Utilization of broad- versus narrow-spectrum antibiotics for the treatment of outpatient community-acquired pneumonia among adults in the United States.

PURPOSE: To characterize antibiotic utilization for outpatient community-acquired pneumonia (CAP) in the United States. METHODS: We conducted a cohort study among adults 18-64 years diagnosed with outpatient CAP and a same-day guideline-recommended oral antibiotic fill in the MarketScan® Commercial Database (2008-2019). We excluded patients coded for chronic lung disease or immunosuppressive disease; recent hospitalization or frequent healthcare exposure (e.g., home wound care, patients with cancer); recent antibiotics; or recent infection. We characterized utilization of broad-spectrum antibiotics (respiratory fluoroquinolone, ß-lactam + macrolide, ß-lactam + doxycycline) versus narrow-spectrum antibiotics (macrolide, doxycycline) overall and by patient- and provider-level characteristics. Per 2007 IDSA/ATS guidelines, we stratified analyses by otherwise healthy patients and patients with comorbidities (coded for diabetes; chronic heart, liver, or renal disease; etc.). RESULTS: Among 263 914 otherwise healthy CAP patients, 35% received broad-spectrum antibiotics (not recommended); among 37 161 CAP patients with comorbidities, 44% received broad-spectrum antibiotics (recommended). Ten-day antibiotic treatment durations were the most common for all antibiotic classes except macrolides. From 2008 to 2019, broad-spectrum antibiotic use substantially decreased from 45% to 19% in otherwise healthy patients (average annual percentage change [AAPC], -7.5% [95% CI -9.2%, -5.9%]), and from 55% to 29% in patients with comorbidities (AAPC, -5.8% [95% CI -8.8%, -2.6%]). In subgroup analyses, broad-spectrum antibiotic use varied by age, geographic region, provider specialty, and provider location. CONCLUSIONS: Real-world use of broad-spectrum antibiotics for outpatient CAP declined over time but remained common, irrespective of comorbidity status. Prolonged duration of therapy was common. Antimicrobial stewardship is needed to aid selection according to comorbidity status and to promote shorter courses.

Comparative Safety and Attributable Healthcare Expenditures Following Inappropriate Versus Appropriate Outpatient Antibiotic Prescriptions Among Adults With Upper Respiratory Infections.

BACKGROUND: Little is known about the clinical and financial consequences of inappropriate antibiotics. We aimed to estimate the comparative risk of adverse drug events and attributable healthcare expenditures associated with inappropriate versus appropriate antibiotic prescriptions for common respiratory infections. METHODS: We established a cohort of adults aged 18 to 64 years with an outpatient diagnosis of a bacterial (pharyngitis, sinusitis) or viral respiratory infection (influenza, viral upper respiratory infection, nonsuppurative otitis media, bronchitis) from 1 April 2016 to 30 September 2018 using Merative MarketScan Commercial Database. The exposure was an inappropriate versus appropriate oral antibiotic (ie, non-guideline-recommended vs guideline-recommended antibiotic for bacterial infections; any vs no antibiotic for viral infections). Propensity score-weighted Cox proportional hazards models were used to estimate the association between inappropriate antibiotics and adverse drug events. Two-part models were used to calculate 30-day all-cause attributable healthcare expenditures by infection type. RESULTS: Among 3 294 598 eligible adults, 43% to 56% received inappropriate antibiotics for bacterial and 7% to 66% for viral infections. Inappropriate antibiotics were associated with increased risk of several adverse drug events, including Clostridioides difficile infection and nausea/vomiting/abdominal pain (hazard ratio, 2.90; 95% confidence interval, 1.31-6.41 and hazard ratio, 1.10; 95% confidence interval, 1.03-1.18, respectively, for pharyngitis). Thirty-day attributable healthcare expenditures were higher among adults who received inappropriate antibiotics for bacterial infections ($18-$67) and variable (-$53 to $49) for viral infections. CONCLUSIONS: Inappropriate antibiotic prescriptions for respiratory infections were associated with increased risks of patient harm and higher healthcare expenditures, justifying a further call to action to implement outpatient antibiotic stewardship programs.

