10 U07.1 “COVID-19”). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the United Kingdom (NHS Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritization for vaccination).ResultsCompared to national estimates, CPRD case estimates underrepresented older adults in both the primary care (age 65-84: 6% in CPRD vs 9% nationally) and hospitalized (31% vs 40%) cohorts, and overrepresented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East, vs 15% nationally). The majority of non-hospitalized cases and all hospitalized cases had not completed primary series vaccination. In primary care, persons meeting high risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score.ConclusionsCPRD primary care data is a robust real-world data source and can be used for some COVID research questions, however limitations of the data availability should be carefully considered. Included in this publication are supplemental files for atotal of over 28,000 codes to define each of three definitions of high risk of severe disease.SUMMARY BOXESWhat is already known on this topic?The UK Government publishes data on cases, hospital admissions and vaccinations related to COVID in England.There are at least three definitions of persons at high-risk of severe COVID in use in England.What this study addsOur study created case definitions for COVID diagnoses, COVID vaccination, and three separate definitions of high risk of severe COVID for use in the Clinical Practice Research Datalink (CPRD), a database covering 24% of England.The COVID population in the CPRD has a different age and regional distribution than national case reports, which future studies may need to consider.

Acute otitis media (AOM) is a common indication for antibiotics in children. We sought to characterize the frequency of nonguideline concordant antibiotic therapy for AOM in the United States, by agent and duration.Using national administrative claims data (2016-2019), we identified children aged 6 months to 17 years with an oral antibiotic dispensed within 3 days of a new diagnosis of suppurative AOM. Use of nonguideline concordant agents and durations, defined based on national treatment guidelines, were summarized by age, race, rurality, region, and insurance type. Subsequent oral antibiotic dispensing within the year after AOM diagnosis was also evaluated. We created sunburst diagrams to visualize longitudinal patterns of within-person antibiotic utilization for AOM, by agent and duration.We identified 789 424 eligible commercially-insured and 502 239 medicaid-insured children. Among commercially insured children, 35% received nonguideline concordant agents for AOM, including cefdinir (16%), amoxicillin-clavulanate (12%), and azithromycin (7%). Fewer children age 2 years received a nonguideline concordant initial agent (27%) compared to age ≥6 years (41%). More children age 2 years received three or more antibiotics over the following year (34% vs. 3% for children age ≥6 years). The most common treatment duration was 10 days for all ages; treatment duration for the initial antibiotic was nonguideline concordant for 95% and 89% of children age 2-5 years and ≥6 years, respectively. Patterns were similar for medicaid-insured children.Nonguideline concordant antibiotic use is common when treating AOM in children, including use of broad-spectrum agents and longer-than-recommended antibiotic durations.

Introduction Romiplostim has been approved in Europe since 2009 to treat patients with chronic primary immune thrombocytopenia (ITP). Using real-world data from seven European countries, we measured the effectiveness and safety outcomes within 24 weeks following romiplostim initiation by duration of ITP: less than 3 months (“newly diagnosed”), 3–12 months (“persistent”), and more than 12 months (“chronic”). Methods Adults with ITP and ≥ 1 romiplostim administration between 2009 and 2012 were included. Endpoints included durable platelet response, median platelet count, rescue therapy, bleeding and adverse events. We used inverse probability of censoring weighted estimators to estimate cumulative risk of each outcome. There were 64 newly diagnosed, 50 persistent, and 226 chronic ITP patients at romiplostim initiation. Results Durable platelet response at 24 weeks ranged from 32% [confidence interval (CI): 18–46%] in newly diagnosed patients to 53% (CI 37–68%) in persistent patients. Median platelet count during follow-up ranged from 88 (CI 80–96) × 109/L in chronic patients to 131 (CI 102–160) × 109/L in newly diagnosed patients. Conclusion Regardless of ITP duration, over half of patients discontinued concomitant ITP medications. Few adverse events were observed. Although only approved for chronic patients, estimates of the romiplostim treatment effect were similar across patients being managed in European clinical practice, regardless of ITP duration at romiplostim initiation. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01727-5.

Little is known about the relationship between COVID-19 severity and subsequent risk of experiencing a cardiovascular event (CVE) after COVID-19 recovery. We evaluated this relationship in a large cohort of US adults.Using a claims database, we performed a retrospective cohort study of adults diagnosed with COVID-19 between April 1, 2020 and May 31, 2021. We evaluated the association between COVID-19 severity and risk of CVE30 days after COVID-19 diagnosis using inverse probability of treatment weighted competing risks regression. Severity was based on level of care required for COVID-19 treatment: intensive care unit (ICU) admission, non-ICU hospitalization, or outpatient care only.1,357,518 COVID-19 patients were included (2% ICU, 3% non-ICU hospitalization, and 95% outpatient only). Compared to outpatients, there was an increased risk of any CVE for patients requiring ICU admission (adjusted hazard ratio [HR]: 1.80 [95%CI: 1.71-1.89]) or non-ICU hospitalization (HR: 1.28 [1.24-1.33]). Risk of subsequent hospitalization for CVE was even higher (HR: 3.47 [3.20-3.76] for ICU and HR: 1.96 [1.85-2.09] for non-ICU hospitalized vs. outpatient only).COVID-19 patients hospitalized or requiring critical care had a significantly higher risk of experiencing and being hospitalized for post-COVID-19 CVE than patients with milder COVID-19 who were managed solely in the outpatient setting even after adjusting for differences between these groups. These findings underscore the continued importance of preventing SARS-CoV-2 infection from progressing to severe illness to reduce potential long-term cardiovascular complications.

Background The 2013 ACC/AHA cholesterol treatment guidelines removed the recommendation to treat adults at risk of cardiovascular disease to goal levels of low-density lipoprotein cholesterol (LDL-C). We anticipated that the frequency of LDL-C testing in clinical practice would decline as a result. To test this hypothesis, we evaluated the frequency of LDL-C testing before and after the guideline release. Methods We used the MarketScan® Commercial and Medicare Supplemental claims data (1/1/2007-12/31/2016) to identify four cohorts: 1) statin initiators (any intensity), 2) high-intensity statin initiators, 3) ezetimibe initiators, and 4) patients at very high cardiovascular risk (≥2 hospitalizations for myocardial infarction or ischemic stroke, with prevalent statin use). Rates of LDL-C testing by calendar year quarter were estimated for each cohort. To estimate rates in the absence of a guideline change, we fit a time-series model to the pre-guideline rates and extrapolated to the post-guideline period, adjusting for covariates, seasonality, and time trend. Results Pre- and post-guideline rates (LDL-C tests per 1,000 persons per quarter) were 248 and 235, respectively, for 3.9 million statin initiators; 263 and 246 for 1.3 million high-intensity statin initiators; 277 and 261 for 323,544 ezetimibe initiators; and 180 and 158 for 42,108 very high-risk patients. For all cohorts, observed post-guideline rates were similar to model-predicted rates. On average, the difference between observed and predicted rates was 8.5 for patients initiating any statin; 2.6 for patients initiating a high-intensity statin; 11.4 for patients initiating ezetimibe, and -0.5 for high-risk patients. Conclusion We observed no discernible impact of the release of the 2013 ACC/AHA guidelines on LDL-C testing rates. Rather, there was a gradual decline in testing rates starting prior to the guideline change and continuing throughout the study period. Our findings suggest that the guidelines had little to no impact on use of LDL-C testing.

