Seeing haemoglobin SC: Challenging the misperceptions.

Historically understudied and regarded as a mild type of sickle cell disease, HbSC can be associated with significant, progressive complications. Prospective studies are urgently needed to address treatment gaps for HbSC disease. Commentary on: Nelson et al. The clinical spectrum of HbSC sickle cell disease-not a benign condition. Br J Haematol 2024;205:653-663.

Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018-2022.

OBJECTIVES: The activated partial thromboplastin time (aPTT) is the most frequently used monitoring assay for bivalirudin in children and young adults on mechanical circulatory support including ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO). However, intrinsic variability of the aPTT complicates management and risks bleeding or thrombotic complications. We evaluated the utility and reliability of a bivalirudin-calibrated dilute thrombin time (Bival dTT) assay for bivalirudin monitoring in this population. DESIGN: Retrospective analysis of clinical data (including aPTT, dilute thrombin time [dTT]) and results of residual plasma samples from VAD patients were assessed in two drug-calibrated experimental assays. One assay (Bival dTT) was validated for clinical use in VAD patients, and subsequently used by clinicians in ECMO patients. Pearson correlation and simple linear regression were used to determine R2 correlation coefficients between the different laboratory parameters using Statistical Package for Social Sciences (Armonk, NY). SETTING: ICUs at Cincinnati Children's Hospital Medical Center. SUBJECTS: Children on VAD or ECMO support anticoagulated with bivalirudin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fifteen plasma samples from 11 VAD patients were analyzed. Both drug-calibrated experimental assays (anti-IIa and Bival dTT) showed excellent correlation with each other ( R2 = 0.94) and with the dTT ( R2 = 0.87), but poor correlation with aPTT ( R2 = 0.1). Bival dTT was selected for validation in VAD patients. Subsequently, clinically ordered results (105) from 11 ECMO patients demonstrated excellent correlation between the Bival dTT and the standard dTT ( R2 = 0.86) but very poor correlation with aPTT ( R2 = 0.004). CONCLUSIONS: APTT is unreliable and correlates poorly with bivalirudin's anticoagulant effect in ECMO and VAD patients. A drug-calibrated Bival dTT offers superior reliability and opportunity to standardize results across institutions. Additional studies are needed to determine an appropriate therapeutic range and correlation with clinical outcomes.

Impact of inflammation and steroids on anti-coagulation in children supported on a ventricular assist device.

Critically ill pediatric patients supported on ventricular assist devices (VADs) are increasingly being anticoagulated on bivalirudin, but with difficulty monitoring anticoagulation. Activated partial thromboplastin time (aPTT) has recently been shown to poorly correlate with bivalirudin plasma concentrations, while dTT had excellent correlation. However, aPTT is the more common monitoring test and dTT testing is rarely used. In addition, effects of frequent clinical VAD scenarios (such as inflammation) on the accuracy of aPTT and dTT testing remains uncertain. We reviewed the effects of clinical scenarios (infection/inflammation, chylothorax, and steroids administration) on anticoagulation monitoring in 10 pediatric VAD patients less than 3 years at Cincinnati Children's Hospital Medical Center from 10/27/2020 to 5/6/2022 using bivalirudin for anticoagulation. There were 16 inflammation/infection, 3 chylothorax, and 6 steroids events. Correlation between dTT and aPTT was significantly lower after infection/inflammation, with dTT increasing prior to inflammation/infection while aPTT remained unchanged. In addition, steroids are administered to VAD patients to reduce inflammation and thus additionally stabilize anticoagulation. However, this anticoagulation stabilization effect was reflected more accurately by dTT compared to aPTT. In children requiring VAD support utilizing bivalirudin anticoagulation, inflammation/infection is a common occurrence resulting in anticoagulation changes that may be more accurately reflected by dTT as opposed to aPTT.

Social inequities in neighborhood health amenities over time in the Wasatch Front Region of Utah: Historical inequities, population selection, or differential investment?

