Primary Composite Outcome Of Death Research Articles

A Review of the Potential Role of Sotagliflozin: A Dual SGLT2 and SGLT1 Inhibitor-in the Treatment of Heart Failure.

Objective: This review provides an overview of the pharmacology, efficacy, and safety of sotagliflozin, a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2), to reduce the risk of cardiovascular death and hospitalization in those with heart failure. Data sources: A search of Embase via Elsevier, PubMed, Web of Science-All Databases, and The Cochrane Library for clinical trials in CENTRAL, as well as the MedRxiv and BioRxiv pre-print servers, was conducted from inception through December 1, 2023. Search terms included sotagliflozin, lx 4211, lp 802034, sar 439954, and (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. Study selection and data extraction: Published phase 1, phase 2, and phase 3 clinical trials, meta-analyses, and systematic reviews. Studies were included if they were published in English and evaluated sotagliflozin pharmacology, pharmacokinetics, efficacy, or safety. Data synthesis: The Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure (SOLOIST-WHF) and Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) phase 3 trials compared sotagliflozin with placebo in patients with type 2 diabetes mellitus. In both the SCORED and SOLOIST-WHF trials, treatment with sotagliflozin resulted in a statistically significant reduction in the primary composite outcome of death from cardiovascular causes, hospitalizations due to heart failure (HF), and urgent visits for HF. Conclusions: Dual SGLT1 and SGLT2 inhibition with sotagliflozin is efficacious in reducing myocardial infarction (MI), stroke, and HF hospitalizations and urgent visits in the SCORED and SOLOIST-WHF trials. However, its impact on reducing cardiovascular mortality remains uncertain due to premature study discontinuation. Owing to these factors and lack of generalizability, further studies are needed to establish its role in renal protection and cardiovascular mortality in broader populations. At this time, more evidence is warranted to definitively establish sotagliflozin in HF.

Evaluation of the Hemocompatibility of the Direct Oral Anticoagulant Apixaban in Left Ventricular Assist Devices: The DOAC LVAD Study

BackgroundPatients receiving left ventricular assist device (LVAD) support require long-term anticoagulation to reduce the risk of thromboembolic complications. Apixaban is a direct oral anticoagulant that has become first-line therapy; however, its safety in LVAD recipients has not been well described. ObjectivesThis study sought to investigate whether, in patients with a fully magnetically levitated LVAD, treatment with apixaban would be feasible and comparable with respect to safety and freedom from the primary composite outcome of death or major hemocompatibility-related adverse events (HRAEs) (stroke, device thrombosis, major bleeding, aortic root thrombus, and arterial non–central nervous system thromboembolism) as compared with treatment with warfarin. MethodsThe DOAC LVAD (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices) trial was a phase 2, open label trial of LVAD recipients randomized 1:1 to either apixaban 5 mg twice daily or warfarin therapy. All patients were required to take low-dose aspirin. Patients were followed up for 24 weeks to evaluate the primary composite outcome. ResultsA total of 30 patients were randomized: 14 patients to warfarin and 16 patients to apixaban. The median patient age was 60 years (Q1-Q3: 52-71 years), and 47% were Black patients. The median time from LVAD implantation to randomization was 115 days (Q1-Q3: 56-859 days). At 24 weeks, the primary composite outcome occurred in no patients receiving apixaban and in 2 patients (14%) receiving warfarin (P = 0.12); these 2 patients experienced major bleeding from gastrointestinal sources. ConclusionsAnticoagulation with apixaban was feasible in patients with an LVAD without an excess of HRAEs or deaths. This study informs future pivotal clinical trials evaluating the safety and efficacy of apixaban in LVAD recipients. (Evaluation of the Hemocompatibility of the Direct Oral Anti-Coagulant Apixaban in Left Ventricular Assist Devices [DOAC LVAD]; NCT04865978)

Three-year outcomes of de novo tacrolimus extended-release tablets (LCPT) compared to twice-daily tacrolimus in adult heart transplantation