Purpose Patients with immune thrombocytopenia (ITP) have low platelet counts and an increased risk of bleeding. We described treatment patterns and clinical outcomes in routine practice in the United States (US). Patients and Methods Using electronic health record data from hematology/oncology clinics linked to administrative claims in the US, we studied 447 adults newly diagnosed with primary ITP from 2011 to 2016. Patients with a secondary cause of thrombocytopenia were excluded. The incidence of ITP treatment initiation, bleeding events, and rescue therapy use were estimated using competing risk models. Results At 1-year post-ITP diagnosis, 50% of patients were prescribed an oral corticosteroid, with the majority being prescribed immediately following diagnosis. Of the more common second-line options, rituximab use was the most frequent (1-year cumulative incidence: 16% [95% confidence interval: 12, 19]), followed by romiplostim (9% [7, 12] and eltrombopag (5% [3, 8]). Use of these drugs was similar at 2 years post-diagnosis. At 6 months post-ITP treatment initiation, the cumulative incidence of bleeding was similar among eltrombopag and romiplostim initiators (17% [6, 33] and 19% [9, 31], respectively) and was slightly lower in rituximab users (12% [6, 20]). However, during this same timeframe, rituximab users had a higher incidence of rescue therapy use (48% [36, 58] versus 29% [14, 46] in eltrombopag and 26% [14, 39] in romiplostim users). Although splenectomy was rare, at 6 months post-surgery nearly 20% had experienced a bleed and nearly 20% had required rescue. Conclusion This study describes the health trajectory of adults with ITP who are managed in hematology clinics in the US and could inform the design of non-interventional studies of comparative effectiveness among treatments.

ObjectivesTo describe the characteristics, healthcare resource use and costs associated with initial hospitalization and readmissions among pediatric patients with COVID-19 in the US.MethodsHospitalized pediatric patients, 0-11 years of age, with a primary or secondary discharge diagnosis code for COVID-19 (ICD-10 code U07.1) were selected from 1 April 2020 through 30 September 2021 in the US Premier Healthcare Database Special Release (PHD SR). Patient characteristics, hospital length of stay (LOS), in-hospital mortality, hospital costs, hospital charges, and COVID-19-associated readmission outcomes were evaluated and stratified by age groups (0-4, 5-11), four COVID-19 disease progression states based on intensive care unit (ICU) and invasive mechanical ventilation (IMV) usage, and three sequential calendar periods. Sensitivity analyses were performed using the US HealthVerity claims database and restricting the analyses to primary discharge code.ResultsAmong 4,573 hospitalized pediatric patients aged 0-11 years, 68.0% were 0-4 years and 32.0% were 5-11 years, with a mean (median) age of 3.2 (1) years; 56.0% were male, and 67.2% were covered by Medicaid. Among the overall study population, 25.7% had immunocompromised condition(s), 23.1% were admitted to the ICU and 7.3% received IMV. The mean (median) hospital LOS was 4.3 (2) days, hospital costs and charges were $14,760 ($6,164) and $58,418 ($21,622), respectively; in-hospital mortality was 0.5%. LOS, costs, charges, and in-hospital mortality increased with ICU admission and/or IMV usage. In total, 2.1% had a COVID-19-associated readmission. Study outcomes appeared relatively more frequent and/or higher among those 5-11 than those 0-4. Results using the HealthVerity data source were generally consistent with main analyses.LimitationsThis retrospective administrative database analysis relied on coding accuracy and inpatient admissions with validated hospital costs.ConclusionsThese findings underscore that children aged 0-11 years can experience severe COVID-19 illness requiring hospitalization and substantial hospital resource use, further supporting recommendations for COVID-19 vaccination.

Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim versus standard-of-care (SOC) therapy among patients with recently diagnosed (≤ 12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the endpoint of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary endpoint. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group versus SOC, precision was limited because of small study size (median difference was 11 x 109 /L (CI: -59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision-makers and the data.

ImportanceA new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code (U09.9 Post COVID-19 condition, unspecified) was introduced by the Centers for Disease Control and Prevention on October 1, 2021.ObjectiveTo examine the use of the U09.9 code and describe concurrently diagnosed conditions to understand physician use of this code in clinical practice.Design, Setting, and ParticipantsThis cohort study of US patients with an ICD-10-CM code for post–COVID-19 condition used deidentified patient-level claims data aggregated by HealthVerity. Children and adolescents (aged 0-17 years) and adults (aged 18-64 and ≥65 years) with a post–COVID-19 condition code were identified between October 1, 2021, and January 31, 2022. To identify a prior COVID-19 diagnosis, 3 months of continuous enrollment (CE) before the post–COVID-19 diagnosis date was required.Main Outcomes and MeasuresPresence of the ICD-10-CM U09.9 code.ResultsThere were 56 143 patients (7723 female patients [61.2%]; mean [SD] age, 47.6 [19.2] years) with a post–COVID-19 diagnosis code, with cases increasing in mid-December 2021 following the trajectory of the Omicron case wave by 3 to 4 weeks. The analysis cohort included 12 622 patients after the 3-month preindex CE criteria was applied. Among this cohort, the median (IQR) age was 49 (35-61) years; however, 1080 (8.6%) were pediatric patients. The U09.9 code was used most often in the outpatient setting, although 305 older adults (14.0%) were inpatients. Only 698 patients (5.5%) had at least 1 of the 5 codes listed as possible concurrent conditions in the coding guidance. Only 8879 patients (70.4%) had a documented acute COVID-19 diagnosis code (569 [52.7%] among children), and the median (IQR) time between acute COVID-19 and post–COVID-19 diagnosis codes was 56 (21-200) days. The most common concurrently coded conditions varied by age; children experienced COVID-19–like symptoms (eg, 207 [19.2%] had cough and 115 [10.6%] had breathing abnormalities), while 459 older adults aged 65 years or older (21.1%) experienced respiratory failure and 189 (8.7%) experienced viral pneumonia.Conclusions and RelevanceThis retrospective cohort study found patients with a post–COVID-19 ICD-10-CM diagnosis code following the acute phase of COVID-19 disease among patients of all ages in clinical practice in the US. The use of the U09.9 code encompassed a wide range of conditions. It will be important to monitor how the use of this code changes as the pandemic continues to evolve.