Socially disadvantaged groups generally are more likely to reside in areas with less desirable conditions. We examined longitudinal relationships between neighborhood resident characteristics and amenities from 1990 to 2010 in an urban area of Utah, U.S. Four temporal patterns of social inequities are described using mixed-effects models: historical inequities; differential selection into amenity-rich tracts; differential investment in amenities; and simultaneous twenty-year change. Results indicate historical differences by neighborhood socioeconomic status, with lower status tracts having fewer green/natural amenities and higher air pollution in 1990 but also greater walkability and more food stores. Differences in amenities by neighborhood socioeconomic status widened over time as aggregate socioeconomic status disproportionately increased in tracts with more green/natural amenities, less air pollution, and lower walkability in 1990, consistent with differential selection. Tract percentage non-Hispanic White did not predict historical differences, but tracts that were less walkable and had fewer healthy food stores in 1990 experienced larger subsequent increases in racial/ethnic diversity. Tracts with higher relative to lower percentage non-Hispanic White in 1990 had larger decreases in air pollution but declining green/natural amenities. This study shows how social inequities in neighborhood amenities change over time, providing evidence of historical socioeconomic differences increasing from differential resident selection.

Barriers to medication adherence in children, adolescents, and young adults prescribed anticoagulation.

Pediatric and adolescent and young adult (AYA) thromboembolism is treated with anticoagulation, but little is known about adherence. The aims of this study were to describe barriers to adherence among children and AYAs (ages 0-25 years) prescribed anticoagulants and to explore the relationship between barriers and self-reported adherence. Nearly 75% of patients and caregivers reported barriers, and a larger number of barriers was associated with missing at least one dose in the past month per both patient (rpb  = 0.48, p = .01) and caregiver (rpb  = 0.52, p = .01) report. Limitations, clinical implications, and future directions are discussed.

Factors influencing practice choices of early-career family physicians in Canada: a qualitative interview study.

BACKGROUND: Comprehensiveness of primary care has been declining, and much of the blame has been placed on early-career family physicians and their practice choices. To better understand early-career family physicians' practice choices in Canada, we sought to identify the factors that most influence their decisions about how to practice. METHODS: We conducted a qualitative study using framework analysis. Family physicians in their first 10 years of practice were recruited from three Canadian provinces: British Columbia, Ontario, and Nova Scotia. Interview data were coded inductively and then charted onto a matrix in which each participant's data were summarized by code. RESULTS: Of the 63 participants that were interviewed, 24 worked solely in community-based practice, 7 worked solely in focused practice, and 32 worked in both settings. We identified four practice characteristics that were influenced (scope of practice, practice type and model, location of practice, and practice schedule and work volume) and three categories of influential factors (training, professional, and personal). CONCLUSIONS: This study demonstrates the complex set of factors that influence practice choices by early-career physicians, some of which may be modifiable by policymakers (e.g., policies and regulations) while others are less so (e.g., family responsibilities). Participants described individual influences from family considerations to payment models to meeting community needs. These findings have implications for both educators and policymakers who seek to support and expand comprehensive care.

Lean legacy, heavy heritage: family history of diabetes and its association with young adult body mass index.

Substantial intergenerational transmission of diabetes mellitus (DM) risk exists. However, less is known regarding whether parental DM and DM among extended family members relate to adult offspring's body mass index (BMI), and whether any of these associations vary by sex. Using data from the National Longitudinal Study of Youth 1997 cohort (NLSY97), we assess the sex-specific relationship between DM present in first-degree parents and second-degree relatives and BMI among the parents' young adult offspring.Multivariate regressions reveal a positive relationship between parental DM and young adults' BMI for both daughters and sons, and the magnitude of coefficients is somewhat larger for the same-sex parent. Further, we observe that the link between parental DM and young adults' BMI is strongest when both parents have diagnosed diabetes. In contrast, the relationship between second-degree relatives with DM and the respondent's BMI is weaker and appears to be sex-specific, through same-sex parent and respondent. Logistic regressions show the association is especially strong when assessing how parental DM status relates to young adults' obesity risk. These results generally persist when controlling for parental BMI. The findings of this study point to the need to better distinguish the role of shared family environments (e.g., eating and physical activity patterns) from shared genes in order to understand factors that may influence young adults' BMI. Young adult offspring of parents with diabetes should be targeted for obesity prevention efforts in order to reduce their risks of obesity and perhaps diabetes.

