Yuan-Shung Huang

Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007.

OBJECTIVES: The goals were to determine whether there has been an increase in the rate of venous thromboembolism (VTE) in pediatric tertiary care hospitals and to evaluate the use of anticoagulants in the treatment of hospitalized pediatric patients with VTE. METHODS: A retrospective cohort study of patients <18 years of age who were discharged from 35 to 40 childrens hospitals (depending on the year) across the United States in 2001–2007 was performed. By using the Pediatric Health Information System administrative database, cases were assessed for discharge diagnosis codes for VTE; the use of anticoagulants was assessed by using patient-specific pharmacy files. RESULTS: During the 7-year study period, in which 11337 hospitalized patients were diagnosed with VTE, the annual rate of VTE increased by 70%, from 34 to 58 cases per 10000 hospital admissions (P < .001). This increase was observed in neonates, infants, children, and adolescents. The majority (63%) of children with VTE had ≥1 coexisting chronic complex medical condition. Pediatric malignancy was the medical comorbid condition associated most strongly with recurrent VTE (P < .001). The proportion of children with VTE who were treated with enoxaparin increased from 29% to 49% during this time period (P < .001); the use of warfarin decreased slightly from 11.4% to 9.6% (P = .02). Increasing age was associated with increased likelihood of patients with VTE being treated with either enoxaparin or warfarin. CONCLUSION: This multicenter study demonstrates a dramatic increase in the diagnosis of VTE at childrens hospitals from 2001 to 2007.

Off-label recombinant factor VIIa use and thrombosis in children: a multi-center cohort study.

OBJECTIVE To describe the off-label use of recombinant factor VIIa (rFVIIa) in tertiary care pediatric hospitals across the United States and to assess thrombotic events. STUDY DESIGN A retrospective multi-center cohort study using the Pediatric Health Information System administrative database. Children 18 years of age or younger who received rFVIIa between 2000 and 2007 were included. A label admission was defined as an admission with an International Classification of Diseases diagnostic code for hemophilia or factor VII deficiency; admissions without these codes were classified as off-label. RESULTS There were 4942 rFVIIa admissions, representing 3764 individual subjects; 74% (3655) of the admissions were off-label. There was a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007 (from 2 to 20.8 per 10 000 hospital admissions, P < .001). The mortality rate in the off-label group was 34% (1258/3655). Thrombotic events occurred in 10.9% (399/3655) of the off-label admissions. CONCLUSIONS The off-label use of rFVIIa in hospitalized children is increasing rapidly despite the absence of adequate clinical trials demonstrating safety and efficacy. Thrombotic events are common and mortality is high among patients receiving off-label rFVIIa. Further studies are warranted to determine whether these adverse events are attributable to rFVIIa.

Risk for Incident Diabetes Mellitus Following Initiation of Second-Generation Antipsychotics Among Medicaid-Enrolled Youths

IMPORTANCE Second-generation antipsychotics (SGAs) have increasingly been prescribed to Medicaid-enrolled children, either singly or in a medication combination. Although metabolic adverse effects have been linked to SGA use in youths, estimating the risk for type 2 diabetes mellitus, a rarer outcome, has been challenging. OBJECTIVE To determine whether SGA initiation was associated with an increased risk for incident type 2 diabetes mellitus. Secondary analyses examined the risk associated with multiple-drug regimens, including stimulants and antidepressants, as well as individual SGAs. DESIGN, SETTING, AND PARTICIPANTS Retrospective national cohort study of Medicaid-enrolled youths between January 2003 and December 2007. In this observational study using national Medicaid Analytic eXtract data files, initiators and noninitiators of SGAs were identified in each month. Included in this study were US youths aged 10 to 18 years with a mental health diagnosis and enrolled in a Medicaid fee-for-service arrangement during the study. Those with chronic steroid exposure, a diagnosis of diabetes mellitus, or SGA use during a 1-year look-back period were ineligible. The mean follow-up time for all participants was 17.2 months. Youths were followed up until diagnosis of diabetes mellitus or end of follow-up owing to censoring caused by the transition into a Medicaid managed care arrangement or Medicaid ineligibility (the end of available data). Propensity weights were developed to balance observed demographic and clinical characteristics between exposure groups. Discrete failure time models were fitted using weighted logistic regression to estimate the risk for incident diabetes mellitus between initiators and noninitiators. EXPOSURE A filled SGA prescription. MAIN OUTCOMES AND MEASURES Incident type 2 diabetes mellitus identified through visit and pharmacy claims during the observation period. RESULTS Among 107,551 SGA initiators and 1,221,434 noninitiators, the risk for incident diabetes mellitus was increased among initiators (odds ratio [OR], 1.51; 95% CI, 1.35-1.69; P < .001). Compared with youths initiating only SGAs, the risk was higher among SGA initiators who used antidepressants concomitantly at the time of SGA initiation (OR, 1.54; 95% CI, 1.17-2.03; P = .002) but was not significantly different for SGA initiators who were concomitantly using stimulants. As compared with a reference group of risperidone initiators, the risk was higher among those initiating ziprasidone (OR, 1.61; 95% CI, 0.99-2.64; P = .06) and aripiprazole (OR, 1.58; 95% CI, 1.21-2.07; P = .001) but not quetiapine fumarate or olanzapine. CONCLUSIONS AND RELEVANCE The risk for incident type 2 diabetes mellitus was increased among youths initiating SGAs and was highest in those concomitantly using antidepressants. Compared with risperidone, newer antipsychotics were not associated with decreased risk.