While pragmatic trials can be conducted using electronic health data, there are aspects of these data sources that must be considered while designing and conducting a study, including issues related to missing data. Missing data is a common problem in electronic health data and can occur as a result of how data are collected in these systems. Here we discuss mechanisms for missing medication data and follow-up information in electronic medical records and insurance claims databases. Missing data issues can be mitigated by using unstructured data, such as free text from electronic medical records, to supplement the information present in the structured fields. However, the use of these more complex data types in pragmatic trial research requires efficient information extraction methods. Natural language processing techniques can be used to automatically extract information from unstructured text in electronic medical records. However, the sensitive nature and intricacies of unstructured clinical text create additional practical and technical challenges for establishing scalable and high-performing natural language processing systems for clinical free text.

Background The 2013 ACC/AHA cholesterol treatment guidelines removed the recommendation to treat adults at risk of cardiovascular disease to goal levels of low-density lipoprotein cholesterol (LDL-C). We anticipated that the frequency of LDL-C testing in clinical practice would decline as a result. To test this hypothesis, we evaluated the frequency of LDL-C testing before and after the guideline release. Methods We used the MarketScan® Commercial and Medicare Supplemental claims data (1/1/2007–12/31/2016) to identify four cohorts: 1) statin initiators (any intensity), 2) high-intensity statin initiators, 3) ezetimibe initiators, and 4) patients at very high cardiovascular risk (≥2 hospitalizations for myocardial infarction or ischemic stroke, with prevalent statin use). Rates of LDL-C testing by calendar year quarter were estimated for each cohort. To estimate rates in the absence of a guideline change, we fit a time-series model to the pre-guideline rates and extrapolated to the post-guideline period, adjusting for covariates, seasonality, and time trend. Results Pre- and post-guideline rates (LDL-C tests per 1,000 persons per quarter) were 248 and 235, respectively, for 3.9 million statin initiators; 263 and 246 for 1.3 million high-intensity statin initiators; 277 and 261 for 323,544 ezetimibe initiators; and 180 and 158 for 42,108 very high-risk patients. For all cohorts, observed post-guideline rates were similar to model-predicted rates. On average, the difference between observed and predicted rates was 8.5 for patients initiating any statin; 2.6 for patients initiating a high-intensity statin; 11.4 for patients initiating ezetimibe, and −0.5 for high-risk patients. Conclusion We observed no discernible impact of the release of the 2013 ACC/AHA guidelines on LDL-C testing rates. Rather, there was a gradual decline in testing rates starting prior to the guideline change and continuing throughout the study period. Our findings suggest that the guidelines had little to no impact on use of LDL-C testing.

Background High-dose influenza vaccine (HDV) is an alternative vaccination strategy in patients with end-stage renal disease (ESRD), though the safety of HDV has not been evaluated in this population. The objective of this study was to estimate the relative occurrence of adverse vaccine reactions in patients with ESRD following vaccination with HDV compared with standard-dose influenza vaccine (SDV). Methods Using data from the United States Renal Data System, we identified patients with ESRD aged ≥ 65 years at influenza vaccination during yearly influenza seasons from 2010 through 2016. Patients were followed after vaccination to observe serious (anaphylaxis, angioedema, seizure, encephalopathy, Guillain-Barre syndrome [GBS], and short-term, all-cause mortality) and milder (urticaria/hives, rash, pain in limb, cellulitis, myalgia/myositis, fever, nausea and vomiting, diarrhea, and syncope) adverse events. Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for HDV versus SDV were estimated with Cox proportional hazards models. Results Of 520,876 vaccinations observed (mean age = 74.7 years at vaccination; 63% white race), 7.4% were HDV. For serious events, the weighted HRs were null for seizure, encephalopathy, and mortality and inestimable due to too few cases for anaphylaxis, angioedema, and GBS. For milder vaccine reactions, the weighted HRs demonstrated generally increased risks in the HDV group, including rash (HR = 1.86; 95% CI, 1.34–2.57), diarrhea (HR = 1.26; 95% CI, 1.07–1.50), pain in limb (HR = 1.23; 95% CI, 1.12–1.34), and myalgia/myositis (HR = 1.16; 95% CI, 1.04–1.30). Conclusions The risks of serious adverse events were low and similar between treatment groups; however, HDV recipients had increased risks of several milder adverse events compared with SDV recipients, consistent with clinical trial findings in the general population of older adults. These results add important information to inform the risk-benefit tradeoff of the use of HDV versus SDV in patients with ESRD.

Purpose: In contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications. Methods: Using MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12-month cumulative risk difference (RD) using inverse probability of treatment and censoring weights. Results: Among 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = −0.6%, 95% CI: −1.1, −0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations. Conclusions: Caution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies.

Leah J McGrath,1 Robert A Overman,1 Diane Reams,1 Karynsa Cetin,2 Alexander Liede,3 Steven A Narod,4 M Alan Brookhart,1 Rohini K Hernandez2 1NoviSci, LLC, Durham, NC, USA; 2Amgen Inc, Thousand Oaks, CA, USA; 3Amgen Inc, South San Franscisco, CA, USA; 4Department of Medicine, University of Toronto, Toronto, Canada Purpose: Bone-modifying agents (BMAs) are recommended for women with bone metastasis from breast cancer to prevent skeletal-related events. We examined the usage patterns and identified the factors associated with the use of BMAs (denosumab and intravenous bisphosphonates) among women in the US. Patients and methods: Electronic health records from oncology clinics were used to identify women diagnosed with bone metastasis from breast cancer between 2013 and 2014. Patients were excluded if they had recently used a BMA or had concurrent cancer at an additional primary site. The incidence of BMA initiation, interruption, and reinitiation were estimated using competing risk regression models. A generalized linear model was used to estimate risk factors for treatment initiation and interruption. Results: There were 589 women diagnosed with bone metastasis from breast cancer. By 1 year, 68% of these patients (95% CI: 64%, 71%) had initiated treatment with a BMA. Denosumab and zoledronic acid were the most commonly used agents, whereas pamidronate was used infrequently. Young women were more likely to initiate a BMA than older women (adjusted risk difference: 6.4 [95% CI: 1.5, 10.9]). Of the 412 patients who initiated a BMA, 46% (95% CI: 41%, 51%) experienced an interruption within 1 year. Seventy-four percent (95% CI: 68%, 79%) of patients who interrupted their treatment had reinitiated therapy within 1 year of interruption. Conclusion: The majority of women diagnosed with bone metastasis from breast cancer initiate a BMA within 1 year of diagnosis, but a large proportion, particularly among the elderly, do not use these therapies. Keywords: bone-modifying agents, breast cancer, bone metastasis, treatment patterns, electronic health records, denosumab, zoledronic acid, pamidronate