BackgroundExtended-release tacrolimus for prophylaxis of allograft rejection in heart transplant (HT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release (IR-) tacrolimus. We compared long-term efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients. Methods25 prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 3 years following transplant was compared between groups using non-inferiority analysis. ResultsLCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 16% (90%CI, −37%, −1%, non-inferiority p = 0.002) up to 3 years following heart transplant. Up to 3-years post-transplant, 14 patients remained on once-daily LCPT and 10 patients were switched to IR-tacrolimus due to lack of insurance coverage. There were no significant differences in the rate of chronic kidney disease requiring dialysis, cytomegalovirus requiring treatment, cardiac allograft vasculopathy, and malignancy within 3 years following transplant. ConclusionLCPT is non-inferior in efficacy to IR-tacrolimus in heart transplantation with a similar safety profile. Narrowly-constrained FDA labels specific to kidney transplant remain a barrier to consistent access to many immunosuppressant medications for recipients of non-kidney solid organs. We recommend the FDA consider developing facile pathways for expanding the approved label of extended-release tacrolimus formulations to heart transplant recipients.

Predictors of outcome in patients with moderate mixed aortic valve disease

ObjectivesGrading the severity of moderate mixed aortic stenosis and regurgitation (MAVD) is challenging and the disease poorly understood. Identifying markers of haemodynamic severity will improve risk stratification and potentially guide...

Exploring the Association of Male Sex With Adverse Outcomes in Severe Bronchopulmonary Dysplasia: A Retrospective, Multicenter Cohort Study

Background and ObjectiveBronchopulmonary dysplasia (BPD) is a significant contributor to morbidity and mortality in infants born premature. Male sex is an independent risk factor for the development of BPD. However, whether male sex is associated with adverse outcomes occurring after formal diagnosis of severe BPD prior to hospital discharge remains unclear. Research QuestionIs male sex associated with a higher risk of adverse outcomes in infants with established severe BPD? Study Design and MethodsA retrospective, multi-center cohort study of infants enrolled in the BPD Collaborative Registry from January 1, 2015, to June 29th, 2022 was performed. Demographics, clinical characteristics, and outcomes were stratified by sex (i.e., male vs. female). Regression modeling was used to estimate the association of sex with the primary composite outcome of death or tracheostomy at hospital discharge. ResultsWe identified 1156 infants with severe BPD, defined at 36 weeks’ postmenstrual age (PMA) by the National Institutes of Health 2001 consensus definition. The cohort was predominantly male (59% males, 41% females). However, rates of mechanical ventilation at 36 weeks’ PMA (i.e. type 2 severe BPD) did not differ by sex. Overall mortality within the cohort was low (5.3% males, 3.6 % females). The odds ratio of death or tracheostomy for males to females was 1.0 (95%CI: 0.7, 1.5). InterpretationOur results lead us to speculate that while sex is an important variable contributing to the development and pathogenesis of severe BPD, it does not appear to be associated with adverse outcomes in this cohort of infants with established disease. The surprising results raise important questions surrounding the temporal role of biological sex in developing severe BPD and its progression during the NICU stay. As we explore the phenotypes and endotypes of BPD, it is imperative to consider how sex modulates the disease from birth through hospital discharge.

Association of pre–left ventricular assist device defibrillator shocks for ventricular arrhythmia with clinical outcomes after left ventricular assist device implantation

Implantable cardioverter-defibrillation (ICD) shocks after left ventricular assist device therapy (LVAD) are associated with adverse clinical outcomes. Little is known about the association of pre-LVAD ICD shocks on post-LVAD clinical outcomes and whether LVAD therapy affects the prevalence of ICD shocks. The purpose of this study was to determine whether pre-LVAD ICD shocks are associated with adverse clinical outcomes post-LVAD and to compare the prevalence of ICD shocks before and after LVAD therapy. Patients 18 years or older with continuous-flow LVADs and ICDs were retrospectively identified within the University of Pittsburgh Medical Center system from 2006-2020. We analyzed the association between appropriate ICD shocks within 1 year pre-LVAD with a primary composite outcome of death, stroke, and pump thrombosis and secondary outcomes of post-LVAD ICD shocks and ICD shock hospitalizations. Among 309 individuals, average age was 57 ± 12 years, 87% were male, 80% had ischemic cardiomyopathy, and 42% were bridge to transplantation. Seventy-one patients (23%) experienced pre-LVAD shocks, and 69 (22%) experienced post-LVAD shocks. The overall prevalence of shocks pre-LVAD and post-LVAD were not different. Pre-LVAD ICD shocks were not associated with the composite outcome. Pre-LVAD ICD shocks were found to predict post-LVAD shocks (hazard ratio [HR] 5.7; 95% confidence interval [CI] 3.42-9.48; P <.0001) and hospitalizations related to ICD shocks from ventricular arrhythmia (HR 10.34; 95% CI 4.1-25.7; P <.0001). Pre-LVAD ICD shocks predicted post-LVAD ICD shocks and hospitalizations but were not associated with the composite outcome of death, pump thrombosis, or stroke at 1 year. The prevalence of appropriate ICD shocks was similar before and after LVAD implantation in the entire cohort.

