Characterization of Interchanging Incretin Analogs in Clinical Practice: A Descriptive Report.

OBJECTIVE: To characterize the tolerability associated with incretin analog interchanges to equipotent or higher strengths based on an interchange process in an adult outpatient setting. METHODS: This was a retrospective chart review of adult patients receiving care through a participating family medicine or endocrinology clinic between January 1, 2022, and November 30, 2022 at a major academic medical center. An incretin analog equivalency table and protocol for interchange was created in response to on-going shortages and need for therapy adjustments to different medications within the same class. Patients were included if a recommended incretin analog interchange was initiated, and a tolerability assessment was conducted. Patients were excluded if they did not meet inclusion criteria or if they were unreachable for tolerability assessments for interchanged agents. RESULTS: There were 156 patients included for characterization and response to tolerability of interchange. It was determined that 96% of patients tolerated the incretin analog interchange. A dose escalation occurred in 58% of patients, 41% were transitioned to an equipotent dose, and 1 patient was considered a dose decrease. Prior authorizations were required 74% of the time for the new therapy. The most common interchanges were dulaglutide 4.5 mg to tirzepatide 7.5 mg, dulaglutide 4.5 mg to tirzepatide 10 mg, and dulaglutide 3 mg to tirzepatide 7.5 mg. These interchanges made up 37.3% of the total population and were observed to have 93% tolerability. Seven patients did not tolerate incretin analog interchange. Five experienced gastrointestinal effects and two experienced injection site reactions. The interchange of incretin analog was estimated to reduce time to maximum dose by a median of three months. During this study, no patients experienced interruption of therapy defined as missing a dose of incretin analog. CONCLUSIONS: This characterization report demonstrates an effective approach to addressing incretin analog interchanges. A high level of tolerability is evident with the defined interchange process. Future studies should continue to confirm effective and safe interchanges of incretin analogs from outcomes and tolerability reports.

A New Risk Assessment Model for Hospital-Acquired Venous Thromboembolism in Critically Ill Children: A Report From the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVES: To create a risk model for hospital-acquired venous thromboembolism in critically ill children upon admission to an ICU. DESIGN: Case-control study. SETTING: ICUs from eight children's hospitals throughout the United States. SUBJECTS: Critically ill children with hospital-acquired venous thromboembolism (cases) 0-21 years old and similar children without hospital-acquired venous thromboembolism (controls) from January 2012 to December 2016. Children with a recent cardiac surgery, asymptomatic venous thromboembolism, or a venous thromboembolism diagnosed before ICU admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The multi-institutional Children's Hospital-Acquired Thrombosis registry was used to identify cases and controls. Multivariable logistic regression was used to determine the association between hospital-acquired venous thromboembolism and putative risk factors present at or within 24 hours of ICU admission to develop the final model. A total of 548 hospital-acquired venous thromboembolism cases (median age, 0.8 yr; interquartile range, 0.1-10.2) and 187 controls (median age, 2.4 yr; interquartile range, 0.2-8.3) were analyzed. In the multivariable model, recent central venous catheter placement (odds ratio, 4.4; 95% CI, 2.7-7.1), immobility (odds ratio 3.6, 95% CI, 2.1-6.2), congenital heart disease (odds ratio 2.9, 95% CI, 1.7-4.7), length of hospital stay prior to ICU admission greater than or equal to 3 days (odds ratio, 2.5; 95% CI, 1.1-5.6), and history of autoimmune/inflammatory condition or current infection (odds ratio, 2.1; 95% CI, 1.2-3.4) were each independently associated with hospital-acquired venous thromboembolism. The risk model had an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.73-0.84). CONCLUSIONS: Using the multicenter Children's Hospital-Acquired Thrombosis registry, we identified five independent risk factors for hospital-acquired venous thromboembolism in critically ill children, deriving a new hospital-acquired venous thromboembolism risk assessment model. A prospective validation study is underway to define a high-risk group for risk-stratified interventional trials investigating the efficacy and safety of prophylactic anticoagulation in critically ill children.

