Considerations for drug trials in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition with potentially serious manifestations. Management has traditionally comprised therapies to palliate symptoms and implantable cardioverter-defibrillators to prevent sudden cardiac death. The need for disease-modifying therapies has been recognized for decades. More recently, an increasing number of novel and repurposed therapies hypothesized to target HCM disease pathways have been evaluated, culminating in the recent regulatory approval of mavacamten, a novel oral myosin inhibitor. HCM poses several unique challenges for clinical trials, which are important to recognize when designing trials and interpreting findings. This manuscript discusses the key considerations in the context of recent and ongoing randomized trials, including the roles of genotype, phenotype and symptom status in patient selection, the evidence base for clinical and mechanistic outcome measurements, trial duration and sample size.

Pre-Emptive Pharmacogenetic Testing in the Acute Hospital Setting: A Cross-Sectional Study.

BACKGROUND: Pharmacogenetic guided prescribing can be used to improve the safety and effectiveness of medicines. There are several approaches by which this intervention might be implemented in clinical practice, which will vary depending on the health system and clinical context. AIM: To understand the clinical utility of panel-based pharmacogenetic testing in patients admitted acutely to hospital and to establish variables which predict if an individual might benefit from the intervention. DESIGN: A cross-sectional study recruiting patients admitted acutely to hospital. METHODS: Participants underwent panel-based pharmacogenetic testing and their genetic results were analysed in their context of the medicines they had been exposed to as an inpatient. The primary outcome was the proportion of patients with clinically actionable gene-drug interactions. Individual variables which predict the clinical utility of pharmacogenetic testing were established via logistic regression. RESULTS: Genetic and prescribing data were available for 482 in-patients (55% male; median age 61.2 years; range: 18 to 96), 97.9% of whom carried a pharmacogenetic result of interest. During their admission, 79.5% of patients were exposed to a medicine for which there is pharmacogenetic prescribing guidance available. Just under 1 in 7 individuals (13.7%) had a clinically actionable gene-drug interaction. Increasing age (> 50-years) was positively correlated with the likelihood (2.7-fold increased risk) of having a clinically actionable interaction. CONCLUSIONS: These findings demonstrate the potential scale, and potential clinical utility, of pharmacogenetic testing as an intervention, highlighting the need to develop infrastructure to support healthcare professionals make use of this emerging tool.

Description and development of a nurse-led cardiac assessment team.

A problem was identified where patient care was affected because of delays in receiving specialist cardiology input. This report describes the experience of developing a specialist cardiac assessment where senior cardiac nurses were trained to provide a 24-hour presence in the emergency department (ED). We describe the service and our evaluation of the service. These dedicated specialised nurses can optimise patient management including admission or safely discharge patients with relevant follow-up when necessary. The team also runs three clinics per week with consultant support. The team of 10 nurses provides a cardiology opinion to approximately 400 patients a month in the ED and 100 patients a month in the acute medical unit (AMU). Eighty-seven per cent of patients are seen in the ED within 30 minutes of referral. Approximately 40% of patients reviewed are accepted directly into cardiology beds thus avoiding admission to the AMU. It has been estimated that 6 bed-days are saved each day, which translated to an estimated £400,000 each year. The team also provides outpatient rapid access services which generates £121,792 income for the directorate. We demonstrate that a cardiac nurse assessment team can provide a cost-effective 24-hour presence in the ED.

Predictors of fever-related admissions to a paediatric assessment unit, ward and reattendances in a South London emergency department: the CABIN 2 study.

OBJECTIVE: To explore the risk factors for ward and paediatric assessment unit (PAU) admissions from the emergency department (ED). DESIGN: Prospective observational study. SETTING AND PATIENTS: Febrile children attending a large tertiary care ED during the winter of 2014-2015. MAIN OUTCOME MEASURES: Ward and PAU admissions, National Institute for Health and Care Excellence (NICE) guidelines classification, reattendance to the ED within 28 days and antibiotic use. RESULTS: A total of 1097 children attending the children's ED with fever were analysed. Risk factors for PAU admission were tachycardia (RR=1.1, 95% CI (1 to 1.1)), ill-appearance (RR=2.2, 95% CI (1.2 to 4.2)), abnormal chest findings (RR=2.1, 95% CI (1.2 to 4.3)), categorised as NICE amber (RR 1.7 95% CI (1.2 to 2.5)). There was a 30% discordance between NICE categorisation at triage and statistical internal validation. Predictors of ward admission were a systemic (RR=6.9, 95% CI (2.4 to 19.8)) or gastrointestinal illness (RR=3.8, 95% (1.4 to 10.4)) and categorised as NICE Red (RR=5.9, 95% CI (2.2 to 15.3)). Only 51 children had probable bacterial pneumonia (4.6%), 52 children had a proven urinary tract infection (4.2%), with just 2 (0.2%) positive blood cultures out of 485 (44%) children who received an antibiotic. 15% of all children reattended by 28 days and were more likely to have been categorised as Amber and had investigations on initial visit. CONCLUSIONS: Risk factors for PAU and ward admissions are different in this setting with high reattendance rates and very low proportion of confirmed/probable serious bacterial infections. Future studies need to focus on reducing avoidable admissions and antibiotic treatment.

Prolonged PR interval, first-degree heart block and adverse cardiovascular outcomes: a systematic review and meta-analysis.