INTRODUCTION: It is recommended that all pregnant women in the U.S. receive tetanus, diphtheria, acellular pertussis (Tdap) immunization to prevent infant pertussis. This study’s objective was to examine the clinical effectiveness of prenatal Tdap, and whether effectiveness varies by gestational age at immunization. METHODS: A nationwide cohort study of pregnant women with deliveries in 2010–2014 and their infants was performed. Commercial insurance claims data were analyzed in 2016–2017 to identify Tdap receipt by the pregnant women, and hospitalizations and outpatient visits for pertussis in their infants until the infants were age 18 months. Pertussis occurrence was compared between infants of mothers who received prenatal Tdap (overall and stratified by gestational age at administration) and infants of unvaccinated mothers. RESULTS: There were 675,167 mother–infant pairs in the cohort. Among infants whose mothers received prenatal Tdap, the rate of pertussis was 43% lower (hazard ratio=0.57, 95% CI=0.35, 0.92) than infants whose mothers did not receive prenatal or postpartum Tdap; this reduction was consistent across pertussis definitions (hazard ratio for inpatient-only pertussis=0.32, 95% CI=0.11, 0.91). Pertussis rates were also lower for infants whose mothers received Tdap during the third trimester. Infants whose mothers received Tdap at

To examine the uptake of prenatal tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) immunization among pregnant women in the United States.Using MarketScan data, we conducted a historical cohort study among pregnant women with employer-based commercial insurance in the United States who delivered between January 1, 2010, and December 31, 2014. We examined temporal trends of uptake, predictors of uptake, and timing of Tdap immunization.Among 1,222,384 eligible pregnancies in 1,147,711 women, receipt of prenatal Tdap immunization increased from 0.0% of women who delivered in January 2010 to 9.8% who delivered in October 2012 (the date of the recommendation by the Advisory Committee on Immunization Practices for Tdap during every pregnancy) to 44.4% who delivered in December 2014. Among women who received Tdap during pregnancy, the majority were immunized between 27 weeks and 36 6/7 weeks of gestation per the Advisory Committee on Immunization Practices recommendation. In multivariable analyses among women who delivered between November 2012 and December 2014, rates of prenatal Tdap immunization were lower for women younger than 25 years of age (eg, 20-24 compared with 30-34 years rate ratio [RR] 0.83, 95% confidence interval [CI] 0.85-0.88), with other children (eg, three compared with zero children: RR 0.86, 95% CI 0.84-0.88), residing in the South compared with the Midwest (RR 0.81, 95% CI 0.80-0.82), or with emergency department visits in early pregnancy (RR 0.93, 95% CI 0.92-0.95). The proportion of pregnant women who received prenatal Tdap increased with increasing gestational age at birth.By the end of 2014, fewer than half of pregnant women in the United States were receiving prenatal Tdap immunization. Implementation and dissemination strategies are needed to increase Tdap coverage among pregnant women, especially those who are young, have other children, or reside in the South.

Purpose Research using healthcare databases often includes patients frequently excluded from clinical trials; yet it is not known whether commonly used data represents the overall population or specific sub-populations of interest. We aimed to examine population representativeness from data sources in recent research studies in the United States (US). Methods We identified data sources from abstracts accepted to the 34th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. The final sample included research studies using ≥1 data source from the US. We classified data sources broadly as claims, linkage, electronic health records (EHR), survey, distributed data network, and other. Studies using claims and EHRs were further classified into more specific categories, including special populations of interest (eg, children). Results We identified 356 abstracts. The majority used claims data (n = 201, 56.5%), followed by data linkages (n = 46, 12.9%), and EHR data (n = 39, 11.0%). Among EHR studies, most (n = 16, 41.0%) came from network data sources (eg, Kaiser Permanente). Almost half (49.4%) of claims-based studies used commercial claims data sources, followed by Medicare (22.1%), Medicaid (11.3%), and Medicare Supplemental (6.1%). Only 15% of studies included children in the study population (n = 53), with 8% focused on a pediatric topic (n = 27). Conclusions We find that certain populations in the US are under-represented in pharmacoepidemiology, particularly Medicaid enrollees and children. Researchers should strive to utilize data sources that may be more representative of the US population, particularly vulnerable populations.

Purpose Patients with immune thrombocytopenia (ITP) have low platelet counts and an increased risk of bleeding. We described treatment patterns and clinical outcomes in routine practice in the United States (US). Patients and Methods Using electronic health record data from hematology/oncology clinics linked to administrative claims in the US, we studied 447 adults newly diagnosed with primary ITP from 2011 to 2016. Patients with a secondary cause of thrombocytopenia were excluded. The incidence of ITP treatment initiation, bleeding events, and rescue therapy use were estimated using competing risk models. Results At 1-year post-ITP diagnosis, 50% of patients were prescribed an oral corticosteroid, with the majority being prescribed immediately following diagnosis. Of the more common second-line options, rituximab use was the most frequent (1-year cumulative incidence: 16% [95% confidence interval: 12, 19]), followed by romiplostim (9% [7, 12] and eltrombopag (5% [3, 8]). Use of these drugs was similar at 2 years post-diagnosis. At 6 months post-ITP treatment initiation, the cumulative incidence of bleeding was similar among eltrombopag and romiplostim initiators (17% [6, 33] and 19% [9, 31], respectively) and was slightly lower in rituximab users (12% [6, 20]). However, during this same timeframe, rituximab users had a higher incidence of rescue therapy use (48% [36, 58] versus 29% [14, 46] in eltrombopag and 26% [14, 39] in romiplostim users). Although splenectomy was rare, at 6 months post-surgery nearly 20% had experienced a bleed and nearly 20% had required rescue. Conclusion This study describes the health trajectory of adults with ITP who are managed in hematology clinics in the US and could inform the design of non-interventional studies of comparative effectiveness among treatments.