Utilization of nonguideline concordant antibiotic treatment following acute otitis media in children in the United States.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Nonguideline concordant antibiotic use is common when treating AOM in children, including use of broad-spectrum agents and longer-than-recommended antibiotic durations.

Association of Adverse Events With Antibiotic Treatment for Urinary Tract Infection.

BACKGROUND: Little is known about the relative harms of different antibiotic regimens prescribed to treat uncomplicated urinary tract infection (UTI). We sought to compare the risk of adverse events associated with commonly used oral antibiotic regimens for the outpatient treatment of uncomplicated UTI. METHODS: Using data from the IBM® MarketScan® Commercial Database, we identified 1 169 033 otherwise healthy, nonpregnant women aged 18-44 years with uncomplicated UTI who initiated an oral antibiotic with activity against common uropathogens from 1 July 2006 to 30 September 2015. We used propensity score-weighted Kaplan-Meier methods and Cox proportional hazards regression models to estimate the association between antibiotic agent and adverse events. RESULTS: Of 2 first-line agents, trimethoprim-sulfamethoxazole (vs nitrofurantoin) was associated with higher risk of several adverse drug events including hypersensitivity reaction (hazard ratio, 2.62; 95% confidence interval, 2.30-2.98), acute renal failure (2.56; 1.55-4.25), skin rash (2.42; 2.13-2.75), urticaria (1.37; 1.19-1.57), abdominal pain (1.14; 1.09-1.19), and nausea/vomiting (1.18; 1.10-1.28), but a similar risk of potential microbiome-related adverse events. Compared with nitrofurantoin, non-first-line agents were associated with higher risk of several adverse drug events and potential microbiome-related adverse events including non-Clostridium difficile diarrhea, C. difficile infection, vaginitis/vulvovaginal candidiasis, and pneumonia. Treatment duration modified the risk of potential microbiome-related adverse events. CONCLUSIONS: The risks of adverse drug events and potential microbiome-related events differ widely by antibiotic agent and duration. These findings underscore the utility of using real-world data to fill evidentiary gaps related to antibiotic safety.

Integrase Strand Transfer Inhibitors Are Associated With Incident Diabetes Mellitus in People With Human Immunodeficiency Virus.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH). Less is known about the risk of other metabolic outcomes such as diabetes mellitus and hyperglycemia. METHODS: IBM® MarketScan® databases for commercially and Medicaid-insured adults were used to identify PWH newly initiating antiretroviral therapy (ART). The primary outcome was a composite of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation and was identified using International Classification of Disease, Ninth revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis and procedure codes and Current Procedural Terminology, 4th Edition (CPT-4) codes. To examine the relationship between INSTI use and the composite outcome, we estimated the risk using Cox proportional hazards models with calendar time-specific standardized mortality ratio weights. RESULTS: Of 42 382 PWH who initiated ART between 1 July 2007 and 30 June 2018, 22 762 (54%) were treated with INSTI-based regimens. Mean age was 38 years, 74% were male, and 19% were Medicaid insured. PWH on INSTIs were 31% more likely to develop new-onset diabetes mellitus/hyperglycemia (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.48]) compared with those who initiated non-INSTI-based regimens. When examined individually, the highest risk was associated with elvitegravir (HR, 1.54; 95% CI, 1.32-1.97; P < .001) and the lowest risk with raltegravir (HR, 1.19; 95% CI, 1.03-1.37; P = .02). CONCLUSIONS: INSTI use was associated with increased risk of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation.

The impact of infectious diseases consultation for children with Staphylococcus aureus bacteremia.

