Rationale and study design of the MINERVA study: Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction-UK multicentre collaboration

Introduction The purpose of this study is to assess the ability of two new ECG markers (Regional Repolarisation Instability Index (R2I2) and Peak Electrical Restitution Slope) to predict sudden cardiac death (SCD) or ventricular arrhythmia (VA) events in patients with ischaemic cardiomyopathy undergoing implantation of an implantable cardioverter defibrillator for primary prevention indication. Methods and analysis Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction is a prospective, open label, single blinded, multicentre observational study to establish the efficacy of two ECG biomarkers in predicting VA risk. 440 participants with ischaemic cardiomyopathy undergoing routine first time implantable cardioverter-defibrillator (ICD) implantation for primary prevention indication are currently being recruited. An electrophysiological (EP) study is performed using a non-invasive programmed electrical stimulation protocol via the implanted device. All participants will undergo the EP study hence no randomisation is required. Participants will be followed up over a minimum of 18 months and up to 3 years. The first patient was recruited in August 2016 and the study will be completed at the final participant follow-up visit. The primary endpoint is ventricular fibrillation or sustained ventricular tachycardia >200 beats/min as recorded by the ICD. The secondary endpoint is SCD. Analysis of the ECG data obtained during the EP study will be performed by the core lab where blinding of patient health status and endpoints will be maintained. Ethics and dissemination Ethical approval has been granted by Research Ethics Committees Northern Ireland (reference no. 16/NI/0069). The results will inform the design of a definitive Randomised Controlled Trial (RCT). Dissemination will include peer reviewed journal articles reporting the qualitative and quantitative results, as well as presentations at conferences and lay summaries

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Implantation of the subcutaneous implantable cardiac defibrillator using conscious titrated intravenous sedation alone without the need for general anaesthesia: a single centre experience

Background: Implantable cardiac defibrillators (ICD) are used routinely for the prevention of sudden cardiac death (SCD). A transvenous lead connected to an implanted generator has been the standard method of implanting such a device. Recently, the subcutaneous implantable cardiac defibrillator (S-ICD) was introduced which negates the need for transvenous leads. It is intended to provide defibrillation therapy for the treatment of life-threatening tachyarrhythmia in patients who do not have symptomatic bradycardia, incessant ventricular tachycardia (VT), or frequently recurring VT that is reliably terminated with anti-tachycardia pacing (ATP). Currently the majority of these implant procedures are performed under general anaesthesia (GA) which requires the resources of the anaesthetic team as well as exposing patients to the risks associated with GA. At present, there is limited experience using conscious, intravenous, and titrated sedation as an alternative. Purpose: To assess the safety, feasibility, tolerability and length of procedure using conscious, intravenous, titrated sedation rather than GA when implanting the S-ICD. Methods: 24 consecutive patients from a single centre who were eligible for an ICD for standard indications were offered the S-ICD from July 2014 to July 2016 with routine device follow-up were assessed on 29/7/16. Intravenous Midazolam and Morphine Sulphate were given to achieve adequate conscious sedation. Peri-operative vital signs were monitored throughout. Standard implant techniques (2 incision approach) were used as recommended by the device manufacturer. Defibrillator Safety Margin (DSM) was performed on all patients after implant. Procedural information and complications at the time of procedure and during routine follow-up were recorded. Results: 17/24 (71%) of procedures were performed using intravenous titrated conscious sedation. The mean age at implant was 48 years (+/- 12years) and 11 (65%) were male. 10 patients had a left ventricular ejection fraction (LVEF) of <35% and the remainder had a normal LVEF. All implants were completed successfully and well tolerated. The overall procedural time when using titrated conscious intravenous sedation was shorter compared to GA (62 mins+/-13 minutes vs. 76 mins +/-22 respectively). The mean dose used for intravenous midazolam was 7.0mg (+/-2.8mg) and morphine sulphate was 7.4mg (+/-3.7mg). A single patient required reversal of sedation with Flumazenil (300mcg) and naloxone (400mcg) post-operatively due to oxygen desaturation. Late complications included one patient receiving an inappropriate shock and one patient treated successfully with antibiotics for a superficial wound infection. Conclusion: The S-ICD can safely be implanted using titrated intravenous conscious sedation. It can reduce overall procedural time and negate unnecessary exposure to GA. This method is feasible and well tolerated by patients