Rationale & Objective Studies of patients on maintenance dialysis therapy suggest that standard-dose influenza vaccine (SDV) may not prevent influenza-related outcomes. Little is known about the comparative effectiveness of SDV versus high-dose influenza vaccine (HDV) in this population. Study Design Cohort study using data from the US Renal Data System. Setting & Participants 507,552 adults undergoing in-center maintenance hemodialysis between the 2010 to 2011 and 2014 to 2015 influenza seasons. Exposures SDV and HDV. Outcomes All-cause mortality, hospitalization due to influenza or pneumonia, and influenza-like illness during the influenza season. Analytic Approach Patients were eligible for inclusion in multiple yearly cohorts; thus, our unit of analysis was the influenza patient-season. To examine the relationship between vaccine dose and effectiveness outcomes, we estimated risk differences and risk ratios using propensity score weighting of Kaplan-Meier functions, accounting for a wide range of patient- and facility-level characteristics. For nonmortality outcomes, we used competing-risk methods to account for the high mortality rate in the dialysis population. Results Within 225,215 influenza patient-seasons among adults 65 years and older, 97.4% received SDV and 2.6% received HDV. We observed similar risk estimates for HDV and SDV recipients for mortality (risk difference, −0.08%; 95% CI, −0.85% to 0.80%), hospitalization due to influenza or pneumonia (risk difference, 0.15%; 95% CI, −0.69% to 0.93%), and influenza-like illness (risk difference, 0.00%; 95% CI, −1.50% to 1.08%). Our findings were similar among adults younger than 65 years, as well as within other subgroups defined by influenza season, age group, dialysis vintage, month of influenza vaccination, and vaccine valence. Limitations Residual confounding and outcome misclassification. Conclusions The HDV does not appear to provide additional protection beyond the SDV against all-cause mortality or influenza-related outcomes for adults undergoing hemodialysis. The additional cost and side effects associated with HDV should be considered when offering this vaccine. Future studies of HDV and other influenza vaccine strategies are warranted.

Background Vaccine hesitancy is increasingly common, but more information is needed on patterns of childhood vaccination. We characterized patterns of vaccine delay among commercially-insured children in the U.S. Methods Using the IBM MarketScan Commercial Database, we identified infants who received a timely first dose of diphtheria-tetanus-acellular pertussis (DTaP) vaccine from October 2009 to June 2017. We used CPT codes to collect vaccine administration history on antigen, formulation, dose, and date. We ascertained injectable and oral vaccine antigens (DTaP, polio, pneumococcal conjugate, rotavirus, Haemophilus influenza type b (Hib), measles, mumps, rubella, varicella). Timely receipt was defined as concomitant administration of the CDC-recommended number of antigens during the following time windows: 2, 4, 6, and 12-15 months of age (grace period: -7, +21 days). We generated heat maps to illustrate age distributions at receipt of specific antigens and doses. We created Sankey diagrams to illustrate the number of antigens received concomitantly during each time window and depict transitions to different states over time (e.g., no vaccine delay to vaccine delay). For each antigen and dose, we estimated the cumulative incidence of receipt. Results Among 1,066,216 eligible infants, the majority (84%) concomitantly received all 5 CDC-recommended antigens at 2 months of age while others only received 1 (1%), 2 (2%), 3 (4%) or 4 (9%) antigens. Many vaccinations were delayed – 30% and 39% of children did not receive all recommended antigens concomitantly at 4 and 6 months, respectively. The heat map shows wide variation in age at vaccination. For several antigens including Hib, measles, mumps, rotavirus, rubella, and varicella, the cumulative incidence increased steeply at ≥2 time points, suggesting vaccine delay for some infants (e.g., the first dose of Hib was administered to 85% of infants by 2 months of age, with subsequent small but distinct increases at 4, 6, 12, and 15 months of age). Conclusion Using real-world data to study early childhood vaccination patterns, we observed evidence of substantial deviation from the CDC-recommended schedule. These results expand current knowledge on the magnitude and timing of antigen- and dose-specific vaccine delay on a population level. Disclosures Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Leah McGrath, PhD, NoviSci, Inc. (Employee)

Nonexperimental studies of the effectiveness of seasonal influenza vaccine in older adults have found 40%–60% reductions in all-cause mortality associated with vaccination, potentially due to confounding by frailty. We restricted our cohort to initiators of medications in preventive drug classes (statins, antiglaucoma drugs, and β blockers) as an approach to reducing confounding by frailty by excluding frail older adults who would not initiate use of these drugs. Using a random 20% sample of US Medicare beneficiaries, we framed our study as a series of nonrandomized “trials” comparing vaccinated beneficiaries with unvaccinated beneficiaries who had an outpatient health-care visit during the 5 influenza seasons occurring in 2010–2015. We pooled data across trials and used standardized-mortality-ratio–weighted Cox proportional hazards models to estimate the association between influenza vaccination and all-cause mortality before influenza season, expecting a null association. Weighted hazard ratios among preventive drug initiators were generally closer to the null than those in the nonrestricted cohort. Restriction of the study population to statin initiators with an uncensored approach resulted in a weighted hazard ratio of 1.00 (95% confidence interval: 0.84, 1.19), and several other hazard ratios were above 0.95. Restricting the cohort to initiators of medications in preventive drug classes can reduce confounding by frailty in this setting, but further work is required to determine the most appropriate criteria to use.

BACKGROUND: Standard influenza vaccines may be of limited benefit to patients with end-stage renal disease (ESRD). These patients may benefit from high-dose influenza vaccine, currently indicated for patients aged ≥65 years. Studies in other populations have demonstrated that high-dose vaccine elicits a stronger immunological response. We compared vaccine uptake in the United States and predictors of receipt for high-dose and standard influenza vaccines. METHODS: Using data from the United States Renal Data System (2010–2013), we conducted a retrospective cohort study of 421,482 adult patients on hemodialysis. We examined temporal trends in uptake of high-dose or standard trivalent influenza vaccine each influenza season, and used multivariate logistic regression to assess the association between individual-level variables (e.g., demographics, comorbidities) and facility-level variables (e.g., facility size and type) with vaccine receipt. RESULTS: The proportion of patients with ESRD who were vaccinated with any influenza vaccine increased from 68.3% in 2010 to 72.4% in 2013. High-dose vaccines were administered to 0.9% of patients during the study period, and 16.7% of high-dose vaccines were administered to patients 79 vs. 65–69 years: OR, 1.29; 95% CI, 1.19–1.41) and patients at hospital-based versus free-standing dialysis facilities (OR, 2.31; 95% CI, 2.13–2.45) were more likely to receive high-dose vaccine, while blacks (vs. whites [OR, 0.66; 95% CI, 0.61–0.71]) and patients with longer duration of ERSD (>9 vs. 0 years: OR, 0.66; 95% CI, 0.55–0.78) were less likely to receive the high-dose vaccine. CONCLUSIONS: While the overall influenza vaccination rate has increased, use of high-dose vaccine among patients with ESRD was very low. Being an older patient, living in the Midwest, and receiving care at hospital-based facilities were the strongest predictors of receiving high-dose vaccine.