Impact of postnatal dexamethasone timing on preterm mortality and bronchopulmonary dysplasia: a propensity score analysis.

Postnatal dexamethasone (PND) is used in high-risk preterm infants after the first week of life to facilitate extubation and prevent bronchopulmonary dysplasia (BPD) but the optimal treatment timing remains unclear. Our objective was to explore the association between the timing of PND commencement and mortality and respiratory outcomes. This was a retrospective National Neonatal Research Database study of 84 440 premature infants born <32 weeks gestational age from 2010 to 2020 in England and Wales. Propensity score weighting analysis was used to explore the impact of PND commenced at three time-points (2-3 weeks (PND2/3), 4-5 weeks (PND4/5) and after 5 weeks (PND6+) chronological age) on the primary composite outcome of death before neonatal discharge and/or severe BPD (defined as respiratory pressure support at 36 weeks) alongside other secondary respiratory outcomes. 3469 infants received PND. Compared with PND2/3, infants receiving PND6+ were more likely to die and/or develop severe BPD (OR 1.68, 95% CI 1.28-2.21), extubate at later postmenstrual age (mean difference 3.1 weeks, 95% CI 2.9-3.4 weeks), potentially require respiratory support at discharge (OR 1.34, 95% CI 1.06-1.70) but had lower mortality before discharge (OR 0.38, 95% CI 0.29-0.51). PND4/5 was not associated with severe BPD or discharge respiratory support. PND treatment after 5 weeks of age was associated with worse respiratory outcomes although residual bias cannot be excluded. A definitive clinical trial to determine the optimal PND treatment window, based on early objective measures to identify high-risk infants, is needed.

To guide future practice, perinatal trials should be much larger, simpler and less fragile with close to 100% ascertainment of mortality and other key outcomes

The Australian Placental Transfusion Study (APTS) randomised 1,634 fetuses to delayed (≥60 s) versus immediate (≤10 s) clamping of the umbilical cord. Systematic reviews with meta-analyses, including this and similar trials, show that delaying clamping in preterm infants reduces mortality and need for blood transfusions. Amongst 1,531 infants in APTS followed up at two years, aiming to delay clamping for 60 s or more reduced the relative risk of the primary composite outcome of death or disability by 17% (p = 0.01). However, this result is fragile because nominal statistical significance (p < 0.05) would be abolished by only 2 patients switching from a non-event to an event, and the primary composite outcome was missing in 112 patients (7%). To achieve more robust evidence, any future trials should emulate the large, simple trials co-ordinated from Oxford which reliably identified moderate, incremental improvements in mortality in tens of thousands of participants, with <1% missing data. Those who fund, regulate, and conduct trials that aim to change practice should repay the trust of those who consent to participate by doing everything possible to minimise missing data for key outcomes.

Impact of Early Hemodynamic Screening on Extremely Preterm Outcomes in a High-Performance Center.