OBJECTIVE: First-degree atrioventricular block is frequently encountered in clinical practice and is generally considered a benign process. However, there is emerging evidence that prolonged PR interval may be associated with adverse outcomes. This study aims to determine if prolonged PR interval is associated with adverse cardiovascular outcomes and mortality. METHODS: We searched MEDLINE and EMBASE for studies that evaluated clinical outcomes associated with prolonged and normal PR intervals. Relevant studies were pooled using random effects meta-analysis for risk of mortality, cardiovascular mortality, heart failure, coronary heart disease, atrial fibrillation and stroke or transient ischaemic attack (TIA). Sensitivity analyses were performed considering the population type and the use of adjustments. RESULTS: Our search yielded 14 studies that were undertaken between 1972 and 2011 with 400,750 participants. Among the studies that adjusted for potential confounders, the pooled results suggest an increased risk of mortality with prolonged PR interval risk ratio (RR) 1.24 95% CI 1.02 to 1.51, five studies. Prolonged PR interval was associated with significant risk of heart failure or left ventricular dysfunction (RR 1.39 95% CI 1.18 to 1.65, three studies) and atrial fibrillation (RR 1.45 95% CI 1.23 to 1.71, eight studies) but not cardiovascular mortality, coronary heart disease or myocardial infarction or stroke or TIA. Similar observations were recorded when limited to studies of first-degree heart block. CONCLUSIONS: Data from observational studies suggests a possible association between prolonged PR interval and significant increases in atrial fibrillation, heart failure and mortality. Future prospective studies are needed to confirm the relationships reported, consider possible mechanisms and define the optimal monitoring strategy for such patients.

High-concentration versus titrated oxygen therapy in ST-elevation myocardial infarction: a pilot randomized controlled trial.

BACKGROUND: The optimal approach to oxygen therapy in ST-elevation myocardial infarction (STEMI) is uncertain. METHODS: A randomized controlled trial was undertaken in which 136 patients presenting with their first STEMI uncomplicated by cardiogenic shock or marked hypoxia were randomized to receive high-concentration (6 L/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturation 93%-96%) for 6 hours after presentation. The main outcome variables were 30-day mortality and infarct size assessed by troponin T level at 72 hours. Secondary outcomes included a meta-analysis of mortality data from this study and previous randomized controlled trials, and infarct size was assessed by magnetic resonance imaging at 4 to 6 weeks. RESULTS: There were 1 of 68 and 2 of 68 deaths in the high-concentration and titrated oxygen groups, respectively; a meta-analysis including these data with those from the 2 previous studies showed an odds ratio for mortality of high-concentration oxygen compared with room air or titrated oxygen of 2.2 (95% CI 0.8-6.0). There was no significant difference between high-concentration versus titrated oxygen in troponin T (ratio of mean levels 0.74, 95% CI 0.50-1.1, P = .14), infarct mass (mean difference -0.8 g, 95% CI -7.6 to 6.1, P = .82), or percent infarct mass (mean difference -0.6%, 95% CI -5.6 to 4.5, P = .83). CONCLUSION: This study found no evidence of benefit or harm from high-concentration compared with titrated oxygen in initially uncomplicated STEMI. However, our estimates have wide CIs, and as a result, large randomized controlled trials are required to resolve the clinical uncertainty.

Left ventricular filling and diastolic myocardial deformation in chronic primary mitral regurgitation.

AIMS: Chronic primary mitral regurgitation (MR) results in enhanced filling of the left ventricle (LV) during early diastole. Filling is impaired with the onset of LV systolic dysfunction, due to increased myocardial stiffness and reduced restoring forces. We investigated echocardiographic parameters of early diastolic function in relation to LV systolic function. METHODS AND RESULTS: Early diastolic transmitral flow and tissue Doppler velocities, propagation velocity of early filling (V(p)), and early diastolic strain rates (SR-E) were measured in 30 patients with chronic degenerative MR and 30 age-matched controls. MR subjects were further subdivided into group 1 (14 subjects) if they had well compensated LV, and group 2 (16 subjects) if they had one or more of the following: functional limitation (> NYHA class I), LV end-systolic diameter >or=4.0 cm, and LV ejection fraction

Circumstances and mode of in-hospital death following 9,914 consecutive patients undergoing percutaneous coronary interventions in the northwest of England.

AIM: To better describe the epidemiological causes of in-hospital death after percutaneous coronary intervention (PCI) in the present stent era. METHODS: Systematic review of all in-hospital deaths following PCI in North West England from 2001 to 2003. Sixty-two in-hospital deaths (0.6%) were identified from 9,914 consecutive PCIs performed during the study period. The medical records of 4 patients were missing, leaving 58 patients to be reviewed with a standard data extraction tool to determine a circumstance and a mode of death. Medical records were reviewed at each center and cases were discussed at regional consensus meetings. All the collected data were validated by random cross-checking of data by exchange site visits. Multivariate logistic regression was used to identify risk factors for deaths related to procedural complications. RESULTS: Low output failure was the most common mode of death, occurring in 42 patients (72.4%). The circumstance of death was a procedural complication in 35 patients (60.3%), and preexisting acute cardiac disease in 23 patients (39.7%). Significant predictors of death from procedural complications were treatment of left main stem (odds ratio [OR] 13.8; p < 0.001) or graft lesions (OR 5.6; p < 0.001), and female sex (OR 3.0; p = 0.002). CONCLUSIONS: Procedural complications account for over half of all post-PCI deaths. We have identified several risk factors that may help reduce the number of deaths related to procedural complications.