Nonexperimental studies of preventive interventions are often biased because of the healthy-user effect and, in frail populations, because of confounding by functional status. Bias is evident when estimating influenza vaccine effectiveness, even after adjustment for claims-based indicators of illness. We explored bias reduction methods while estimating vaccine effectiveness in a cohort of adult hemodialysis patients. Using the United States Renal Data System and linked data from a commercial dialysis provider, we estimated vaccine effectiveness using a Cox proportional hazards marginal structural model of all-cause mortality before and during 3 influenza seasons in 2005/2006 through 2007/2008. To improve confounding control, we added frailty indicators to the model, measured time-varying confounders at different time intervals, and restricted the sample in multiple ways. Crude and baseline-adjusted marginal structural models remained strongly biased. Restricting to a healthier population removed some unmeasured confounding; however, this reduced the sample size, resulting in wide confidence intervals. We estimated an influenza vaccine effectiveness of 9% (hazard ratio = 0.91, 95% confidence interval: 0.72, 1.15) when bias was minimized through cohort restriction. In this study, the healthy-user bias could not be controlled through statistical adjustment; however, sample restriction reduced much of the bias.

Healthy worker survivor bias may occur in occupational studies due to the tendency for unhealthy individuals to leave work earlier, and consequently accrue less exposure, compared with their healthier counterparts. If occupational data are not analyzed using appropriate methods, this bias can result in attenuation or even reversal of the estimated effects of exposures on health outcomes. Recent advances in computing power, coupled with state-of-the-art statistical methods, have greatly increased the ability of analysts to control healthy worker survivor bias. However, these methods have not been widely adopted by occupational epidemiologists. We update the seminal review by Arrighi and Hertz-Picciotto (Epidemiology.1994; 5: 186-196) of the sources and methods to control healthy worker survivor bias. In our update, we discuss methodologic advances since the publication of that review, notably with a consideration of how directed acyclic graphs can inform the choice of appropriate analytic methods. We summarize and discuss methods for addressing this bias, including recent work applying g-methods to account for employment status as a time-varying covariate affected by prior exposure. In the presence of healthy worker survivor bias, g-methods have advantages for estimating less biased parameters that have direct policy implications and are clearly communicated to decision-makers.

Many countries recommend combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis immunization (Tdap) during pregnancy to stimulate transplacental transmission of pertussis antibodies to newborns. The immune system can be altered during pregnancy, potentially resulting in differing immunization risks in pregnant women. The safety of widespread Tdap immunization during pregnancy needs to be established. Our objective was to assess whether prenatal Tdap immunization was associated with adverse birth outcomes, and to evaluate the effect of timing of Tdap administration on these outcomes. We identified pregnancies at delivery in a large insurance claims database (2010-2014). Tdap immunization was categorized as optimal prenatal (27+weeks), early prenatal (

Introduction: Immune thrombocytopenia (ITP) is a rare platelet disorder that can lead to an increased tendency to bleed. Recommended first-line therapies include corticosteroids, intravenous immunoglobulin (IVIg) and intravenous (IV) anti-D. An estimated two-thirds of adult patients with ITP will develop persistent or chronic disease (ITP lasting 3-12 months or >12 months, respectively). Several evidence-based options for second-line treatment exist, but no randomized trials have directly compared one therapy to another. Patterns of treatment in routine clinical practice therefore vary. There is a paucity of data on current real-world treatment dynamics in ITP, and such data could help identify gaps in care and inform future studies of real-world comparative effectiveness and safety. We described the types of treatments administered following an ITP diagnosis, as well as the subsequent occurrence of bleeding and requirement for rescue therapy among adults being managed in routine practice in the United States (US). Methods: We used electronic health record data from hematology clinics across the US (Flatiron Health, Inc.) linked to MarketScan® employer-based and Medicare Supplemental administrative health insurance claims databases (Truven Health Analytics, Inc.). We included patients aged 18 years or older with a new ITP diagnosis from January 1, 2011 through June 30, 2016, continuous enrollment in MarketScan prior to diagnosis, and no previous diagnosis of a secondary cause of thrombocytopenia. The cumulative incidence of each ITP treatment after diagnosis was estimated using competing risk models to account for deaths occurring before initiation. Estimates were provided specifically for 90 days and 1 year following diagnosis to describe treatment uptake in the newly diagnosed and persistent phases, respectively. The incidence of bleeding events and rescue therapy was quantified after the start of the more prevalent second-line therapies: rituximab, splenectomy, and thrombopoietin receptor agonists (TPO RAs) - eltrombopag and romiplostim. Rescue therapies (those that rapidly increase platelet counts in the setting of severe thrombocytopenia or active bleeding) included IV anti-D, IVIg, IV steroids, and platelet transfusions. Results: Among the cohort of 447 adults diagnosed with primary ITP, 47% were male, 61% were white, 32% were 65 years or older, and the median lowest platelet count in the 60 days prior to diagnosis was 85x109/L (IQR: 39, 125). Use of each ITP therapy by 90 days and 12 months post-diagnosis are provided in the Table. Oral corticosteroids were the most commonly used; the cumulative incidence of initiation was 41% by 90 days and 50% by 1 year following ITP diagnosis. IV steroids and rituximab were the next most frequently used medications (16% and 11% at 90 days; and 26% and 16% by 1 year, respectively). The cumulative incidence of the TPO RAs, eltrombopag and romiplostim, by 90 days was 3% and 7%, respectively, and by 1 year was 5% and 9%, respectively. Splenectomy was relatively rare ( Conclusions: In this descriptive study of patients with primary ITP receiving care in the US, oral steroids were the most commonly used medication after diagnosis, reflecting their continued role as a frontline therapy. By 1 year after diagnosis, approximately 15% received rituximab, nearly 10% received romiplostim, and 5% received eltrombopag. Splenectomy was less common. Among the medical treatments, although bleeding risk overall appeared lowest in rituximab patients, oral steroid and rescue therapy use were lowest among the patients who initiated TPO RAs. Table. Table. Disclosures Cetin: Amgen Inc: Employment, Equity Ownership. Sharma:Amgen: Employment, Equity Ownership. Brookhart:Amgen Inc: Consultancy, Research Funding; NoviSci: Equity Ownership; Union Chimique Belge: Consultancy; GlaxoSmithKline: Consultancy; Merck: Consultancy; Genentech: Consultancy; TargetPharma: Consultancy; RxAnte: Consultancy; AstraZeneca: Research Funding. Altomare:Genentech: Consultancy; Ipsen: Other: Advisory Board Member; Amgen: Consultancy; Celgene: Other: Advisory Board Member; Novartis: Consultancy; Bayer: Consultancy; Incyte: Consultancy. Wasser:Amgen Inc: Consultancy; Novartis: Consultancy; Becton Dickinson: Equity Ownership; Abbott Labs: Equity Ownership; Biogen: Equity Ownership; Allergan: Equity Ownership; Eli Lilly: Equity Ownership; Incyte: Research Funding; Merck: Equity Ownership, Research Funding; Pfizer: Equity Ownership, Research Funding; Guardant: Research Funding.