Rationale: Increasing survival of extremely preterm infants with a stable rate of severe intraventricular hemorrhage represents a growing health risk for neonates. Objectives: To evaluate the role of early hemodynamic screening (HS) on the risk of death or severe intraventricular hemorrhage. Methods: All eligible patients 22-26+6 weeks' gestation born and/or admitted <24 hours postnatal age were included. As compared with standard neonatal care for control subjects (January 2010-December 2017), patients admitted in the second epoch (October 2018-April 2022) were exposed to HS using targeted neonatal echocardiography at 12-18 hours. Measurements and Main Results: A primary composite outcome of death or severe intraventricular hemorrhage was decided a priori using a 10% reduction in baseline rate to calculate sample size. A total of 423 control subjects and 191 screening patients were recruited with a mean gestation and birth weight of 24.7 ± 1.5 weeks and 699 ± 191 g, respectively. Infants born at 22-23 weeks represented 41% (n = 78) of the HS epoch versus 32% (n = 137) of the control subjects (P = 0.004). An increase in perinatal optimization (e.g., antepartum steroids) but with a decline in maternal health (e.g., increased obesity) was seen in the HS versus control epoch. A reduction in the primary outcome and each of severe intraventricular hemorrhage, death, death in the first postnatal week, necrotizing enterocolitis, and severe bronchopulmonary dysplasia was seen in the screening era. After adjustment for perinatal confounders and time, screening was independently associated with survival free of severe intraventricular hemorrhage (OR 2.09, 95% CI [1.19, 3.66]). Conclusions: Early HS and physiology-guided care may be an avenue to further improve neonatal outcomes; further evaluation is warranted.

Association of Trauma With Long-Term Risk of Death and Immune-Mediated or Cancer Disease in Same-Sex Twins

Immediate consequences of trauma include a rapid and immense activation of the immune system, whereas long-term outcomes include premature death, physical disability, and reduced workability. To investigate if moderate to severe trauma is associated with long-term increased risk of death or immune-mediated or cancer disease. This registry-based, matched, co-twin control cohort study linked the Danish Twin Registry and the Danish National Patient Registry to identify twin pairs in which 1 twin had been exposed to severe trauma and the other twin had not from 1994 to 2018. The co-twin control design allowed for matching on genetic and environmental factors shared within twin pairs. Twin pairs were included if 1 twin had been exposed to moderate to severe trauma and the other twin had not (ie, co-twin). Only twin pairs where both twins were alive 6 months after the trauma event were included. Twin pairs were followed up from 6 months after trauma until 1 twin experienced the primary composite outcome of death or 1 of 24 predefined immune-mediated or cancer diseases or end of follow-up. Cox proportional hazards regression was used for intrapair analyses of the association between trauma and the primary outcome. A total of 3776 twin pairs were included, and 2290 (61%) were disease free prior to outcome analysis and were eligible for the analysis of the primary outcome. The median (IQR) age was 36.4 (25.7-50.2) years. The median (IQR) follow-up time was 8.6 (3.8-14.5) years. Overall, 1268 twin pairs (55%) reached the primary outcome; the twin exposed to trauma was first to experience the outcome in 724 pairs (32%), whereas the co-twin was first in 544 pairs (24%). The hazard ratio for reaching the composite outcome was 1.33 (95% CI, 1.19-1.49) for twins exposed to trauma. Analyses of death or immune-mediated or cancer disease as separate outcomes provided hazard ratios of 1.91 (95% CI, 1.68-2.18) and 1.28 (95% CI, 1.14-1.44), respectively. In this study, twins exposed to moderate to severe trauma had significantly increased risk of death or immune-mediated or cancer disease several years after trauma compared with their co-twins.

Relevance of age and hypertension for blood pressure targets in comatose survivors of cardiac arrest