A systematic review of adherence to anticoagulation regimens in pediatric patients.

Thromboembolic disease rates are increasing in pediatric patients. Anticoagulation is prescribed for treatment and prevention of thromboembolic disease. While nonadherence to anticoagulation regimens predicts poor health outcomes in adults, data in anticoagulated pediatric patients are limited. We systematically reviewed the rates, outcomes, and predictors of anticoagulation nonadherence in the pediatric population. Out of a total of 3581 unique articles identified for review, 17 studies met inclusion criteria. These studies primarily evaluated patients with cardiac disease treated with vitamin K antagonists. Overall nonadherence rates varied from 3% to 42%, based upon population, definition of adherence, and measurement strategy. Patient age, goal international normalized ratio (INR), and number of concurrent potentially interacting medications correlated with nonadherence. Data examining the relationship between nonadherence and health outcomes were included in only two studies. Limitations of current literature, as well as critical knowledge gaps that require future study, are discussed.

Urinary 11-dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid-organ transplant patients.

BACKGROUND: Evidence for aspirin efficacy testing in pediatrics is limited, especially outside of cardiology, yet thrombotic events have high morbidity in other areas such as pediatric transplant surgery. Debates about whether thromboembolic events while on aspirin represent "aspirin resistance" or "high on-treatment platelet reactivity" persist, given the poor intertest agreement between testing platforms. PROCEDURE: This prospective observational study involved measuring aspirin efficacy using ex vivo testing of platelet aggregation (VerifyNow-Aspirin, VN) and urine 11-dehydrothromboxane B2 (AsprinWorks, UTxB2) contemporaneously at up to three time points after major noncardiac organ transplant surgery. The collection days (CD) were the second and seventh days after stable aspirin dosing and then a convalescent time point 2-9 months later. RESULTS: Fifty-five participants (age range, 0-21 years) were enrolled, having undergone total pancreatectomy with islet autotransplantation (N = 36), orthotopic liver transplantation (N = 18), and combined liver-kidney transplantation (N = 1). Platelet reactivity measured by VN remained unchanged, whereas UTxB2, which was elevated postoperatively, decreased significantly from CD1 to CD2 and CD3. Discordance in therapeutic efficacy was noted per manufacturer cutoffs, with therapeutic VN results in 86% of tests, whereas 12% of UTxB2 were therapeutic. Age-based stratification of UTxB2 results using previously published pediatric median levels increased overall UTxB2 therapeutic rates (80%) and intertest concordance (67% vs 27% if using adult range). No thrombotic events were observed. CONCLUSIONS: Our data suggest that urine thromboxane production may be an underappreciated reflection of postoperative inflammation. Validation of pediatric normal ranges for UTxB2 is a critical next step.

Influences on intentions for obstetric practice among family physicians and residents in Canada: an explorative qualitative inquiry.

BACKGROUND: Many family medicine residency graduates indicate a desire to provide obstetric care, but a low proportion of family physicians (FPs) provide obstetric care within their practice. This suggests personal preference alone may not account for the low proportion of FPs who ultimately provide full obstetric care. If decisionmakers plan to augment the number of FPs providing obstetric care, barriers to the provision of such care must first be identified. Within this paper, we explore the perspectives of both family practice residents and early-career FPs on the factors that shaped their decision to provide obstetric care. METHODS: In this qualitative study, we analyzed a subset of interview data from three Canadian provinces: British Columbia, Ontario, and Nova Scotia (n = 18 family practice residents; n = 39 early-career FPs). We used thematic analysis to analyze data relevant to obstetric care practice, applying the socio-ecological model and comparing themes across participant types, gender, and province. RESULTS: Participants described influences affecting their decision about providing obstetric care. Key influencing factors aligned with the levels of the socio-ecological model of public policy (i.e., liability), community (i.e., community needs), organizational (e.g., obstetric care trade-offs, working in teams, sufficient exposure in training), interpersonal practice preferences (i.e., impact on family life, negative interactions with other healthcare professionals), and individual factors (i.e., defining comprehensive care as "everything but obstetrics"). Many participants were interested in providing obstetric care within their practice but did not provide such care. Participants' decision-making around providing or not providing obstetric care included considerations of personal preferences and outside influences. CONCLUSIONS: Individual-level factors alone do not account for the decrease in the type and amount of obstetric care offered by FPs. Instead, FPs' choice to provide or not provide obstetric care is influenced by factors at higher levels of the socio-ecological model. Policymakers who want to encourage obstetric practice by FPs should implement interventions at the public policy, community, organizational, interpersonal, and individual levels.