Development of a Risk Model for Pediatric Hospital-Acquired Thrombosis: A Report from the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVE: To identify pertinent clinical variables discernible on the day of hospital admission that can be used to assess risk for hospital-acquired venous thromboembolism (HA-VTE) in children. STUDY DESIGN: The Children's Hospital-Acquired Thrombosis Registry is a multi-institutional registry for all hospitalized participants aged 0-21 years diagnosed with a HA-VTE and non-VTE controls. A risk assessment model (RAM) for the development of HA-VTE using demographic and clinical VTE risk factors present at hospital admission was derived using weighted logistic regression and the least absolute shrinkage and selection (Lasso) procedure. The models were internally validated using 5-fold cross-validation. Discrimination and calibration were assessed using area under the receiver operating characteristic curve and Hosmer-Lemeshow goodness of fit, respectively. RESULTS: Clinical data from 728 cases with HA-VTE and 839 non-VTE controls, admitted between January 2012 and December 2016, were abstracted. Statistically significant RAM elements included age <1 year and 10-22 years, cancer, congenital heart disease, other high-risk conditions (inflammatory/autoimmune disease, blood-related disorder, protein-losing state, total parental nutrition dependence, thrombophilia/personal history of VTE), recent hospitalization, immobility, platelet count >350 K/µL, central venous catheter, recent surgery, steroids, and mechanical ventilation. The area under the receiver operating characteristic curve was 0.78 (95% CI 0.76-0.80). CONCLUSIONS: Once externally validated, this RAM will identify those who are at low-risk as well as the greatest-risk groups of hospitalized children for investigation of prophylactic strategies in future clinical trials.

Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia.

BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague. AIM: To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs. METHODS: Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months. RESULTS: Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%). CONCLUSION: Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.

Evaluation of venous thromboembolism risk factors reveals subtype heterogenicity in children with central venous catheters: a multicenter study from the Children's Hospital Acquired Thrombosis consortium.

BACKGROUND: Acutely ill and medically complex children frequently rely on central venous catheters (CVCs) to provide life-sustaining treatment. Unfortunately, catheter-related thrombosis (CRT) is a serious and common complication. Little is known why some with a CVC develop CRT and others develop venous thromboembolism unrelated to the CVC (non-CRT). OBJECTIVES: The aim of this study was to identify factors associated with CRT in children with hospital-acquired venous thromboembolism (HA-VTE). METHODS: This case-case study included participants in the Children's Hospital Acquired Thrombosis Registry with HA-VTE and CVC aged 0 to 21 years from 8 US children's hospitals. Participants were excluded if they developed HA-VTE prior to CVC insertion or if the CVC insertion date was unknown. Logistic regression models were used to assess associations between clinical factors and CRT status. RESULTS: There were 1144 participants with HA-VTE who had a CVC. CRT developed in 833 participants, and 311 developed non-CRT. Multivariable analysis showed increased odds of CRT (compared with non-CRT) in participants with peripherally inserted central catheters (odds ratio [OR], 3.80; 95% CI, 2.04-7.10; p < .001), CVCs inserted in the femoral vein (OR, 4.45; 95% CI, 1.70-11.65; p = .002), multiple CVCs (OR, 1.42; 95% CI, 1.18-1.71; p < .001), and CVC malfunction (OR, 3.30; 95% CI, 1.80-6.03; p < .001). CONCLUSION: The findings of this study provide new insights on risk factor differences between CRT and non-CRT. Prevention efforts should be directed at modifying the type of CVC, insertion location, and/or number of CVCs placed, if possible, to decrease the incidence of CRT.

Research from the bedside to the lab bench & back.

Transgenic mice represent a unique opportunity in biomedical research to discover the genes underlying disease and understand how manipulating the function of single genes and proteins alters physiology in a whole animal system. These advances in biomedical research may accelerate the time between when basic discoveries are made and when the research can be 'translated', that is, when the research will positively impact the lives of patients. The purpose of this article is to present some examples of promising mouse models of human diseases.

Risk factors for hospital acquired venous thromboembolism in congenital heart disease patients: A report from the children's hospital acquired thrombosis (CHAT) consortium.

INTRODUCTION: The incidence of pediatric hospital-acquired venous thromboembolism (HA-VTE) has increased over time. Congenital heart disease (CHD) as a co-morbidity has been demonstrated to significantly increase HA-VTE risk among hospitalized children. OBJECTIVE: To identify specific risks factors for the development of HA-VTE in hospitalized children with CHD. MATERIALS AND METHODS: This retrospective case-control study included hospitalized participants aged 0-21 years within the Children's Hospital Acquired Thrombosis (CHAT) Consortium Registry with a co-morbidity of CHD. Participants with HA-VTE and non-VTE controls with a past medical history of CHD were selected from the CHAT Registry and data regarding multiple clinical variables were extracted. These variables were then analyzed to assess their association with HA-VTE development. RESULTS: Three hundred and thirty-three participants with a co-morbidity of CHD were identified, comprising 275 HA-VTE cases and 58 controls. Median age for HA-VTE cases was 0.4 (IQR = 0-2.6) years compared to 3.4 (IQR = 0.7-6.5) for controls. Male participants were predominant in both groups (57.5 % HA-VTE cases vs 51.7 % controls). Multivariable analysis identified prior recent hospitalization (OR = 4.12, 95%CI = 1.66-10.24), intensive care unit (ICU) admission (OR = 3.29, 95 % CI = 1.15-9.40), and CVC placement (OR = 9.14, 95 % CI = 3.38-24.72) as significant risk factors for HA-VTE in subjects with CHD. CONCLUSIONS: ICU admission, CVC placement, and prior hospitalization were identified as statistically significant predictors associated with HA-VTE development in hospitalized children with history of CHD. Prospective studies are needed to validate these results and help develop strategies to mitigate HA-VTE development in these patients.

