Background
Acute thrombotic thrombocytopenic purpura (TTP) is a life‐threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality.
Objectives
To compare ...current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX.
Patients/Methods
The trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP.
Results
Data on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on‐site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two‐thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation.
Conclusions
This is the first multi‐center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life‐saving intervention.
The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy.
...The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2-positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF > or = 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction.
Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure CHF, 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m(2) v 257 mg/m(2)) or epirubicin (480 mg/m(2) v 422 mg/m(2)) and had a lower screening LVEF and a higher body mass index.
Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.
The Psychosocial Factors Outcome Study (PFOS) investigated the prevalence of depression and anxiety and the relationship of psychosocial factors to mortality in outpatients with heart failure (HF).
...Considerable evidence links psychosocial factors to coronary heart disease mortality and sudden cardiac death (SCD). The contribution of psychosocial factors independent of disease severity to HF outpatient mortality is not well elucidated.
Patients (N = 153) from 20 Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) sites participated in the PFOS. SCD-HeFT provided demographic, medical history, and cardiac data. Participants completed questionnaires to assess psychosocial status at PFOS entry.
Depression and anxiety were common in HF outpatients (36% Beck Depression Inventory-II ≥13; 45% State Trait Anxiety Inventory ≥40). Depression, anxiety, and social support amount did not differ in the SCD-HeFT treatment groups: implantable cardioverter defibrillator, amiodarone, and placebo medication. Fifteen (9.8%) patients died during mean follow-up at 23.6 months (SD = 8.2). In Cox regression controlling for treatment, depression, anxiety, and social isolation separately predicted mortality; perceived HF-specific functional status did not. Depression (ln)
P = .04, hazard ratio (HR) = 1.81 and social isolation (
P = .04, HR = 2.25), but not anxiety, predicted mortality independent of demographics, clinical predictors, and treatment. When simultaneously including significant demographic, clinical, and psychosocial predictors and treatment groups, depression (ln) (
P = .022, HR = 2.2) and social isolation (
P = .094, HR = 1.75) predicted mortality. All-cause mortality was 12% for depressed patients and 9% for others.
This study finds a high prevalence of anxiety and confirms the high prevalence of depression in the HF outpatient population. Depression and social isolation predicted mortality independent of demographic and clinical status in HF outpatients.
Bisphenol A (BPA) was evaluated at concentrations of 0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm (∼ 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg/day of BPA) administered in the diet ad libitum to 30 CD® ...Sprague-Dawley rats/sex/dose for 3 offspring generations, 1 litter/generation, through F3 adults. Adult systemic toxicity at 750 and 7500 ppm in all generations included: reduced body weights and body weight gains, reduced absolute and increased relative weanling and adult organ weights (liver, kidneys, adrenals, spleen, pituitary, and brain), and female slight/mild renal and hepatic pathology at 7500 ppm. Reproductive organ histopathology and function were unaffected. Ovarian weights as well as total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD). Mating, fertility, gestational indices; ovarian primordial follicle counts; estrous cyclicity; precoital interval; gestational length; offspring sex ratios; postnatal survival; nipple/areolae retention in preweanling males; epididymal sperm number, motility, morphology; daily sperm production (DSP), and efficiency of DSP were all unaffected. At 7500 ppm, vaginal patency (VP) and preputial separation (PPS) were delayed in F1, F2, and F3 offspring, associated with reduced body weights. Anogenital distance (AGD) on PND 0 was unaffected for F2 and F3 males and F3 females (F2 female AGD was increased at some doses, not at 7500 ppm, and was considered not biologically or toxicologically relevant). Adult systemic no observed adverse effect level (NOAEL) = 75 ppm (5 mg/kg/day); reproductive and postnatal NOAELs = 750 ppm (50 mg/kg/day). There were no treatment-related effects in the low-dose region (0.001–5 mg/kg/day) on any parameters and no evidence of nonmonotonic dose-response curves across generations for either sex. BPA should not be considered a selective reproductive toxicant, based on the results of this study.