Merging of the National Cancer Institute–funded cooperative oncology group data with an administrative data source to develop a more effective platform for clinical trial analysis and comparative effectiveness research: a report from the Children's Oncology Group

The National Cancer Institute–funded cooperative oncology group trials have improved overall survival for children with cancer from 10% to 85% and have set standards of care for adults with malignancies. Despite these successes, cooperative oncology groups currently face substantial challenges. We are working to develop methods to improve the efficiency and effectiveness of these trials. Specifically, we merged data from the Childrens Oncology Group (COG) and the Pediatric Health Information Systems (PHIS) to improve toxicity monitoring, to estimate treatment‐associated resource utilization and costs, and to address important clinical epidemiology questions.

Outcome of pediatric acute myeloid leukemia patients receiving intensive care in the United States.

Objective: Children with acute myeloid leukemia are at risk for sepsis and organ failure. Outcomes associated with intensive care support have not been studied in a large pediatric acute myeloid leukemia population. Our objective was to determine hospital mortality of pediatric acute myeloid leukemia patients requiring intensive care. Design: Retrospective cohort study of children hospitalized between 1999 and 2010. Use of intensive care was defined by utilization of specific procedures and resources. The primary endpoint was hospital mortality. Setting: Forty-three children’s hospitals contributing data to the Pediatric Health Information System database. Patients: Patients who are newly diagnosed with acute myeloid leukemia and who are 28 days through 18 years old (n = 1,673) hospitalized any time from initial diagnosis through 9 months following diagnosis or until stem cell transplant. A reference cohort of all nononcology pediatric admissions using the same intensive care resources in the same time period (n = 242,192 admissions) was also studied. Interventions: None. Measurements and Main Results: One-third of pediatric patients with acute myeloid leukemia (553 of 1,673) required intensive care during a hospitalization within 9 months of diagnosis. Among intensive care admissions, mortality was higher in the acute myeloid leukemia cohort compared with the nononcology cohort (18.6% vs 6.5%; odds ratio, 3.23; 95% CI, 2.64–3.94). However, when sepsis was present, mortality was not significantly different between cohorts (21.9% vs 19.5%; odds ratio, 1.17; 95% CI, 0.89–1.53). Mortality was consistently higher for each type of organ failure in the acute myeloid leukemia cohort versus the nononcology cohort; however, mortality did not exceed 40% unless there were four or more organ failures in the admission. Mortality for admissions requiring intensive care decreased over time for both cohorts (23.7% in 1999–2003 vs 16.4% in 2004–2010 in the acute myeloid leukemia cohort, p = 0.0367; and 7.5% in 1999–2003 vs 6.5% in 2004–2010 in the nononcology cohort, p < 0.0001). Conclusions: Pediatric patients with acute myeloid leukemia frequently required intensive care resources, with mortality rates substantially lower than previously reported. Mortality also decreased over the time studied. Pediatric acute myeloid leukemia patients with sepsis who required intensive care had a mortality comparable to children without oncologic diagnoses; however, overall mortality and mortality for each category of organ failure studied was higher for the acute myeloid leukemia cohort compared with the nononcology cohort.

Leveraging Administrative Data to Monitor Rituximab Use in 2875 Patients at 42 Freestanding Children's Hospitals across the United States

OBJECTIVE To describe the pharmacoepidemiology of rituximab use in children and to estimate the frequency of infectious events within a 1-year period after rituximab exposure. STUDY DESIGN This is a retrospective cohort study of patients who received rituximab at 1 of 42 childrens hospitals contributing data to the Pediatric Health Information System between January 1999 and June 2011. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis codes were analyzed to categorize underlying diseases (hematologic malignancies, primary immunodeficiencies, autoimmune diseases, and transplant recipients) and to estimate inpatient infectious complication rates within each category. RESULTS A total of 2875 patients with 4639 rituximab admissions were identified. The median age at index admission was 11 years (IQR, 5-15 years). The rate of rituximab admissions increased from 3 to 185 per 100,000 admissions per year over the study interval. During the 1-year follow-up period, 463 patients (16%) died. Infectious events were assessed in 2246 of the rituximab-exposed patients; 6.1% were diagnosed with sepsis and 2.0% with septic shock. The frequency of sepsis ranged from 2.4% in patients with autoimmune diseases to 12.2% in those with primary immunodeficiencies. Three patients were assigned an ICD-9-CM discharge diagnosis code for Pneumocystis joroveci pneumonia, 1 patient was assigned an ICD-9-CM discharge diagnosis code for hepatitis B, and 1 patient was assigned an ICD-9-CM discharge diagnosis code for progressive multifocal leukoencephalopathy. CONCLUSION The use of rituximab has increased significantly in children with a variety of underlying diseases. Based on ICD-9-CM code data, the rates of sepsis and other life-threatening infections after rituximab exposure vary depending on the underlying condition. Based on surveillance of infection using ICD-9-CM diagnosis codes, the rates of opportunistic infections appear to be low.