High-dose inactivated, influenza vaccine was licensed by the FDA in December 2009 for adults aged 65 y and older. The ACIP did not issue or state a preference for a specific vaccine in the elderly population. The extent of its on-label and off-label use is unknown. Using the MarketScan Commercial Claims and Encounters and the Medicare Supplemental database, we identified individuals who received the high-dose influenza vaccine or the standard, seasonal trivalent influenza vaccine between January 1, 2010 and December 31, 2012. For people aged ≥65 y, we used multivariable regression to assess the association between patient and provider level variables and high-dose influenza vaccine versus standard influenza vaccine. We characterized all off-label high-dose vaccine administered to people younger than 65 y of age, and investigated whether sicker patients were targeted for off-label use by examining the association between various comorbid conditions and receipt of the high-dose vaccine among adults aged 18-64. Among patients aged ≥65 y who received an influenza vaccine, 18.4% received the high-dose vaccine. Uptake was minimal in 2010, but 25% and 32% of influenza shots were the high-dose formulation in 2011 and 2012, respectively. Almost 27,000 seniors received a second high-dose vaccine with a median of 368 d (IQR: 350-387 days) between doses. Older age, family practice physicians, and having PPO insurance were positively associated with receiving high-dose vaccine. There were 36,624 off-label high-dose vaccines administered. Half of the patients receiving off-label doses were aged 50-64. Adults aged 18-64 y receiving high-dose vaccine were more likely to have chronic comorbidities than people receiving standard influenza vaccine; however, there was not one specific illness that seemed to be targeted by physicians. In the first 3 y since licensure, use of the high-dose vaccine among seniors has been limited. The safety of this vaccine should be monitored closely among 2 groups of people - seniors receiving repeat doses and people

Background The Centers for Disease Control and Prevention recommends that all pregnant women in the United States receive tetanus-diphtheria-acellular pertussis (Tdap) immunization to prevent infant pertussis. While the vaccine may be administered at any time during pregnancy, the recommendations define administration at 27 to 36 weeks of gestation as optimal timing to prevent infant pertussis. These recommendations were primarily based on immunogenicity studies. The objective of this study was to examine the clinical effectiveness of prenatal Tdap, and to understand whether effectiveness varies by gestational age at immunization. Methods We performed a nationwide cohort study of pregnant women with deliveries in 2010–2014 and their infants. Commercial insurance claims data were used to identify receipt of Tdap immunization in the pregnant women, and hospitalizations and outpatient visits for pertussis in their infants until 18 months of age. To address the difficulties in diagnosing pertussis, we also employed a “probable pertussis” definition, as an inpatient or outpatient diagnosis of pertussis, plus antibiotic treatment with a macrolide or trimethoprim/sulfamethoxazole within 7 days of diagnosis. Pertussis occurrence was compared between infants of mothers who received prenatal Tdap (overall, and stratified by gestational age at administration) and infants of unvaccinated mothers. Results There were 675,167 mother–infant pairs included in the cohort. Among infants whose mothers received Tdap at any time during pregnancy, the rate of pertussis hospitalization was 50% lower (adjusted hazards ratio (HR) = 0.50, 95% CI: 0.23, 1.09), and the rate of probable pertussis was 42% lower (HR = 0.58, 95% CI: 0.38, 0.89) than infants of unimmunized mothers. Pertussis rates were also lower for infants whose mothers received prenatal Tdap during the third trimester. Infants whose mothers received Tdap before the third trimester also tended to have lower rates of pertussis, but these estimates were imprecise. Conclusion Infants of mothers who received prenatal Tdap experienced half the rate of pertussis as compared with infants of unimmunized mothers. Our results do not provide evidence to support changing the currently recommended timing of Tdap administration in pregnancy. Disclosures S. Becker-Dreps, Pfizer: Consultant and Grant Investigator, Consulting fee and Research grant; A. M. Butler, Astra Zeneca: Consultant, Support to institution; Amgen: Grant Investigator, Investigator initiated grant to institution; D. J. Weber, Merck: Consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium; Pfizer: Consultant, Consulting fee; J. B. Layton, Merck: Member of Center for Pharmacoepidemiology, Support to institution; GlaxoSmithKline: Member of Center for Pharmacoepidemiology, Support to institution; UCB Biosciences: Member of Center for Pharmacoepidemiology, Support to institution

The association between radon gas exposure and lung cancer has been well-documented in cohorts of underground uranium miners.1-7 However, traditional regression analysis techniques used in these studies focus on quantifying cumulative exposure-response functions that do not directly address the types of questions that concern regulators. The public health impacts of different policy options regarding radon concentrations in the workplace may be more useful to regulators than the estimated change in the excess relative rate of lung cancer per unit increase in cumulative exposure to radon. We apply the extended parametric g-formula8,9 to estimate the risk of lung cancer death had several historical radon exposure standards been in place throughout follow-up in an important cohort study of underground miners. The policy interventions that we consider are specified in terms of caps on monthly occupational radon exposure rather than limits on cumulative exposure (i.e., “limit radon exposure to X working level months per month while at work, and set monthly radon exposure to 0 working level months when not at work”). The interventions we consider are “threshold interventions”10 in which the intervention on radon exposure for a given month depends on the observed exposure for that month. The extended parametric g-formula has been used to estimate cumulative risk under threshold interventions in diverse substantive areas 11-15 . This approach was described by Robins9 to extend the standard parametric g-formula estimator to allow interventions to depend on the natural value of exposure. A formal discussion of the identifying conditions under which the extended parametric g-formula estimator can have a causal interpretation can be found in recent work by Richardson and Robins 16 and Young.17 Our implementation of the parametric g-formula also accommodates competing risks, as outlined by Taubman 11 and Cole.15 Here, we use the g-formula to estimate cumulative incidence of lung cancer mortality under various intervention scenarios and compute risk difference and risk ratio measures, which are often the most relevant estimates to present to the lay public and policy makers. These effect measures have intuitive interpretations as the estimated difference (or ratio) in cumulative incidence that would have been seen had the same population of miners been exposed to different dynamic exposure regimes corresponding to hypothetical industry guidelines. Estimates of attributable risk due to lung cancer derived in previous reports, such as the Biological Effects of Ionizing Radiation (BEIR) IV and BEIR VI reports, and life table calculations also aim to facilitate communication of the public health impact of radon exposure. However, the BEIR reports estimate the attributable fraction of radon-related excess lung cancer deaths, which conforms to change in risk given complete elimination of radon, while we focus on public health impacts of plausible policy interventions (i.e., reduction in radon exposure to specific limits, rather than elimination of radon exposure). In this work, we use the extended parametric g-formula to compare observed lung cancer mortality in the Colorado Plateau Uranium Miners cohort to estimated lung cancer mortality if radon exposure had been limited to three historical radon exposure standards in the U.S.