BACKGROUND: Despite clear benefit of improved outcomes in adults, the impact of infectious diseases (ID) consultation for Staphylococcus aureus bacteremia in children remains understudied. METHODS: To assess the impact of pediatric ID consultation on management and outcomes, we conducted a cohort study of children with S. aureus bacteremia at St. Louis Children's Hospital from 2011 to 2018. We assessed adherence to six established quality-of-care indicators (QCIs). We applied propensity score methodology to examine the impact of ID consultation on risk of treatment failure, a composite of all-cause mortality or hospital readmission within 90 days. RESULTS: Of 306 patients with S. aureus bacteremia, 193 (63%) received ID consultation. ID consultation was associated with increased adherence to all QCIs, including proof-of-cure blood cultures, indicated laboratory studies, echocardiography, source control, targeted antibiotic therapy, and antibiotic duration. Obtaining proof-of-cure blood cultures and all indicated laboratory studies were associated with improved outcomes. In propensity score-weighted analyses, risk of treatment failure was similar among patients who did and did not receive ID consultation. However, the number of events was small and risk estimates were imprecise. CONCLUSIONS: For children with S. aureus bacteremia, ID consultation improved adherence to QCIs, some of which were associated with improved clinical outcomes. IMPACT: In children with Staphylococcus aureus bacteremia, consultation by an infectious diseases (ID) physician improved adherence to established quality-of-care indicators (QCIs). The current literature regarding ID consultation in pediatric S. aureus bacteremia is sparse. Three prior international studies demonstrated improved quality of care with ID consultation, though results were disparate regarding clinical outcomes. This article impacts the current literature by strengthening the evidence that ID consultation in children improves adherence to QCIs, and demonstrates that adherence to QCIs improves clinical outcomes.

Estimating the Effectiveness of Rotavirus Vaccine Schedules.

BACKGROUND: Important questions exist regarding the comparative effectiveness of alternative childhood vaccine schedules; however, optimal approaches to studying this complex issue are unclear. METHODS: We applied methods for studying dynamic treatment regimens to estimate the comparative effectiveness of different rotavirus vaccine (RV) schedules for preventing acute gastroenteritis-related emergency department (ED) visits or hospitalization. We studied the effectiveness of six separate protocols: one- and two-dose monovalent rotavirus vaccine (RV1); one-, two-, and three-dose pentavalent rotavirus vaccine (RV5); and no RV vaccine. We used data on all infants to estimate the counterfactual cumulative risk for each protocol. Infants were censored when vaccine receipt deviated from the protocol. Inverse probability of censoring-weighted estimation addressed potentially informative censoring by protocol deviations. A nonparametric group-based bootstrap procedure provided statistical inference. RESULTS: The method yielded similar 2-year effectiveness estimates for the full-series protocols; weighted risk difference estimates comparing unvaccinated children to those adherent to either full-series (two-dose RV1, three-dose RV5) corresponded to four fewer hospitalizations and 12 fewer ED visits over the 2-year period per 1,000 children. We observed dose-response relationships, such that additional doses further reduced risk of acute gastroenteritis. Under a theoretical intervention to fully vaccinate all children, the 2-year risk differences comparing full to observed adherence were 0.04% (95% CI = 0.03%, 0.05%) for hospitalizations and 0.17% (95% CI = 0.14%, 0.19%) for ED visits. CONCLUSIONS: The proposed approach can generate important evidence about the consequences of delaying or skipping vaccine doses, and the impact of interventions to improve vaccine schedule adherence.

Risk of antibiotic treatment failure in premenopausal women with uncomplicated urinary tract infection.