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Novo Nordisk Foundation. Background Baseline arterial blood pressure (BP) is influenced by age. Therefore, age and previous hypertension may alter the appropriate BP target after out-of-hospital cardiac arrest (OHCA). Purpose To examine whether the optimal BP target after OHCA is affected by age and a history of arterial hypertension. Methods The Blood Pressure and Oxygenation Targets in Post Resuscitation Care (BOX) trial was a randomized, controlled, double-blind trial comprising 789 comatose patients ≥18 years of age, resuscitated after OHCA of presumed cardiac cause. Patients were randomized to a mean arterial BP target of either 63 mm Hg (low BP target group) or 77 mm Hg (high BP target group). The primary outcome was a composite of death from any cause or hospital discharge with severe cerebral disability within one year. The relationship between age or prevalent hypertension and clinical outcomes was evaluated using Cox proportional-hazards regression. Age was stratified into quartiles. We further determined if the effects of BP target varied across the age spectrum (and according to prevalent hypertension). Results Three-hundred and ninety-three patients were assigned to the high BP target group and 396 to the low BP target group. In all, 204 (25.9%), 201 (25.5%), 186 (23.6%), and 198 (25.1%) were ≤54, 55-64, 65-72, and ≥73 years. Mean age was similar between the two study groups (high BP target 63 ± 13 years versus low BP target 62 ± 14 years; P = 0.60). A total of 176 (45%) patients in the high BP target group and 186 (47%) patients in the low BP target group had known hypertension. At 90 days, 133 patients (34%) in the high BP target group and 127 patients (32%) in the low BP target group had experienced the primary outcome. The risk of the primary outcome increased with higher age (Figure 1). Hazard ratios of the primary outcome according to BP targets within each age quartile (with low BP target as reference) were as follows: ≤54: 1.71; 95% confidence interval [CI], 0.99 to 2.95; P = 0.054, 55-64: 0.92; 95% CI, 0.57 to 1.49; P = 0.73, 65-72: 1.12; 95% CI, 0.73 to 1.74; P = 0.59 and ≥73: 0.88; 95% CI, 0.60 to 1.27; P = 0.48 (Figure 2). The hazard ratio of the primary outcome was 0.99; 95% CI, 0.72 to 1.37; P = 0.97 in patients without prevalent hypertension, and 1.14; 95% CI, 0.83 to 1.54; P = 0.42 in patients with prevalent hypertension. Conclusions In patients resuscitated after OHCA, there was a significant association between age and the primary composite outcome of death, severe disability, or coma. The effect of BP target on the primary outcome did not appear to differ according to age groups or prevalent hypertension. Therefore, age and prevalent hypertension should not influence the choice of BP targets after OHCA.

Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone Among Patients With Septic Shock

Patients with septic shock may benefit from the initiation of corticosteroids. However, the comparative effectiveness of the 2 most studied corticosteroid regimens (hydrocortisone with fludrocortisone vs hydrocortisone alone) is unclear. To compare the effectiveness of adding fludrocortisone to hydrocortisone vs hydrocortisone alone among patients with septic shock using target trial emulation. This retrospective cohort study from 2016 to 2020 used the enhanced claims-based Premier Healthcare Database, which included approximately 25% of US hospitalizations. Participants were adult patients hospitalized with septic shock and receiving norepinephrine who began hydrocortisone treatment. Data analysis was performed from May 2022 to December 2022. Addition of fludrocortisone on the same calendar day that hydrocortisone treatment was initiated vs use of hydrocortisone alone. Composite of hospital death or discharge to hospice. Adjusted risk differences were calculated using doubly robust targeted maximum likelihood estimation. Analyses included 88 275 patients, 2280 who began treatment with hydrocortisone-fludrocortisone (median [IQR] age, 64 [54-73] years; 1041 female; 1239 male) and 85 995 (median [IQR] age, 67 [57-76] years; 42 136 female; 43 859 male) who began treatment with hydrocortisone alone. The primary composite outcome of death in hospital or discharge to hospice occurred among 1076 (47.2%) patients treated with hydrocortisone-fludrocortisone vs 43 669 (50.8%) treated with hydrocortisone alone (adjusted absolute risk difference, -3.7%; 95% CI, -4.2% to -3.1%; P < .001). In this comparative effectiveness cohort study among adult patients with septic shock who began hydrocortisone treatment, the addition of fludrocortisone was superior to hydrocortisone alone.

Abstract 13385: Long Term Outcomes in Catheter Ablation of Atrial Fibrillation Compared to Medical Therapy