"At the mercy of some of the regulations": the impact of the residency match and return of service requirement on the early-career decisions of international medical graduates in Canada.

BACKGROUND: Return-of-service (ROS) agreements require international medical graduates (IMGs) who accept medical residency positions in Canada to practice in specified geographic areas following completion of training. However, few studies have examined how ROS agreements influence career decisions. We examined IMG resident and early-career family physicians' perceptions of the residency matching process, ROS requirements, and how these factors shaped their early career decisions. METHODS: As part of a larger project, we conducted semi-structured qualitative interviews with early-career family physicians and family medicine residents in British Columbia, Ontario and Nova Scotia. We asked participants about their actual or intended practice characteristics (e.g., payment model, practice location) and factors shaping actual or intended practice (e.g., personal/professional influences, training experiences, policy environments). Interviews were transcribed verbatim and a thematic analysis approach was employed to identify recurring patterns and themes. RESULTS: For this study, we examined interview data from nine residents and 15 early-career physicians with ROS agreements. We identified three themes: IMGs strategically chose family medicine to increase the likelihood of obtaining a residency position; ROS agreements limited career choices; and ROS agreements delayed preferred practice choice (e.g., scope of practice and location) of an IMGs' early-career practice. CONCLUSIONS: The obligatory nature of ROS agreements influences IMG early-career choices, as they necessitate strategically tailoring practice intentions towards available residency positions. Existing analyses of IMGs' early-career practice choices neglect to distinguish between ROS and practice choices made independently of ROS requirements. Further research is needed to understand how ROS influences longer term practice patterns of IMGs in Canada.

The ASH-ASPHO Choosing Wisely Campaign: 5 hematologic tests and treatments to question.

Choosing Wisely is a medical stewardship and quality-improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The American Society of Hematology (ASH) has been an active participant in the Choosing Wisely project. In 2019, ASH and the American Society of Pediatric Hematology/Oncology (ASPHO) formed a joint task force to solicit, evaluate, and select items for a pediatric-focused Choosing Wisely list. By using an iterative process and an evidence-based method, the ASH-ASPHO Task Force identified 5 hematologic tests and treatments that health care providers and patients should question because they are not supported by evidence, and/or they involve risks of medical and financial costs with low likelihood of benefit. The ASH-ASPHO Choosing Wisely recommendations are as follows: (1) avoid routine preoperative hemostatic testing in an otherwise healthy child with no previous personal or family history of bleeding, (2) avoid platelet transfusion in asymptomatic children with a platelet count 10 × 103 /µL unless an invasive procedure is planned, (3) avoid thrombophilia testing in children with venous access-associated thrombosis and no positive family history, (4) avoid packed red blood cells transfusion for asymptomatic children with iron deficiency anemia and no active bleeding, and (5) avoid routine administration of granulocyte colony-stimulating factor for prophylaxis of children with asymptomatic autoimmune neutropenia and no history of recurrent or severe infections. We recommend that health care providers carefully consider the anticipated risks and benefits of these identified tests and treatments before performing them.

Itineraries and Transformations: John of Burgundy's Plague Treatise.