PURPOSE: Acute uncomplicated urinary tract infections (UTIs) are among the most common indications for antibiotic prescriptions in otherwise healthy women. We compared the risk of treatment failure of antibiotic regimens for outpatient treatment of UTI in real-world practice. METHODS: We identified non-pregnant, premenopausal women diagnosed with uncomplicated, lower tract UTI and prescribed an oral antibiotic with activity against common uropathogens. We used propensity score-weighted Kaplan-Meier functions to estimate 30-day risks and risk differences (RD) for pyelonephritis and UTI-related antibiotic prescription switch. RESULTS: Of 1 140 602 patients, the distribution of index prescriptions was 44% fluoroquinolones (non-first-line), 28% trimethoprim-sulfamethoxazole (TMP/SMX) (first-line), 24% nitrofurantoin (first-line), 3% narrow-spectrum ß-lactams (non-first-line), 1% broad-spectrum ß-lactams (non-first-line), and 1% amoxicillin/ampicillin (non-recommended). Compared to the risk of pyelonephritis for nitrofurantoin (0.3%), risks were higher for TMP/SMX (RD, 0.2%; 95% CI, 0.2%-0.2%) and broad-spectrum ß-lactams (RD, 0.2%; 95% CI, 0.1%-0.4%). Compared to the risk of prescription switch for nitrofurantoin (12.7%), the risk was higher for TMP/SMX (RD 1.6%; 95% CI 1.3%-1.7%) but similar for broad-spectrum ß-lactams (RD -0.7%; 95% CI -1.4%-0.1%) and narrow-spectrum ß-lactams (RD -0.3%; 95% CI -0.8%-0.2%). Subgroup analyses suggest TMP/SMX treatment failure may be due in part to increasing uropathogen resistance over time. CONCLUSIONS: The risk of treatment failure differed by antibiotic agent, with higher risk associated with TMP/SMX versus nitrofurantoin, and lower or similar risk associated with broad- versus narrow-spectrum ß-lactams. Given serious safety warnings for fluoroquinolones, these results suggest that nitrofurantoin may be preferable as the first-line agent for outpatient treatment of uncomplicated UTI.

Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccine Among Patients Receiving Maintenance Hemodialysis.

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.

Association of State Legislation of Human Papillomavirus Vaccination with Vaccine Uptake Among Adolescents in the United States.

We assessed the association of state legislation with adolescent human papillomavirus (HPV) vaccination rates in states that legislated information dissemination or administration of HPV vaccination. Using insurance claims, we calculated monthly HPV vaccination rates (November 2009-December 2017) among adolescents in states that passed HPV vaccination legislation during that period: Missouri (July 2010), Kentucky (February 2012), Indiana (March 2013), Oregon (June 2013). We used segmented regression to estimate levels and trends of HPV vaccination rates, comparing pre-legislation to post-legislation segments, adjusting for seasonal vaccination patterns and changes to the vaccination recommendation among males during the study period. Indiana's legislation allowed pharmacists to administer HPV vaccination; legislation in Kentucky, Missouri, and Oregon included provisions HPV and cervical cancer education. No statistically significant increases in HPV vaccination levels or trends were observed in the post-legislation segments among adolescents overall; however, a significant post-legislation increase in vaccination trends was observed among boys in Missouri (ß = 0.16, p = 0.03). Evidence for a positive impact of legislation on HPV vaccination rates is limited. The scarcity of policies that directly facilitate or promote HPV vaccination, and the breadth of exemptions to school vaccination requirements, may limit the effectiveness of these policies. Continuing efforts to introduce and pass legislation that directly facilitates HPV vaccination, combined with promoting existing evidence-based interventions, can provide opportunities to identify the most effective strategies to increase adolescent HPV vaccination rates.

Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness: Comparison of High-dose Versus Standard-dose Vaccines.