Load management, i.e., prescribing, monitoring, and adjusting training load, is primarily aimed at preventing injury and maximizing performance. The search for objective monitoring tools to assess ...the external and internal load of athletes is of great interest for sports science research. In this 4-week pilot study, we assessed the feasibility and acceptance of an extensive monitoring approach using biomarkers, neuromuscular performance, and questionnaires in an elite youth soccer setting. Eight male players (mean ± SD: age: 17.0 ± 0.6 years, weight: 69.6 ± 8.2 kg, height: 177 ± 7 cm, VO
2max
: 62.2 ± 3.8 ml/min/kg) were monitored with a local positioning system (e.g., distance covered, sprints), biomarkers (cell-free DNA, creatine kinase), questionnaires, neuromuscular performance testing (counter-movement jump) and further strength testing (Nordic hamstring exercise, hip abduction and adduction). Feasibility was high with no substantial impact on the training routine and no adverse events such as injuries during monitoring. Adherence to the performance tests was high, but adherence to the daily questionnaires was low, and decreased across the study period. Occasional significant correlations were observed between questionnaire scores and training load data, as well as between questionnaire scores and neuromuscular performance. However, due to the small sample size, these findings should be treated with caution. These preliminary results highlight the feasibility of the approach in elite soccer, but also indicate that modifications are needed in further large-scale studies, particularly in relation to the length of the questionnaire.
Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to ...investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients.
In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033.
Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 95% CI 0·8–1·2; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 >70 mm Hg associated with worse outcomes), right atrial volume index (pinteraction=0·012 ≥29·7 mL/m2, worse outcomes), and sex (pinteraction=0·02 men, worse outcomes). There were no differences in the composite safety endpoint between the two groups (n=116 38% for shunt device vs n=97 31% for sham procedure; p=0·11).
Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%.
Corvia Medical.
Heart failure with preserved ejection fraction represents a major unmet clinical need with limited treatment options. Recent device therapies under investigation have focused on decompression of the ...left atrium through an implantable interatrial shunt. Although these devices have shown favorable safety and efficacy signals, an implant is required to maintain shunt patency, which may increase the patient risk profile and complicate subsequent interventions requiring transseptal access.
The Alleviant System is a no-implant approach to creating an interatrial shunt using radiofrequency energy to securely capture, excise, and extract a precise disk of tissue from the interatrial septum. Acute preclinical studies in healthy swine (n = 5) demonstrated the feasibility of the Alleviant System to repeatably create a 7 mm interatrial orifice with minimal collateral thermal effect and minimal platelet and fibrin deposition observed histologically.
Chronic animal studies (n = 9) were carried out to 30- and 60-day time points and exhibited sustained shunt patency with histology demonstrating completely healed margins, endothelialization, and no trauma to adjacent atrial tissue. Preliminary clinical safety and feasibility were validated in a first-in-human study in patients with heart failure with preserved ejection fraction (n = 15). All patients demonstrated shunt patency by transesophageal echocardiographic imaging at 1, 3, and 6 months, as well as cardiac computed tomography imaging at 6-month follow-up timepoints.
Combined, these data support the safety and feasibility of a novel no-implant approach to creating an interatrial shunt using the Alleviant System. Continued follow-up and subsequent clinical studies are currently ongoing.
•Patency of interatrial shunts via radiofrequency septectomy is maintained in swine and humans.•Interatrial shunts created via radiofrequency septectomy heal with minimal thermal effect.•A no-implant shunt method may be beneficial for treating congestive heart failure.
Many patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure.
This study sought to characterize patients with normal ...resting LA pressure (pulmonary capillary wedge pressure PCWP <15 mm Hg) but exercise-induced left atrial hypertension (EILAH).
The REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH).
Patients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e′, and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present.
Patients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure REDUCE LAP-HF TRIAL II; NCT03088033)
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