An Economic Evaluation of a Streamlined Day-Case Atrial Fibrillation Ablation Protocol and Conventional Cryoballoon Ablation versus Antiarrhythmic Drugs in a UK Paroxysmal Atrial Fibrillation Population.

BACKGROUND AND AIMS: Symptom control for atrial fibrillation can be achieved by catheter ablation or drug therapy. We assessed the cost effectiveness of a novel streamlined atrial fibrillation cryoballoon ablation protocol (AVATAR) compared with optimised antiarrhythmic drug (AAD) therapy and a conventional catheter ablation protocol, from a UK National Health Service (NHS) perspective. METHODS: Data from the AVATAR study were assessed to determine the cost effectiveness of the three protocols in a two-step process. In the first stage, statistical analysis of clinical efficacy outcomes was conducted considering either a three-way comparison (AVATAR vs. conventional ablation vs. optimised AAD therapies) or a two-way comparison (pooled ablation protocol data vs. optimised AAD therapies). In the second stage, models assessed the cost effectiveness of the protocols. Costs and some of the clinical inputs in the models were derived from within-trial cost analysis and published literature. The remaining inputs were derived from clinical experts. RESULTS: No significant differences between the ablation protocols were found for any of the clinical outcomes used in the model. Results of a within-trial cost analysis show that AVATAR is cost-saving (£1279 per patient) compared with the conventional ablation protocol. When compared with optimised AAD therapies, AVATAR (pooled conventional and AVATAR ablation protocols efficacy) was found to be more costly while offering improved clinical benefits. Over a lifetime time horizon, the incremental cost-effectiveness ratio of AVATAR was estimated as £21,046 per quality-adjusted life-year gained (95% credible interval £7086-£71,718). CONCLUSIONS: The AVATAR streamlined protocol is likely to be a cost-effective option versus both conventional ablation and optimised AAD therapy in the UK NHS healthcare setting.

RETRO-mapping: A novel algorithm automating wavefront categorization using activation mapping during persistent atrial fibrillation demonstrates a reduction in wavefront collisions following pulmonary vein isolation.

RETRO-mapping was developed to automate activation mapping of atrial fibrillation (AF). We used the algorithm to study the effect of pulmonary vein isolation (PVI) on the frequency of focal, planar, and colliding wavefronts in persistent AF. An AFocusII catheter was placed on the left atrial endocardium to record 3 s of AF at six sites pre and post-PVI in patients undergoing wide circumferential PVI for persistent AF. RETRO-mapping analyzed each segment in 2 ms time windows for evidence of focal, planar, and colliding waveforms and the automated categorizations manually validated. Ten patients were recruited. A total of 360 s of data in 120 segments of 3 s from 60 left atrial locations were analyzed. RETRO-map was highly effective at identifying focal waves and collisions during AF. PVI significantly reduced collision frequency but not focal and planar activation frequency. However, there was a significant reduction in the dispersion of activation directions. Larger studies may help determine factors associated with successful clinical outcome.

A randomized controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalized with COVID-19: the COVID-19 Acute Coronary Syndrome trial.

BACKGROUND: Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. OBJECTIVES: To investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors. METHODS: A randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death). RESULTS: Three hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not significantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, -4 to 0; 2% probability that it was worse). CONCLUSION: Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.

A randomized controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalized with COVID-19: the COVID-19 Acute Coronary Syndrome trial

BACKGROUND: patients hospitalised with covid-19 suffer thrombotic complications. risk factors for poor outcomes are shared with coronary artery disease. Objectives: to investigate efficacy of an acute coronary syndrome regimen in patients hospitalised with covid-19 and coronary disease risk factors. PATIENTS/METHODS: a randomised controlled open-label trial across acute hospitals (uk and brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28-days. primary efficacy and safety outcomes were 30-day mortality and bleeding. the key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, death). RESULTS: 320 patients from 9 centres were randomised. the trial terminated early due to low recruitment. at 30 days there was no significant difference in mortality (intervention: 11.5% vs control: 15%, unadjusted or 0.73, 95%ci 0.38 to 1.41, p=0.355). significant bleeds were infrequent and not significantly different between the arms (intervention: 1.9% vs control 1.9%, p>0.999). using a bayesian markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (or 1.46, 95% cri 0.88 to 95 2.37, pr(beta>0) =93%; adjusted or 1.50, 95% cri 0.91 to 2.45, pr(beta>0) =95%) and median time to discharge home was two days shorter (95% cri -4 to 0, 2% probability that it was worse). CONCLUSIONS: acute coronary syndrome treatment regimen was associated with a 99 reduction in the length of hospital stay without an excess in major bleeding. a larger trial is needed to evaluate mortality.