BACKGROUND: Estimating influenza vaccine effectiveness using an unvaccinated comparison group may result in biased effect estimates. OBJECTIVES: To explore the reduction of confounding bias in an active comparison of high-dose versus standard-dose influenza vaccines, as compared with vaccinated versus unvaccinated comparisons. METHODS: Using Medicare data from the United States end-stage renal disease program (2009-2013), we compared the risk of all-cause mortality among recipients of high-dose vaccine (HDV) versus standard-dose vaccine (SDV), HDV versus no vaccine, and SDV versus no vaccine. To quantify confounding bias, analyses were restricted to the preinfluenza season, when the protective effect of vaccination should not yet be observed. We estimated the standardized mortality ratio-weighted cumulative incidence functions using Kaplan-Meier methods and calculated risk ratios (RRs) and risk differences between groups. RESULTS: Among 350,921 eligible patients contributing 825,642 unique patient preinfluenza seasons, 0.8% received HDV, 70.5% received SDV, and 28.7% remained unvaccinated. Comparisons with unvaccinated patients yielded spurious decreases in mortality risk during the preinfluenza period, for HDV versus none [RR, 0.60; 95% confidence interval (CI), 0.51-0.70)] and SDV versus none (RR, 0.72; 95% CI, 0.70-0.75). The effect estimate was attenuated in the HDV versus SDV comparison (RR, 0.89; 95% CI, 0.77-1.03). Estimates on the absolute scale followed a similar pattern. CONCLUSIONS: The HDV versus SDV comparison yielded less-biased estimates of the all-cause mortality before influenza season compared to those with nonuser comparison groups. Vaccine effectiveness and safety researchers should consider the active comparator design to reduce bias due to differences in underlying health status between vaccinated and unvaccinated individuals.

Informative censoring by health plan disenrollment among commercially insured adults.

PURPOSE: Health plan disenrollment occurs frequently in commercial insurance claims databases. If individuals who disenroll are different from those who remain enrolled, informative censoring may bias descriptive statistics as well as estimates of causal effect. We explored whether patterns of disenrollment varied by patient or health plan characteristics. METHODS: In a large cohort of commercially insured adults (2007-2013), we examined two primary outcomes: (a) within-year disenrollment between January 1 and December 30, which was considered to occur due to patient disenrollment from the health plan, and (b) end-of-year disenrollment on December 31, which was considered to occur due to either patient disenrollment from the health plan or withdrawal of the entire health plan from the commercial insurance database. In yearly cohorts, we identified factors independently associated with disenrollment by using log-binomial regression models to estimate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Among 2 053 100 unique patient years, the annual proportion of within-year disenrollment remained steady across years (range, 13% to 14%) whereas the annual proportion of end-of-year disenrollment varied widely (range, 8% to 26%). Independent predictors of within-year disenrollment were related to health status, including age, comorbidities, frailty, hospitalization, emergency room visits, use of durable medical equipment, use of preventive care, and use of prescription medications. In contrast, independent predictors of end-of-year disenrollment were related to health plan characteristics including insurance plan type and geographic characteristics. CONCLUSIONS: Differential risk of disenrollment suggests that analytic approaches to address selection bias should be considered in studies using commercial insurance databases.

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

Rotavirus vaccination and short-term risk of adverse events in US infants.

BACKGROUND: The aim of this study was to evaluate the short-term risk of adverse events associated with rotavirus vaccine (RV) in infants, overall and by vaccine formulation (three-dose pentavalent, RV5; two-dose monovalent, RV1). METHODS: We identified US newborns with commercial insurance during 2006-2014 receiving a diphtheria-tetanus-pertussis vaccine (DTaP) dose and assessed if RV was administered concurrently. We followed infants for 30 days after each dose for diagnoses of intussusception, other gastrointestinal events, seizures, Kawasaki disease, thrombocytopenia, otitis media, all-cause emergency department visits, and all-cause hospitalisations. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) with multivariable Cox proportional hazards models comparing: (a) those receiving DTaP+RV vs those receiving DTaP alone; and (b) RV5 vs RV1. Analyses were performed separately within DTaP doses and then meta-analysed across doses. RESULTS: We identified 1 031 431 first DTaP doses, 821 833 second doses, and 615 293 third doses; 79.2% had a concurrent RV, 94.1% of which were RV5. Absolute risks of serious outcomes were very low. Compared to infants who received DTaP alone, infants who received RV+DTaP did not experience consistently increased risk of intussusception (hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.68, 1.88) or any other outcome except for otitis media after dose 2: HR 1.11, 95% CI 1.08, 1.15. This increased otitis media risk was not as pronounced in RV5 when comparing RV5 to RV1; HR 0.92, 95% CI 0.89, 0.95. CONCLUSIONS: These data were not consistent with an increased risk of intussusception or other adverse events following vaccination with RV, except potentially for a small increased risk of otitis media, particularly in RV1.