As one of the most popular medieval plague treatises produced during the Second Plague Pandemic, John of Burgundy's tract offers an excellent example of how medical books changed over time and place: in their material formats (such as manuscript to print), their textual contents and meanings, the people involved in their production, their readership, and sometimes even their purpose. The seemingly formulaic structure and medical contents of plague tracts has contributed to a long-standing perception that they were largely static or even ahistorical, one treatise easily exchanged for another. However, by examining copies of the treatise as individual and unique productions, rather than simply seeing the apparent uniformity of a few exemplars (or even the entire genre), we can begin to trace the itineraries through which they traveled and the rich tapestries of change that mark their life stories.

Tricuspid regurgitation velocity and other biomarkers of mortality in children, adolescents and young adults with sickle cell disease in the United States: The PUSH study.

In the US, mortality in sickle cell disease (SCD) increases after age 18-20 years. Biomarkers of mortality risk can identify patients who need intensive follow-up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3-20 years into an observational study in 2006-2010 and followed 497 patients for a median of 88 months (range 1-105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18 years was 99% and to 25 years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV ≥2.7 m/second (>2 SD above the mean in age-matched and gender-matched non-SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P = .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin ≥2000 µg/L (observed in 60% of patients who died vs 7.8% of survivors, P < .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P < .001), and neutrophil count ≥10x109 /L (30.0% of patients who died vs 7.9% of survivors, P = .018). In SCD children, adolescents and young adults, steady-state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.

Impact of exogenous antithrombin on low molecular weight heparin anti-Xa activity assays in a pediatric and young adult leukemia and lymphoma cohort with variable antithrombin levels.

BACKGROUND: Low molecular weight heparin (LMWH) remains the most commonly prescribed pediatric anticoagulant. There is debate whether LMWH anti-Xa assays with or without exogenous antithrombin (AT) best reflect anticoagulation effect, and how much discrepancy exists between assay types. OBJECTIVES: We assessed the effect of variable AT activity on LMWH anti-Xa levels in plasma samples from anticoagulated pediatric and young adult acute lymphoblastic leukemia and lymphoma (ALL/L) patients, using two instruments and their commercial kits with and without exogenous AT (ie, four platforms). METHODS: We analyzed LMWH anti-Xa levels on 60 plasma samples with known AT activity from 12 enoxaparin-treated ALL/L patients, using four commercial kits from Siemens and Stago containing AT or not, on Siemens BCS and Stago STA R Max, respectively. RESULTS: Of 236/240 samples with interpretable results, mean AT activity was 80% (46-138%). Correlation was acceptable for published kit ranges of LMWH anti-Xa levels when comparing kits containing AT (r = 0.82, P < .0001), or not (r = 0.93, P < .0001), and within a manufacturer (Berichrom to Innovance, r = 0.92, P < .0001; Stachrom to STA-Liquid Anti-Xa r = 0.98, P < .0001). LMWH anti-Xa levels were lower in platforms without added AT (P < .0001). For Stago kits, this effect increased when AT < 70% (P = .001, n = 19, mean 56%). Assay variability, measured as mean percent difference, was less pronounced with Stago kits (14.7%, n = 49) than Siemens (41.9%, n = 50). CONCLUSIONS: Although LMWH levels from anti-Xa assays with added AT trend higher than in those without, correlation was fairly good between platforms in pediatric ALL/L plasmas, even when AT activity was <70%.

Aspirin in childhood acute ischemic stroke: The evidence for treatment and efficacy testing.

Aspirin is the most commonly prescribed antiplatelet agent worldwide, but evidence supporting its use varies by age and disease process. Despite its frequent use in childhood acute ischemic stroke prevention and management, major knowledge gaps exist about optimal pediatric aspirin use, particularly in this setting, where high-quality clinical trials are urgently needed. This review focuses upon the evidence for aspirin use in childhood acute ischemic stroke, includes a summary of aspirin pharmacology to highlight misconceptions and common clinical situations which may limit its efficacy, and discusses the techniques and potential role of laboratory monitoring of aspirin efficacy in children.

Capped antithrombin III dosing is cost effective in the management of asparaginase-associated thrombosis.