Objectives Guidelines to treat acute otitis media (AOM) were published in 2004. Initial declines in prescribing were shown, but it's unknown if they were sustained. We examine trends in antibiotic dispensing patterns to treat AOM among a large population of children. We also document trends in antibiotic failure. Study Design Children aged 3 months to 12 years with an AOM diagnosis, enrolled in a commercial claims database between January 1, 2000-December 31, 2011 were included. Pharmacy claims within 7 days of diagnosis were searched for antibiotic prescriptions. Antibiotic failure was defined as a dispensing of a different antibiotic class within 2-18 days after the first prescription. We analyzed trends in antibiotic use and failure by class of antibiotic and year. Results We identified over 4 million children under 13 years with AOM. The proportion of antibiotic dispensing decreased from 66.0% in 2005 to 51.9% in 2007, after which the instances of dispensing rebounded to pre-guideline levels. However, levels began decreasing again in 2010 and the antibiotic use rate in 2011 was 57.6%. Cephalosporin prescriptions increased by 41.5% over eleven years. Antibiotic failure decreased slightly, and macrolides had the lowest proportion of failures, while all other classes had failure rates around 10%. Conclusions In recent years, antibiotic dispensing to treat AOM remains high. In addition, the use of broad-spectrum antibiotics is increasing despite having a high rate of treatment failure. Overprescribing of antibiotics and use of non-penicillin therapy for AOM treatment could lead to the development of antibiotic-resistant infections.

BACKGROUND Observational studies of preventive medications, such as vaccinations, can suffer from the healthy-user bias because vaccinated patients may be healthier than unvaccinated patients. Indicators of health status and frailty suitable for attenuating this bias could be identified in administrative data. OBJECTIVE To examine the association of baseline variables and time-dependent hospitalization and skilled nursing care with the receipt of influenza vaccination in patients with end-stage renal disease. RESEARCH DESIGN Observational cohort study using United States Renal Data System files each year from 1999 to 2005. SUBJECTS Population-based cohorts that included >115,000 adult, hemodialysis patients each year. MEASURES We estimated hazard ratios for the association of baseline variables and time-dependent hospitalization days and skilled nursing days with influenza vaccination, controlling for demographic and baseline health status variables. RESULTS Vaccination coverage increased from 47% in 1999 to 60% in 2005. Patients with any length of hospitalization were less likely to be vaccinated, however, the association was stronger in patients with longer stays [15-25 d: hazard ratio=0.64 (95% confidence interval, 0.62-0.65); 26-30 d: 0.40 (0.38-0.42)]. Patients with any length of skilled nursing care of >1 day had similar estimates; these patients were also less likely to be vaccinated [26-30 d: 0.66 (0.64-0.69)]. CONCLUSIONS Patients with long hospitalizations or skilled nursing stays were less likely to be vaccinated suggesting evidence of the healthy-user effect. These variables could be used to account for bias in studies of preventive services in patients on dialysis.

Background Although the influenza vaccine is recommended for patients with end-stage renal disease, little is known about its effectiveness. Observational studies of vaccine effectiveness (VE) are challenging because vaccinated subjects may be healthier than unvaccinated subjects. Methods Using US Renal Data System data, we estimated VE for influenza-like illness, influenza/pneumonia hospitalization, and mortality in adult patients undergoing hemodialysis by using a natural experiment created by the year-to-year variation in the match of the influenza vaccine to the circulating virus. We compared vaccinated patients in matched years (1998, 1999, and 2001) with a mismatched year (1997) using Cox proportional hazards models. Ratios of hazard ratios compared vaccinated patients between 2 years and unvaccinated patients between 2 years. We calculated VE as 1 − effect measure. Results Vaccination rates were less than 50% each year. Conventional analysis comparing vaccinated with unvaccinated patients produced average VE estimates of 13%, 16%, and 30% for influenza-like illness, influenza/pneumonia hospitalization, and mortality, respectively. When restricted to the preinfluenza period, results were even stronger, indicating bias. The pooled ratio of hazard ratios comparing matched seasons with a placebo season resulted in a VE of 0% (95% CI, −3% to 2%) for influenza-like illness, 2% (−2% to 5%) for hospitalization, and 0% (−3% to 3%) for death. Conclusions Relative to a mismatched year, we found little evidence of increased VE in subsequent well-matched years, suggesting that the current influenza vaccine strategy may have a smaller effect on morbidity and mortality in the end-stage renal disease population than previously thought. Alternate strategies (eg, high-dose vaccine, adjuvanted vaccine, and multiple doses) should be investigated.

Health care utilization for HIV-1-infected patients appears to be declining in the United States as a result of highly active antiviral therapy (HAART); yet the opposite appears true in the HIV/hepatitis C virus (HCV) coinfected population. The reasons for this difference are not well understood. We examined the rates and reasons for emergency department visits and hospital admissions at an academic tertiary care medical center for HIV/HCV coinfected patients as compared to HIV-1 monoinfected patients, using a retrospective matched cohort study design. HIV/HCV coinfected patients had higher rates of health care utilization (emergency department visits 43.9 versus 7.1 per 100 person-years; hospital admissions 18.2 versus 6.7 per 100 person-years, for HIV coinfected and monoinfected, respectively). This increase was not solely due to liver related events. Instead, comorbidities such as diabetes, renal disease, and psychiatric/substance abuse played a larger role in the health-care utilization in the HIV/HCV coinfected population.