Treatment dynamics of bone-targeting agents among men with bone metastases from prostate cancer in the United States.

PURPOSE: To examine the dynamics of treatment with 2 bone-targeting agents (BTAs)-denosumab and zoledronic acid-among men with bone metastases from prostate cancer. METHODS: Using electronic health record data from oncology practices across the US, we identified prostate cancer patients diagnosed with bone metastasis in 2012/2013 without evidence of BTA use within 6 months prior to diagnosis. We examined the risk and predictors of BTA initiation, interruption, and re-initiation. RESULTS: Among 897 men diagnosed with prostate cancer, the cumulative incidence of BTA initiation after bone metastasis diagnosis was 34% (95% confidence interval [CI], 31-37%) at 30 days, 64% (95% CI, 61-68%) at 180 days, and 88% (95% CI, 85-91%) at 2 years. Denosumab was initiated more frequently than zoledronic acid. Men with diabetes, more bone lesions, history of androgen deprivation therapy, or no hospice enrollment were more likely to initiate treatment. Following initiation, the cumulative incidence of treatment interruption was 17% (95% CI, 14-19%) at 60 days and 70% (95% CI, 66-74%) at 2 years, with interruption more likely among patients receiving emerging therapies for prostate cancer or enrolling in hospice. The cumulative incidence of re-initiation following interruption was 36.3% (95% CI, 32.7-40.2%) at 15 days, 49.8% (95% CI, 45.9-54.1%) at 30 days, and 81.0% (95% CI, 77.5-84.7%) at 1 year. CONCLUSIONS: Bone-targeting agent therapy is initiated by the majority of men living with bone metastases following a prostate cancer diagnosis; however, the timing of initiation is highly variable. Once on treatment, gaps or interruptions in therapy are common.

Comparative Effectiveness of Iron and Erythropoiesis-Stimulating Agent Dosing on Health-Related Quality of Life in Patients Receiving Hemodialysis.

BACKGROUND: The potential effects of iron-dosing strategies and erythropoiesis-stimulating agents (ESAs) on health-related quality of life (HRQoL) in the dialysis population are unclear. We examined the independent associations of bolus versus maintenance iron dosing and high versus low ESA dosing on HRQoL. STUDY DESIGN: Retrospective cohort design. SETTING & PARTICIPANTS: Clinical data (2008-2010) from a large dialysis organization merged with data from the US Renal Data System. 13,039 patients receiving center-based hemodialysis were included. PREDICTOR: Iron and ESA dosing were assessed during 1-month (n=14,901) and 2-week (n=15,296) exposure periods. OUTCOMES: HRQoL was measured by the Kidney Disease Quality of Life (KDQOL) instrument (0-100 scale) during a 3-month follow-up period. MEASUREMENTS: Generalized linear mixed models, adjusting for several covariates, were used to estimate associations between iron and ESA dosing and HRQoL overall and for clinically relevant subgroups. RESULTS: For the 1-month exposure period, patients with lower baseline hemoglobin levels who received higher ESA dosing had higher physical health and kidney disease symptom scores (by 2.4 [95% CI, 0.6-4.2] and 5.6 [95% CI, 2.8-8.4] points, respectively) in follow-up than patients who received lower ESA dosing. For the 2-week exposure period, patients with low baseline hemoglobin levels who received bolus dosing had higher mental health scores (by 1.9 [95% CI, 0.0-3.8] points) in follow-up. Within the low-baseline-hemoglobin subgroup, individuals with a catheter or dialysis vintage less than 1 year who received higher ESA dosing had higher HRQoL scores in follow-up (by 5.0-9.9 points) and individuals with low baseline transferrin saturations who received bolus dosing had higher HRQoL scores in follow-up (by 2.6-5.8 points). LIMITATIONS: Observational design; short duration of observation. CONCLUSIONS: For individuals with low baseline hemoglobin levels, higher ESA dosing and bolus iron dosing were associated with slightly higher HRQoL scores in follow-up. These differences became more pronounced and clinically relevant for specific subgroups.

