Identification of heart failure hospitalization from NHS Digital data: comparison with expert adjudication.

AIMS: Population-wide, person-level, linked electronic health record data are increasingly used to estimate epidemiology, guide resource allocation, and identify events in clinical trials. The accuracy of data from NHS Digital (now part of NHS England) for identifying hospitalization for heart failure (HHF), a key HF standard, is not clear. This study aimed to evaluate the accuracy of NHS Digital data for identifying HHF. METHODS AND RESULTS: Patients experiencing at least one HHF, as determined by NHS Digital data, and age- and sex-matched patients not experiencing HHF, were identified from a prospective cohort study and underwent expert adjudication. Three code sets commonly used to identify HHF were applied to the data and compared with expert adjudication (I50: International Classification of Diseases-10 codes beginning I50; OIS: Clinical Commissioning Groups Outcomes Indicator Set; and NICOR: National Institute for Cardiovascular Outcomes Research, used as the basis for the National Heart Failure Audit in England and Wales). Five hundred four patients underwent expert adjudication, of which 10 (2%) were adjudicated to have experienced HHF. Specificity was high across all three code sets in the first diagnosis position {I50: 96.2% [95% confidence interval (CI) 94.1-97.7%]; NICOR: 93.3% [CI 90.8-95.4%]; OIS: 95.6% [CI 93.3-97.2%]} but decreased substantially as the number of diagnosis positions expanded. Sensitivity [40.0% (CI 12.2-73.8%)] and positive predictive value (PPV) [highest with I50: 17.4% (CI 8.1-33.6%)] were low in the first diagnosis position for all coding sets. PPV was higher for the National Heart Failure Audit criteria, albeit modestly [36.4% (CI 16.6-62.2%)]. CONCLUSIONS: NHS Digital data were not able to accurately identify HHF and should not be used in isolation for this purpose.

Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. METHODS: The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. CONCLUSION: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM. TRIAL REGISTRATION NUMBERS: NCT04706429 and ISRCTN57145331.

Copper chelation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Disturbances of copper (Cu) homeostasis can lead to hypertrophic cardiac phenotypes (eg, Wilson's disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and, therefore, hypothesised that Cu2+-selective chelation with trientine dihydrochloride may slow or reverse disease progression in HCM. The aim of this study was, therefore to explore the clinical efficacy, safety and tolerability of trientine in HCM. METHODS: In this medicines and healthcare products regulatory agency (MHRA) registered open-label pilot study, we treated 20 HCM patients with trientine for 6 months. Patients underwent a comprehensive assessment schedule including separate cardiac magnetic resonance imaging (CMR) and CMR 31P-spectroscopy at baseline and end of therapy. Predefined end points included changes in left ventricular mass (LVM), markers of LV fibrosis, markers of LV performance and myocardial energetics. Ten matched patients with HCM were studied as controls. RESULTS: Trientine treatment was safe and tolerated. Trientine caused a substantial increase in urinary copper excretion (0.42±0.2 vs 2.02±1.0, p=0.001) without affecting serum copper concentrations. Treatment was associated with significant improvements in total atrial strain and global longitudinal LV strain using both Echo and CMR. LVM decreased significantly in the treatment arm compared with the control group (-4.2 g v 1.8 g, p=0.03). A strong trend towards an absolute decrease in LVM was observed in the treatment group (p=0.06). These changes were associated with a significant change in total myocardial volume driven by a significant reduction in extracellular matrix (ECM) volume (43.83±18.42 mL vs 41.49±16.89 mL, p=0.04) as opposed to pure cellular mass reduction and occurred against a background of significant ECM volume increase in the control group (44.59±16.50 mL vs 47.48±19.30 mL, p=0.02). A non-significant 10% increase in myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio with trientine therapy (1.27±0.44 vs 1.4±0.39) was noted. CONCLUSIONS: Cu2+-selective chelation with trientine in a controlled environment is safe and a potential future therapeutic target. A phase 2b trial is now underway.

Use of awake proning to avoid invasive ventilation in a patient with severe COVID-19 pneumonitis.

A 60-year-old man with swab-positive COVID-19 and extensive ground-glass change seen on CT imaging was successfully managed on our COVID-19 high-dependency unit with only low-flow oxygen and strict awake proning instructions. He was successfully weaned off oxygen entirely without any requirement for non-invasive or invasive ventilation and made a recovery to be discharged home after an 18-day hospital stay.

Fungal sensitisation in severe asthma is associated with the identification of Aspergillus fumigatus in sputum.

BACKGROUND: Fungal sensitisation is an important factor in severe asthma, not only for allergic bronchopulmonary aspergillosis (ABPA) but also the more recently described severe asthma with fungal sensitisation (SAFS). It is not known whether these diseases are driven by the presence of airway fungal colonisation. We aimed to determine if both SAFS and ABPA were associated with airway isolation of Aspergillus fumigatus and whether the frequency of isolation changed following anti-fungal treatment. METHODS: Sputum samples were collected from patients with SAFS, ABPA and a control group without fungal sensitisation. We recorded details of antifungal treatment, serum IgE and A. fumigatus specific IgE levels. In a subgroup (n = 9) we recorded serial sputum PCR measurements before and during itraconazole therapy. RESULTS: 244 sputum samples were provided by 135 patients, 41(17%) ABPA, 168(69%) SAFS, and 35(14%) controls. Sputum Aspergillus fumigatus PCR was positive in 61 SAFS patients (70%) and 6 ABPA patients (50%) not on anti-fungal treatment at the time of the test, compared to 3 (9%) in controls (χ(2) = 37.90, p < 0.001). Consequently, 19 patients with SAFS who were taking antifungal treatment (23%) were significantly less likely to be PCR positive than the 61 patients not on treatment (70%) (χ(2) = 36.66, p < 0.001). All 9 patients assessed serially during therapy had positive sputum PCR pre-treatment and all became negative during itraconazole treatment. CONCLUSION: We have shown that isolation of fungus from the airway of severe asthma patients with fungal sensitisation is very common, supporting the hypothesis of a mechanistic link between fungal colonisation and sensitisation.