Introduction: The long-term effects of catheter ablation (CA) compared to medical therapy on cardiovascular outcomes for atrial fibrillation (AF) remain undetermined. We examined the outcomes associated with CA compared to rate or rhythm control therapy in a population cohort with AF. Methods: Using Alberta administrative data, patients with AF as the primary diagnosis during hospitalization or emergency department/physician visit were included between 2008-2018. Based on therapy received, patients were assigned to CA, rate (digoxin, calcium channel or beta blocker) or rhythm control (amiodarone, sotalol, flecainide, propafenone, dronedarone). If treatment changed over time, the patient was censored in the prior treatment arm and assigned to the new arm. The association of treatment (included as time-varying covariate) with the primary composite outcome of death, hospitalization for heart failure or stroke was examined using multivariable Cox models after adjusting for age, sex, comorbidities and baseline medications. Secondary outcomes included cardiovascular hospitalizations, and individual components of the composite. Results: There were 2,149 (4.0%) patients treated with CA and 51,315 with medical treatment (rate : 41,948, (81.5%) rhythm: 9,367 (18.2%). During a median follow-up of 4.2 years, CA for AF was associated with a lower crude incidence of the composite outcome (rate per 100 person-years was 3.3 for CA, 9.5 for rate control, and 6.3 for rhythm control). In multivariate analysis, compared to CA, both rate (adjusted hazard ratio (aHR) 1.55, 95% confidence interval (CI), 1.44 to 1.68) and rhythm control (aHR 1.37; 95% CI 1.27 to 1.49) were associated with a higher risk of the primary composite outcome.(Figure) Secondary outcomes are shown in the Figure. Conclusions: Only a small percentage of patients with AF undergo CA. Patients selected for CA have a lower risk of long-term adverse outcomes compared to medical therapy in patients with AF.

Neonatal Morbidities and Feeding Tolerance Outcomes in Very Preterm Infants, before and after Introduction of Probiotic Supplementation.

While probiotics are reported to reduce the risks of neonatal morbidities, less is known about probiotics and feeding tolerance. With this retrospective cohort study, we investigate whether introduction of probiotic supplementation as the standard of care was associated with fewer neonatal morbidities and improved feeding tolerance in very preterm infants. Using the Swedish Neonatal Quality Register, 345 live-born very preterm infants (28–31 weeks’ gestation), from January 2019–August 2021, in NICUs in Stockholm, Sweden, either received probiotic supplementation (Bifidobacterium infantis, Bifidobacterium lactis, Streptococcus thermophilus) (139) or no supplementation (206); they were compared regarding a primary composite outcome of death, sepsis, and/or necrotising enterocolitis and secondary outcomes: time to full enteral feeding and antibiotics use. Probiotics seemed associated with a reduced risk of the composite outcome (4.3% versus 9.2%, p = 0.08). In the subgroup of 320 infants without the primary outcome, probiotics were associated with shorter time to full enteral feeding (6.6 days versus 7.2 days) and less use of antibiotics (5.2 days versus 6.1 days). Our findings suggest that probiotics improve feeding tolerance and further support that very preterm infants may benefit from probiotic supplementation.

New study gives F to vitamin C treatment in septic ICU patients

New study gives F to vitamin C treatment in septic ICU patients

Validity of the vasoactive-inotropic score in preterm neonates receiving cardioactive therapies

BackgroundVasoactive-Inotropic Score (VIS) is a weighted sum of various vasopressors and inotropes; its utility among preterm neonates is understudied. ObjectiveTo investigate the association between maximum VIS (VISmax) during the first 12, 24 and 48 h of treatment among preterm neonates who received vasopressors/inotropes, and the composite outcome of death/severe neuroinjury (sNI). MethodsRetrospective cohort study, over 6-years, including neonates <35 weeks gestational age (GA). Infants who met the primary composite outcome of death or sNI (defined as new intraventricular hemorrhage ≥grade 3 or periventricular leukomalacia) were compared to those who survived without sNI. Maximum VIS was categorized as <10, 10–19 or ≥ 20 for comparison. Results192 infants (mean GA and birth weight 26.8 ± 3.3 weeks and 952 ± 528 g, respectively) were included. The most common primary diagnosis was sepsis/necrotizing enterocolitis (69 %). Median VIS for the entire cohort was 10. Death/sNI was associated with lower GA at birth and treatment, as well as higher frequency of VISmax of 10–19 or ≥20, compared to <10, during each time period (all p < 0.01). Multivariable regression revealed GA at treatment and VISmax ≥ 20 [not 10–19, referenced to <10] were associated death/sNI; adjusted odds ratio (95 % CI) for VISmax ≥ 20 within 12, 24, and 48 h were 4.2 (1.6–11.0), 4.9 (1.9–12.3), and 6.7 (2.7–16.7), respectively. ConclusionsVasoactive-Inotropic Score may be a valid measure to quantify cardiovascular support in preterm infants needing hemodynamic support. Maximum VIS ≥20 within 48 h of treatment initiation may identify patients at high risk of adverse outcomes.