Asparaginase therapy induces a transient antithrombin III (ATIII) deficiency, which contributes to the risk of asparaginase-induced thrombosis. At Cincinnati Children's Hospital Medical Center, management of asparaginase-induced thrombosis includes ATIII supplementation during therapeutic anticoagulation with enoxaparin. Due to the expense associated with ATIII, a capped dosing approach for ATIII was evaluated in this population. Peak ATIII levels were obtained following capped doses to evaluate response. In this pilot evaluation, 11 patients received a total of 138 capped doses for a total cost savings of $803 782. This pilot evaluation represents the first reported analysis of capped ATIII dosing in oncology patients.

Alpaca embryo transfer on a private Canadian farm.

This study evaluated the feasibility of using an embryo transfer protocol in an alpaca farm in Canada. Alpaca donors and recipients were synchronized with 2 doses of gonadotrophin-releasing hormone (GnRH), 12 days apart. In donors (n = 5), superstimulation was induced with follicle stimulating hormone (FSH) given daily (40 mg) for 5 days beginning 2 days after the second GnRH treatment. Cloprostenol was given on the last day of FSH, the donors were bred 2 days later, embryos were collected 7 days after breeding. In recipients (n = 8), the second dose of GnRH was given the day before donor mating, and embryos were transferred on the day of donor collection. On average (± SEM), 5.2 ± 1.4 corpora lutea were detected and 2.5 ± 1.2 transferable embryos were collected in the donors. A mature corpus luteum was detected in 6/8 synchronized recipients and a single embryo was transferred to each. One recipient alpaca became pregnant and delivered a healthy baby 349 days after embryo transfer. This is the first report of successful embryo transfer in alpacas in Canada.

Transfert d'un embryon d'alpaga dans une ferme privée canadienne. Cette étude a évalué la faisabilité de l'utilisation d'un protocole de transfert d'un embryon dans une ferme d'alpagas au Canada. Les alpagas donneurs et récipiendaires ont été synchronisés avec deux doses d'hormone de gonadolibérine (GnRH), à 12 jours d'intervalle. Chez les donneurs (n = 5), la super-stimulation a été induite avec une hormone follicostimulante (FSH) administrée quotidiennement (40 mg) pendant 5 jours deux jours après le deuxième traitement de GnRH. Le cloprosténol a été administré le dernier jour de FSH, les donneurs ont été accouplés 2 jours plus tard et les embryons ont été prélevés 7 jours après l'accouplement. Chez les récipiendaires (n = 8), la deuxième dose de GnRH a été administrée la journée avant l'accouplement des donneurs et les embryons ont été transférés le jour du prélèvement du donneur. En moyenne (± SEM), 5,2 ± 1,4 corpora lutea ont été détectés et 2,5 ± 1,2 embryons transférables ont été prélevés des donneurs. Un corpus luteum mature a été détecté chez 6/8 récipiendaires synchronisés et un seul embryon a été transféré à chacun. Un alpaga récipiendaire est devenu gravide et a donné naissance à un petit en santé 349 jours après le transfert de l'embryon. Il s'agit du premier rapport d'un transfert d'embryon réussi chez des alpagas au Canada.(Traduit par Isabelle Vallières).

Knowledge insufficient: the management of haemoglobin SC disease.

Although haemoglobin SC (HbSC) accounts for 30% of sickle cell disease (SCD) in the United States and United Kingdom, evidence-based guidelines for genotype specific management are lacking. The unique pathology of HbSC disease is complex, characterized by erythrocyte dehydration, intracellular sickling and increased blood viscosity. The evaluation and treatment of patients with HbSC is largely inferred from studies of SCD consisting mostly of haemoglobin SS (HbSS) patients. These studies are underpowered to allow definitive conclusions about HbSC. We review the pathophysiology of HbSC disease, including known and potential differences between HbSS and HbSC, and highlight knowledge gaps in HbSC disease management. Clinical and translational research is needed to develop targeted treatments and to validate management recommendations for efficacy, safety and impact on quality of life for people with HbSC.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.