Patients managed by non-cardiologists are less likely to be assessed for implantable cardioverter defibrillators

Background: Implantable cardioverter defibrillators (ICD) are effective in treating ventricular arrhythmia and thus averting sudden cardiac death (SCD). Studies have expanded evidence on ICD benefits in patients at high SCD risk thus broadening the indications for this therapy. Despite these indications, there is considerable variation in implantation rates across Europe. ICD therapy is not without its own risks and cost, hence a considered decision between the physician and the patient should be taken when deciding whether an ICD is appropriate. Left ventricular systolic dysfunction (LVSD) forms the main risk stratification parameter when considering an ICD for primary prevention. Purpose: The purpose of this study is to determine whether patients identified to be at risk of SCD are being considered for ICD implantation. We look to determine whether there are any differences between patients managed by cardiologists compared to those managed by non-cardiologists. Methods: All transthoracic echocardiograms (TTE) performed at a single centre within a one-month period were retrospectively reviewed to identify patients with severe LVSD. A cross-sectional, observational assessment of whether an ICD was considered at 1 year after the echocardiogram was documented. The specialty of the consultant responsible for the patient’s care was documented as either a cardiologist or a non-cardiologist. Results: There were 1173 TTEs performed with 129 (11%) identified to have severe LVSD. 89 (69%) patients were managed by a cardiologist. The mean age was 75 years (+/- 1SD 12.6). 71% were male. 41% had ischaemic cardiomyopathy. Survival at one year was 78%. The reasons an ICD was not implanted were: (1) improvement in subsequent LV assessment (12%); (2) the decision was deferred (9%); (3) the patient declined (2%); (4) deemed by the physician to be inappropriate (18%). 47% of potentially eligible patients were not documented to have been considered for ICD implantation. Of those who were managed by a cardiologist, 63.9% had a decision regarding ICD considered, compared to a significantly lower proportion (30.0%) of those managed by non-cardiologists (OR 4.0, 95% CI 1.8-8.8, p=0.001). Survival at one year was significantly higher in patients managed by cardiologists compared to non-cardiologists (89.9% vs. 52.5%, OR 8.1 95% CI 3.2-20.4, p<0.001). Conclusions: A TTE is a widely available cardiac investigation that is requested by a diversity of specialties. This study shows that a large number of patients are identified to have severe LVSD during routine clinical practice and therefore may be candidates for an ICD. However, many of these patients are not documented to have been formally assessed for potentially lifesaving ICD. The reasons why patients are not being considered will need to be identified and whether this affects mortality in longer term follow up will need to be evaluated in future work

Striking difference between cardiac sub-specialties during consideration for implantable cardioverter defibrillators

Background: Implantable cardioverter defibrillators (ICD) are effective at treating ventricular arrhythmia and thus avert sudden cardiac death (SCD). An expansive evidence base has identified those at high-risk of SCD which has been incorporated into current guidelines. Despite these indications, there is considerable variation in implantation rates across Europe. ICD therapy is not without its own risks and cost, hence a considered decision between the physician and the patient should be taken when deciding whether an ICD is appropriate. Purpose: The purpose of this study is to determine whether patients identified to be at risk of SCD are being considered for ICD implantation by a cardiac physician. We also look to investigate whether there are any differences between the cardiac subspecialties. Methods: All transthoracic echocardiograms (TTE) performed at a single tertiary centre between 1st – 30th June 2016 were retrospectively reviewed to identify patients with severe left ventricular systolic dysfunction. A cross-sectional, observational assessment of whether an ICD was considered at 1 year after the echocardiogram was documented. The cardiac subspecialty of the cardiac physician was documented. Results: Of the 1173 TTEs, 129 (11%) were identified to have severe LVSD. 89 patients were managed by a cardiologist. Of these, 57(59%) were managed by an ICD device implanting or heart failure (DevHF) subspecialist. The mean age was 71 years (+/- 1SD 12.5). 75% were male. 45% had ischaemic cardiomyopathy. Survival at one year was 89.9%. An ICD was not implanted due to an improvement in subsequent LV assessment (16%), the decision was deferred (13%), the patient declined (4%), or was deemed by the physician to be inappropriate (18%). 37% were not documented to have been considered for ICD implantation. Of those who were managed by a DevHF subspecialty, 75.0% had a decision regarding appropriateness for ICD considered, compared to a significantly lower proportion (45.9%) in those managed by non-DevHF subspecialists (OR 3.5, 95% CI 1.4-8.7, p=0.005). However, there was no significant difference in survival at one-year post-TTE between these two groups. Conclusions: This study shows that a large number of patients are being identified during routine clinical practice as being at risk of SCD. A majority of these patients are under the care of a cardiologist. Despite being managed by a cardiologist, many of these patients are not being assessed for potentially lifesaving treatment. Amongst cardiologists, there is a significant variation in practice, with patients who are not managed by Dev-HF physicians the least likely to be referred for an ICD. The reasons why patients are not being considered will need to be identified and whether this affects mortality in longer term follow-up should be visited in future work