Blanket temperature during therapeutic hypothermia and outcomes in hypoxic ischemic encephalopathy.

Determine whether blanket temperatures during therapeutic hypothermia (TH) are associated with 18-22 month outcomes for infants with hypoxic ischemic encephalopathy (HIE). Retrospective cohort study of 181 infants with HIE who received TH in two randomized trials within the Neonatal Research Network. We defined summative blanket temperature constructs and evaluated for association with a primary composite outcome of death or moderate/ severe disability at 18-22 months. Each 0.5 °C above 33.5 °C in the mean of the highest quartile blanket temperature was associated with a 52% increase in the adjusted odds of death/ disability (aOR 1.52, 95% CI 1.09-2.11). Having >8 consecutive blanket temperatures above 33.5 °C rendered an aOR of death/disability of 5.04 in the first 24 h (95% CI 1.54-16.6) and 6.92 in the first 48 h (95% CI 2.20-21.8) of TH. Higher blanket temperature during TH may be an early, clinically useful biomarker of HIE outcome.

EBNEO Commentary: Effect of systemic hydrocortisone initiated 7-14days after birth in ventilated preterm infants on mortality and neurodevelopment at 2years' corrected age.

Halbmeijer NM, Onland W, Cools F, Swarte R, van der Heide-Jalving M, Merkus MP, van Kaam AH. Effect of Systemic Hydrocortisone Initiated 7–14 Days after Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 years' Corrected Age. JAMA 2021; 324 (6):355–357. PMID 34313697. The safety and effectiveness of postnatal corticosteroids (PCS) to prevent or treat BPD remain an active area of research. After fluctuations in their popularity over the past 40 years, PCS remain widely used as treatments for extremely preterm infants with evolving BPD in neonatal intensive care units worldwide. The Cochrane Library has two reviews of PCS, based on the timing of drug commencement: ‘early’ use (<8 days of age)1 and ‘late’ use (>7 days of age).2 Dexamethasone and hydrocortisone have been the primary systemic PCS of interest. Dexamethasone has been studied more extensively than hydrocortisone as ‘early’ therapy (21/32 randomised trials on the Cochrane review were on Dexamethasone) and despite an important reduction in rates of death or BPD rate at 36 weeks' PMA, the incidence of cerebral palsy is higher (RR 1.42, 95% CI 1.06–1.91)2 in these infants who received Dexamethasone. The PREMILOC3 trial in 2016 attempted to assess the effect of ‘early’ systemic hydrocortisone use in premature neonates treated within the first 10 days of life and despite the early cessation of the trial, demonstrated improved survival without BPD at 36 weeks' PMA (OR 1.48, 95% CI 1.02–2.16, p = 0.04) with no increased risk for long-term neurodevelopmental impairment at 22 months' corrected age.4 From this study, it was postulated that hydrocortisone may be the early PCS of choice for the prevention of BPD. The STOP-BPD trial is the first to address the ‘late’ use of hydrocortisone in infants at high risk of BPD. It reported no important difference in the primary composite outcome of death or BPD at 36 weeks' PMA (70.7% hydrocortisone vs 73.7% in placebo, p = 0.54), although there was a reduction in mortality at 36 weeks' PMA (15.5% vs 23.7%, OR 0.59; 95% CI 0.35–0.995 p = 0.048). The authors acknowledged that the study was not powered to detect smaller differences in the primary outcome, also limiting the ability to detect important differences at 2 years. At the 2-year follow-up assessment, the composite outcome of death and NDI was not statistically significantly different (OR 0.79 95% CI 0.51–1.22 p = 0.28). However, the reduced risk of death in the hydrocortisone group persisted. The risk of death was lower in the hydrocortisone group (39/181 vs 56/190) by 8%, a clinically important effect size, even if the result did not reach accepted levels of statistical significance. These results demonstrate that dichotomous composite endpoints in neonatal trials, where the components that are not equal in importance, can be fraught.5 We note the high rate of open-label hydrocortisone use within this trial. Table 26 in the primary study shows that 108/190 (57%) infants in the placebo group eventually received ‘rescue’ hydrocortisone for their clinical status. This may have reduced the power of the trial to demonstrate beneficial or harmful effects of hydrocortisone, both in the short (36 weeks' PMA) and longer term (2 years). This study further fuels the discussion regarding the interaction between baseline BPD risk and the treatment effect of PCS on longer term outcomes in extremely preterm infants.7 Patient selection, timing and choice of systemic PCS remain topics of research. Current trials are underway of alternative methods of administering PCS to prevent BPD in the sickest preterm infants.8 https://ebneo.org/stop-bpd-2-years Prof Peter Davis is co-author for the cited reference 6 and was a co-investigator for the DART study. A/Prof Brett Manley and Prof Peter Davis are current co-investigators on the PLUSS trial of intratracheal budesonide. A/Prof Brett Manley is a co-author on the updated Cochrane Reviews of early and late postnatal corticosteroids which are in press at time of writing.