Symptomatic pulmonary embolus after catheter removal in children with catheter related thrombosis: A report from the CHAT Consortium.

BACKGROUND: Appropriate timing of central venous catheter (CVC) removal, in relation to start of anticoagulation, in children after the diagnosis of a CVC-related thrombosis (CRT) is not well established. OBJECTIVES: This retrospective cohort study evaluated the incidence of symptomatic pulmonary embolism (PE) after CVC removal using data from the multi-institutional Children's Hospital-Acquired Thrombosis (CHAT) Consortium Registry. PATIENTS/METHODS: The CHAT Registry consists of data from children aged 0-21 years with a hospital-acquired venous thromboembolism. Eligible subjects were those with CRT diagnosed <3 days after CVC removal. Subjects were excluded if the CRT was due to a failed CVC insertion. Subjects were divided into three groups: those with CVC removal without anticoagulation, those with CVC removal <48 h after starting anticoagulation, and those with CVC removal ≥48 h after starting anticoagulation. RESULTS: A total of 687 CRT events from 663 subjects were included. A majority of CRT events were in subjects with peripherally inserted central catheters (62.3%, n = 428). For the 611 CRT events in which the CVC was removed, there was only one case of symptomatic PE (0.16%), which occurred <48 h after initiation of anticoagulation. CONCLUSIONS: While current guidelines suggest anticoagulation before CVC removal in the setting of a CRT to prevent embolization, CVC removal is not associated with symptomatic PE regardless of duration of anticoagulation before CVC removal.

Primary thromboprophylaxis in hospitalized children: A multi-center retrospective analysis.

BACKGROUND/OBJECTIVES: Hospital acquired venous thromboembolism in children is associated with significant morbidity/mortality. Prevention strategies include sequential compression devices and prophylactic anticoagulation but these interventions carry risk and are poorly studied in children. Objectives were to evaluate primary thromboprophylaxis use in hospitalized children over time and the associated bleeding risk. MATERIALS AND METHODS: Retrospective study of hospitalized patients aged 10-18 years within the Pediatric Health Information System administrative database from January 2008-September 2015. Factors associated with thromboprophylaxis receipt and bleeding were identified using generalized linear mixed effects models. RESULTS: Of 1,075,383 hospitalizations, 10,544 (1%) received prophylactic enoxaparin and 58,768 (5%) received mechanical compression. Mechanical thromboprophylaxis increased slightly over time (4.3% in 2008, 6.2% in 2015), enoxaparin use did not (0.8% in 2008, 1.2% in 2015). Patients aged 16-18 were more likely than younger children (10-12) to receive pharmacologic (adjusted odds ratio [aOR] 3.1, 95% confidence interval [CI] 2.9-3.3) or mechanical thromboprophylaxis (aOR 2.9, 95% CI 2.9-3). Patients on rehabilitation medical service were more likely to receive prophylactic enoxaparin (aOR 53, 95% CI 44.1-64.5). 5.6% (589/10,544) of patients receiving enoxaparin prophylaxis had bleeding. Thromboprophylaxis use by hospital varied with a range of 0.25-3.3% for enoxaparin and 2-26.2% for mechanical compression. CONCLUSION: Thromboprophylaxis is infrequently utilized in hospitalized children. Pharmacologic prophylaxis with enoxaparin remains low and has not substantially increased over time. Significant variability exists across hospitals and services in the administration of both mechanical and pharmacologic thromboprophylaxis highlighting the need for further evidence to standardize practice.

Clinical and molecular characterization of novel deletions causing epsilon gamma delta beta thalassemia: Report of two cases.