Cancer incidence among US Medicare ESRD patients receiving hemodialysis, 1996-2009.

BACKGROUND: Patients with end-stage renal disease (ESRD) receiving dialysis have been reported to have increased risk of cancer. However, contemporary cancer burden estimates in this population are sparse and do not account for the high competing risk of death characteristic of dialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: US adult patients enrolled in Medicare's ESRD program who received in-center hemodialysis. FACTORS: Demographic/clinical characteristics. OUTCOMES: For overall and site-specific cancers identified using claims-based definitions, we calculated annual incidence rates (1996-2009). We estimated 5-year cumulative incidence since dialysis therapy initiation using competing-risk methods. RESULTS: We observed a constant rate of incident cancers for all sites combined, from 3,923 to 3,860 cases per 100,000 person-years (annual percentage change, 0.1; 95% CI, -0.4 to 0.6). Rates for some common site-specific cancers increased (ie, kidney/renal pelvis) and decreased (ie, colon/rectum, lung/bronchus, pancreas, and other sites). Of 482,510 incident hemodialysis patients, cancer was diagnosed in 37,128 within 5 years after dialysis therapy initiation. The 5-year cumulative incidence of any cancer was 9.48% (95% CI, 9.39%-9.57%) and was higher for certain subgroups: older age, males, nonwhites, non-Hispanics, nondiabetes primary ESRD cause, recent dialysis therapy initiation, and history of transplantation evaluation. Among blacks and whites, we observed 35,767 cases compared with 25,194 expected cases if the study population had experienced rates observed in the US general population (standardized incidence ratio [SIR], 1.42; 95% CI, 1.41-1.43). Risk was most elevated for cancers of the kidney/renal pelvis (SIR, 4.03; 95% CI, 3.88-4.19) and bladder (SIR, 1.57; 95% CI, 1.51-1.64). LIMITATIONS: Claims-based cancer definitions have not been validated in the ESRD population. Information for cancer risk factors was not available in our data source. CONCLUSIONS: These results suggest a high burden of cancer in the dialysis population compared to the US general population, with varying patterns of cancer incidence in subgroups.

Trends in Anemia Management in Hemodialysis Patients with Cancer.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs), intravenous iron, and blood transfusion are used to treat anemia in both end-stage renal disease (ESRD) and cancer. However, anemia treatment patterns have not been described among ESRD patients undergoing hemodialysis with concurrent cancer, especially in the recent era of ESA-related safety concerns. METHODS: We analyzed Medicare data from a cohort of hemodialysis patients diagnosed with incident cancer. We used multivariable generalized linear models to estimate trends and patterns in ESA use, iron use, transfusion use, epoetin alfa (EPO) dose, iron dose, and resulting hemoglobin levels (2000-2011). RESULTS: Of 43,760 eligible patients, quarterly ESA use declined slightly from a peak of 94.1 to 90.0%. Quarterly EPO dose increased from 2000 to 2004, then declined; quarterly hemoglobin levels followed a similar pattern. Iron use increased rapidly from 46.9 to 79.3%. Iron dose increased until 2010 and then declined. There was an increase in the quarterly transfusion use (6.3-11.7%) and in the mean number of transfusion days per year (1.4-1.8). Anemia treatment patterns varied by demographic/clinical subgroups, especially among patients receiving chemotherapy, who required higher ESA use, EPO dose, and frequency of transfusions. CONCLUSIONS: Despite safety concerns about ESAs in both the ESRD and cancer populations, the proportion of hemodialysis patients with cancer who used ESAs between 2000 and 2011 remained extremely high. EPO dose and hemoglobin levels increased and then decreased. Iron use, iron dose, and transfusions increased substantially. Future research examining the risk-benefit profile of different anemia management strategies in the dialysis population with cancer is needed.

Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia.

OBJECTIVE: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. DESIGN: We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations. RESULTS: Two correlated SNPs--rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. CONCLUSIONS: This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.