LifeMap: towards the development of a new technology in sudden cardiac death risk stratification for clinical use.

Sudden cardiac death (SCD) is a major cause of mortality presenting a significant unmet clinical need. Patients at risk of SCD are implanted with implantable cardioverter-defibrillators (ICDs) according to international guidelines based on clinical trial evidence. Implantable cardioverter-defibrillators are not inexpensive and not without problem in terms of inappropriate shocks and infection risk. Also, only a minority of patients implanted with the ICD ever use the device during its battery lifetime highlighting the fact that methods used for SCD risk stratification are inadequate. Better ways of predicting who is at risk of SCD are needed. In addition, there is no effective prevention due to the lack of understanding of the electrical mechanisms underlying SCD. Our group has been investigating the electrophysiological basis of ventricular fibrillation and have successfully applied our preclinical findings to translational studies in patients with ischaemic cardiomyopathy. We have developed two ECG markers which have been shown to be strong predictors of ventricular arrhythmias and SCD. Ongoing clinical studies are being carried out including a multicentre UK study to consolidate the evidence base. They are being incorporated into the technology, LifeMap, with the aim to develop a successful clinical tool for the assessment of SCD risk. We hereby present the scientific data leading to the technology and the development to date. The information provided here was presented at the European Heart Rhythm Association (EHRA) Europace/Cardiostim conference at which LifeMap won the EHRA Inventors Award 2016

Could regional electrogram desynchronization identified using mean phase coherence be potential ablation targets in persistent atrial fibrillation?

BackgroundIt remains controversial as to whether rotors detected using phase mapping during persistent atrial fibrillation (persAF) represent main drivers of the underlying mechanism as others found rotors to be located near line of conduction block. Regional electrogram desynchronization (RED) has been suggested as successful targets for persAF ablation, but automatic tools and quantitative measures are lacking.PurposeWe aim to use mean phase coherence (MPC) to automatically identify RED regions during persAF. This method was compared with phase singularity density (PSD) maps.MethodsPatients undergoing left atrial (LA) persAF ablation were enrolled (n = 10). 2048-channel virtual electrograms (VEGMs) were collected from each patient using non-contact mapping (St Jude Velocity System, Ensite Array) for 10 seconds. To remove far field ventricular activities, QRS onset and T wave end locations were detected from ECG lead I (Figure 1A) and only the VEGM segments from T end to QRS onset were included in the analysis. VEGMs were reconstructed using sinusoidal wavelets fitting and the phase of VEGMs determined using Hilbert transform. Phase singularities (PS) were detected using the topological charge method and repetitive PSD maps were generated. RED was defined as the average of MPC of each node against direct neighbouring nodes on the 3D mesh (Figure 1A-B). Linear regression analysis was used to compare the average MPC vs. PSD and vs. the standard deviation of MPC (MPC_SD).ResultsA total of 221,184 VEGM segments were analysed with mean duration of 364.2 milliseconds. MPC has shown the ability to quantify the level of synchronisation between VEGMs (Figure 1B). Inverse correlation was found between PSD and average MPC values for all 10 patients (p ConclusionWe have proposed a method to quantify the level of synchronisation between VEGMs. Phase density mapping showed a considerable agreement with RED regions reflecting regional conducting delays, which supports the previous finding where rotors found at conduction block. Inverse correlation between local average MPC and MPC_SD suggests that conduction delays of the identified regions are not heterogenous, posing directional preferences. Rather than solely looking for rotational activities, this method could identify comprehensive RED regions, which may also explain the conflicting results from different studies targeting rotational activities, where incomplete subsets of RED regions could have been targeted. Atrial RED regions can easily be identified with simultaneously collected electrograms from multi-polar catheters and should be targeted in future persAF studies.</div