Geographical variations in left main coronary artery revascularisation: a prespecified analysis of the EXCEL trial.

The EXCEL trial reported similar five-year rates of the primary composite outcome of death, myocardial infarction (MI), or stroke after percutaneous coronary intervention (PCI) compared with coronary artery bypass grafting (CABG) for treatment of obstructive left main coronary artery disease (LMCAD). We sought to determine whether these outcomes remained consistent regardless of geography of enrolment. We performed a prespecified subgroup analysis based on regional enrolment. Among 1,905 patients randomised to PCI (n=948) or CABG (n=957), 1,075 (56.4%) were recruited at 52 European Union (EU) centres, and 752 (39.5%) were recruited at 67 North American (NA) centres. EU versus NA patients varied according to numerous baseline demographics, anatomy, pharmacotherapy and procedural characteristics. Nonetheless, the relative rates of the primary endpoint after PCI versus CABG were consistent across EU versus NA centres at 30 days and 5 years. However, NA participants had substantially higher late rates of ischaemia-driven revascularisation (IDR) after PCI, driven predominantly by the need for greater target vessel and lesion revascularisation. This culminated in a significant difference in the relative risk of the secondary composite outcome of death, MI, stroke, or IDR at 5 years (pinteraction=0.02). In the EXCEL trial, the relative risks for the 30-day and five-year primary composite outcome of death, MI or stroke after PCI versus CABG were consistent irrespective of geography. However, five-year rates of IDR after PCI were significantly higher in NA centres, a finding the Heart Team and patients should consider when making treatment decisions. ClinicalTrials.gov identifier: NCT01205776.

De novo tacrolimus extended-release tablets (LCPT) versus twice-daily tacrolimus in adult heart transplantation: Results of a single-center non-inferiority matched control trial.

Extended‐release tacrolimus for prophylaxis of allograft rejection in orthotopic heart transplant (OHT) recipients is currently not FDA‐approved. One such extended‐release formulation of tacrolimus known as LCPT allows once‐daily dosing and improves bioavailability compared to immediate‐release tacrolimus (IR‐tacrolimus). We compared the efficacy and safety of LCPT to IR‐tacrolimus applied de novo in adult OHT recipients. Twenty‐five prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR‐tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 1 year was compared using non‐inferiority analysis. LCPT demonstrated non‐inferiority to IR‐tacrolimus, with a primary outcome risk reduction of 20% (90% CI: ‐40%, ‐.5%; non‐inferiority P = .001). Tacrolimus trough levels peaked at 2–3 months and were higher in LCPT (median 14.5 vs. 12.7 ng/ml; P = .03) with similar dose levels (LCPT vs. IR‐tacrolimus: .08 vs. .09 mg/kg/day; P = .33). Cardiovascular‐related readmissions were reduced by 62% (P = .046) in LCPT patients. The complication rate per transplant admission and all‐cause readmission rate did not differ significantly. These results suggest that LCPT is non‐inferior in efficacy to IR‐tacrolimus with a similar safety profile and improved bioavailability in OHT.