Induction mortality and resource utilization in children treated for acute myeloid leukemia at free-standing pediatric hospitals in the United States

Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients.

Assembly of a cohort of children treated for acute myeloid leukemia at free-standing children's hospitals in the United States using an administrative database.

Pediatric Health Information System data were used to establish a multi‐center cohort of 1,686 children treated for newly diagnosed acute myeloid leukemia (AML). The cohort assembly process, which included myeloid leukemia ICD‐9 discharge diagnosis codes and manual review of induction chemotherapy, was validated by chart review at a single institution. The use of ICD‐9 codes alone resulted in a poor positive predictive value (PPV; 31%). Inclusion of the results from the chemotherapy review improved the PPV to 100% without compromising sensitivity (95.7%). This cohort provides a reliable source for future comparative effectiveness and clinical epidemiology studies in pediatric AML. Pediatr Blood Cancer 2013; 60: 508–511.

Significant Increase in Clopidogrel Use Across U.S. Children’s Hospitals

The primary aim of this study was to describe the use of the antiplatelet agent clopidogrel in pediatric tertiary care hospitals and to evaluate how it has changed over time. This retrospective cohort study of pediatric inpatients from 2000 to 2009 used the Pediatric Health Information System database (PHIS) which contains data from 42 U.S. tertiary care children’s hospitals. Pharmacy billing codes were used to identify hospital admissions during which clopidogrel was administered. Patient demographics and concurrent use of other anticoagulant and antiplatelet drugs were collected. The International Classification of Diseases, ninth edition (ICD-9) codes were used to categorize admissions by potential indications for antiplatelet drugs and to identify bleeding and thrombotic events. From 2001 to 2009, clopidogrel use increased 15-fold, from 6 to 89.5 per 100,000 admissions. Patients with cardiac disease accounted for the largest proportion (75%), followed by stroke (9.4%) and Kawasaki disease (6.1%). Among those with cardiac disease, hypoplastic left heart syndrome (38%) and pulmonary artery anomalies (37%) were the most common. Aspirin was used concurrently during 52% of the admissions, enoxaparin during 9%, and warfarin during 5%. The use of clopidogrel is increasing rapidly among children with cardiovascular diseases. This population has a high risk of bleeding, thrombosis, and mortality. It therefore is imperative that future studies continue to evaluate the safety and efficacy of clopidogrel for these children.

Association of Weekend Admission With Hospital Length of Stay, Time to Chemotherapy, and Risk for Respiratory Failure in Pediatric Patients With Newly Diagnosed Leukemia at Freestanding US Children’s Hospitals

IMPORTANCE In adult patients with leukemia, weekend admission is associated with increased inpatient mortality. It is unknown whether weekend diagnostic admissions in pediatric patients with leukemia demonstrate similar adverse outcomes. OBJECTIVE To estimate adverse clinical outcomes associated with weekend admission in the first hospitalization of pediatric patients with newly diagnosed leukemia. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study from 1999 to 2011 featured index hospital admissions identified from the Pediatric Health Information System database. Participants were children with newly diagnosed acute lymphoid leukemia or acute myeloid leukemia. EXPOSURES Weekend (Saturday and Sunday) or weekday index admission. MAIN OUTCOMES AND MEASURES Inpatient mortality, length of inpatient stay, time to chemotherapy, and organ-system failure in index admission. RESULTS A total of 10 720 patients with acute lymphoid leukemia and 1323 patients with acute myeloid leukemia were identified; 2009 patients (16.7%) were admitted on the weekend. While the total daily number of patients receiving intensive care unit-level care was constant regardless of the day of admission, these patients represented a larger percentage of total admissions on weekends. In adjusted analyses, patients admitted on the weekend did not have an increased rate of mortality during the first admission (odds ratio, 1.0; 95% CI, 0.8-1.6). Patients whose initial admission for leukemia occurred during a weekend had a significantly increased length of stay (1.4-day increase; 95% CI, 0.7-2.1), time to initiation of chemotherapy (0.36-day increase; 95% CI, 0.3-0.5), and risk for respiratory failure (odds ratio, 1.5; 95% CI, 1.2-1.7) after adjusting for demographics, severity of illness, and hospital-level factors. CONCLUSIONS AND RELEVANCE While pediatric patients with newly diagnosed leukemia admitted on weekends do not have higher mortality rates, they have a prolonged length of stay, increased time to chemotherapy, and higher risk for respiratory failure. Patients who are severely ill at presentation represent a higher proportion of weekend index admissions. Optimizing weekend resources by increasing staffing and access to diagnostic and therapeutic resources may help to reduce hospital length of stay across all weekend admissions and may also ensure the availability of comprehensive care for those weekend admissions with higher acuity.