Epsilon gamma delta beta (εγδß)0 - thalassemia is a very rare disorder that results from large deletions in the ß-globin gene cluster which abolish all regional globin chain gene expression from that allele. Since it is an exceedingly rare cause of neonatal anemia and is not detected by routine newborn screening, it is usually not suspected clinically and commonly undiagnosed or misdiagnosed. In this study, we describe two patients diagnosed in our hospital with (εγδß)0-thalassemia based on the results obtained from DNA microarray analysis of their peripheral blood. The first patient of mixed European descent presented as a neonate with microcytic hemolytic anemia, hyperbilirubinemia, hypoglycemia and hypothermia, and was found to have a 2.2 Mb loss that included the entire ß-globin gene cluster and the locus control region (LCR). The second patient, also of mixed European descent, presented in the neonatal period with anemia, thrombocytopenia and cutaneous extramedullary hematopoiesis, and was found to have a 59 kb loss that included the ß-globin LCR, HBE1, HBG1, and HBG2 genes. Both cases highlight the importance of recognizing the clinical features of (εγδß)0-thalassemia and implementing appropriate testing to clarify the diagnosis and manage the condition.

Increasing rates of thrombosis in children with congenital heart disease undergoing cardiac surgery.

OBJECTIVE: To determine thrombosis incidence, morbidities, and mortality of children with congenital heart disease who develop thrombosis after cardiac surgery. MATERIALS AND METHODS: This retrospective study reviewed patients <18 years old within the Pediatric Health Information System (PHIS) database who underwent cardiac surgery from 2004-2012. Thrombosis rates were compared for each procedure. Mortality was modeled using proportional hazards, adjusting for important clinical and demographic factors. RESULTS: Of 91909 CHD patients who underwent surgery, 2655 (2.9%) developed thrombosis within the ensuing 12 months. The rate of thrombosis increased 253% (p<0.001), from 1.7% in 2004 to 4.4% in 2012. Systemic to pulmonary shunt placement (34.3%) and septostomy (26.1%) had the highest thrombosis percentages. Children <28 days had the highest prevalence (61%). Those with thrombosis had longer lengths of stay than those without [median 27 hospital days and 10 ICU days vs. 6 and 2 (p<0.001)]. Mean risk-adjusted cost was higher with thrombosis; $126,257 vs. $40,773 (p<0.001). Thrombosis was also associated with higher rates of bacteremia [8.3% vs. 3.4%, p<0.001], endocarditis [0.7% vs. 0.2%, p<0.001], and mortality [12.3% vs. 0.8%, p<0.001]. The adjusted hazard ratio for mortality in patients with thrombosis was 5.5 (95% CI: 4.6-6.5). CONCLUSIONS: Thrombosis rates in CHD patients after cardiac surgery is increasing. Thrombosis is associated with longer hospital stay, increased ICU days, and cost. CHD patients with thrombosis also have increased bacteremia and mortality rates. More research is needed to understand contributors to thrombosis which may help develop strategies to mitigate morbidity and mortality.

Risk Factors, Prophylaxis, and Treatment of Venous Thromboembolism in Congenital Heart Disease Patients.

Congenital heart disease (CHD) is a common condition in the pediatric population, affecting up to 1% of all live births (i.e., around 40,000 newborns/year in the United States). Although CHD does have a wide range of severity, by the age of 5 years approximately 80% of patients will require at least one surgical intervention to achieve a complete/palliative cardiac repair. Today, in light of their much-improved surgical survival, the care of these patients focuses on morbidity prevention and/or treatment. One such morbidity has been the increased frequency of thrombotic occlusions [e.g., cardioembolic arterial ischemic strokes; arterial, cardiac, and/or newly created shunt thrombosis; venous thromboembolism (VTE)]. Patients with CHD are at high risk of developing thrombosis due to the disruption of blood flow, CHD-related coagulopathy, inflammation, and/or platelet activation secondary to extracorporeal circulation support required during open-heart surgery or as a bridge to recovery, which can increase thrombus formation. In this article, we will discuss how the coagulation system is altered in patients with CHD in regard to the patient's anatomy, procedures they undergo to correct their congenital heart defect, and other risk factors that may increase their thrombotic risk, focusing on VTE. We will also discuss the most recently published reports pertaining to guidelines on prophylaxis and treatment of VTE in this population. Finally, we will briefly address the long-term VTE outcomes for patients with CHD.

Inherited thrombophilia in children.

Thrombosis in children has multiple etiologies, including inherited disorders such as factor V Leiden mutation, prothrombin 20210A mutation, and deficiencies in protein C, S, or antithrombin. Epidemiology of the disorders varies, as does the risk of thrombosis. Venous thromboembolism is the typical presentation. However, more severe anticoagulant protein deficiencies may present with purpura fulminans. Treatment of thrombosis is relatively uniform, regardless of the underlying genetic risk factor. In this article, we discuss the most well-studied inherited thrombophilias and the epidemiology, pathophysiology, and relative thrombotic risk of each. Treatment of thrombosis is also briefly reviewed.