Feasibility of mapping and ablating ectopy-triggering ganglionated plexus reproducibly in persistent atrial fibrillation.

BACKGROUND: Ablation of autonomic ectopy-triggering ganglionated plexuses (ET-GP) has been used to treat paroxysmal atrial fibrillation (AF). It is not known if ET-GP localisation is reproducible between different stimulators or whether ET-GP can be mapped and ablated in persistent AF. We tested the reproducibility of the left atrial ET-GP location using different high-frequency high-output stimulators in AF. In addition, we tested the feasibility of identifying ET-GP locations in persistent atrial fibrillation. METHODS: Nine patients undergoing clinically-indicated paroxysmal AF ablation received pacing-synchronised high-frequency stimulation (HFS), delivered in SR during the left atrial refractory period, to compare ET-GP localisation between a custom-built current-controlled stimulator (Tau20) and a voltage-controlled stimulator (Grass S88, SIU5). Two patients with persistent AF underwent cardioversion, left atrial ET-GP mapping with the Tau20 and ablation (Precision™, Tacticath™ [n = 1] or Carto™, SmartTouch™ [n = 1]). Pulmonary vein isolation (PVI) was not performed. Efficacy of ablation at ET-GP sites alone without PVI was assessed at 1 year. RESULTS: The mean output to identify ET-GP was 34 mA (n = 5). Reproducibility of response to synchronised HFS was 100% (Tau20 vs Grass S88; [n = 16] [kappa = 1, SE = 0.00, 95% CI 1 to 1)][Tau20 v Tau20; [n = 13] [kappa = 1, SE = 0, 95% CI 1 to 1]). Two patients with persistent AF had 10 and 7 ET-GP sites identified requiring 6 and 3 min of radiofrequency ablation respectively to abolish ET-GP response. Both patients were free from AF for > 365 days without anti-arrhythmics. CONCLUSIONS: ET-GP sites are identified at the same location by different stimulators. ET-GP ablation alone was able to prevent AF recurrence in persistent AF, and further studies would be warranted.

Evaluation of RETRO-Mapping for electrophysiological features including direction of plane activity during atrial fibrillation using multipolar catheters in humans.

INTRODUCTION: A quantifiable, automated standard of analyzing heart rhythm has long eluded cardiologists due, in part, to the limitations in technology and the ability to analyze large electrogram datasets. In this proof-of-concept study, we propose new measures to quantify plane activity in atrial fibrillation (AF) using our Representation of Electrical Tracking of Origin (RETRO)-Mapping software. METHODS: We recorded 30 s segments of electrograms at the lower posterior wall of the left atrium using a 20-pole double loop catheter (AFocusII). The data were analyzed with the custom RETRO-Mapping algorithm in MATLAB. Thirty second segments were analyzed for number of activation edges, conduction velocity (CV), cycle length (CL), activation edge direction, and wavefront direction. These features were compared across 34 613 plane edges in three types of AF: persistent AF treated with amiodarone (11 906 wavefronts), persistent AF without amiodarone (14 959 wavefronts), and paroxysmal AF (7748 wavefronts). Change in activation edge direction between subsequent frames and change in overall wavefront direction between subsequent wavefronts were analyzed. RESULTS: All activation edge directions were represented across the lower posterior wall. The median change in activation edge direction followed a linear pattern for all three types of AF with R2 = 0.932 for persistent AF treated without amiodarone, R2 = 0.942 for paroxysmal AF, and R2 = 0.958 for persistent AF treated with amiodarone. All medians and the standard deviation error bars remained below 45° (suggesting all activation edges were traveling within a 90° sector, a criterion for plane activity). The directions of approximately half of all wavefronts (56.1% for persistent without amiodarone, 51.8% for paroxysmal, 48.8% for persistent with amiodarone) were predictive of the directions of the subsequent wavefront. CONCLUSION: RETRO-Mapping can measure electrophysiological features of activation activity and this proof-of-concept study suggests that this can be extended to the detection of plane activity in three types of AF. Wavefront direction may have a role in future work for predicting plane activity. For this study, we focused more on the ability of the algorithm to detect plane activity and less the differences between the types of AF. Future work should be in validating these results with a larger data set and comparing with other types of activation such as rotational, collision, and focal. Ultimately, this work can be implemented in real-time for prediction of wavefronts during ablation procedures.

Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation: a prospective, randomized, multi-centre, open label trial.

AIMS: There is rising healthcare utilization related to the increasing incidence and prevalence of atrial fibrillation (AF) worldwide. Simplifying therapy and reducing hospital episodes would be a valuable development. The efficacy of a streamlined AF ablation approach was compared to drug therapy and a conventional catheter ablation technique for symptom control in paroxysmal AF. METHODS AND RESULTS: We recruited 321 patients with symptomatic paroxysmal AF to a prospective randomized, multi-centre, open label trial at 13 UK hospitals. Patients were randomized 1:1:1 to cryo-balloon ablation without electrical mapping with patients discharged same day [Ablation Versus Anti-arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent (AVATAR) protocol]; optimization of drug therapy; or cryo-balloon ablation with confirmation of pulmonary vein isolation and overnight hospitalization. The primary endpoint was time to any hospital episode related to treatment for atrial arrhythmia. Secondary endpoints included complications of treatment and quality-of-life measures. The hazard ratio (HR) for a primary endpoint event occurring when comparing AVATAR protocol arm to drug therapy was 0.156 (95% CI, 0.097-0.250; P < 0.0001 by Cox regression). Twenty-three patients (21%) recorded an endpoint event in the AVATAR arm compared to 76 patients (74%) within the drug therapy arm. Comparing AVATAR and conventional ablation arms resulted in a non-significant HR of 1.173 (95% CI, 0.639-2.154; P = 0.61 by Cox regression) with 23 patients (21%) and 19 patients (18%), respectively, recording primary endpoint events (P = 0.61 by log-rank test). CONCLUSION: The AVATAR protocol was superior to drug therapy for avoiding hospital episodes related to AF treatment, but conventional cryoablation was not superior to the AVATAR protocol. This could have wide-ranging implications on how demand for AF symptom control is met. TRIAL REGISTRATION: Clinical Trials Registration: NCT02459574.

Ectopy-triggering ganglionated plexuses ablation to prevent atrial fibrillation: GANGLIA-AF study.

BACKGROUND: The ganglionated plexuses (GPs) of the intrinsic cardiac autonomic system may play a role in atrial fibrillation (AF). OBJECTIVE: We hypothesized that ablating the ectopy-triggering GPs (ET-GPs) prevents AF. METHODS: GANGLIA-AF (ClinicalTrials.gov identifier NCT02487654) was a prospective, randomized, controlled, 3-center trial. ET-GPs were mapped using high frequency stimulation, delivered within the atrial refractory period and ablated until nonfunctional. If triggered AF became incessant, atrioventricular dissociating GPs were ablated. We compared GP ablation (GPA) without pulmonary vein isolation (PVI) against PVI in patients with paroxysmal AF. Follow-up was for 12 months including 3-monthly 48-hour Holter monitors. The primary end point was documented ≥30 seconds of atrial arrhythmia after a 3-month blanking period. RESULTS: A total of 102 randomized patients were analyzed on a per-protocol basis after GPA (n = 52; 51%) or PVI (n = 50; 49%). Patients who underwent GPA had 89 ± 26 high frequency stimulation sites tested, identifying a median of 18.5% (interquartile range 16%-21%) of GPs. The radiofrequency ablation time was 22.9 ± 9.8 minutes in GPA and 38 ± 14.4 minutes in PVI (P < .0001). The freedom from ≥30 seconds of atrial arrhythmia at 12-month follow-up was 50% (26 of 52) with GPA vs 64% (32 of 50) with PVI (log-rank, P = .09). ET-GPA without atrioventricular dissociating GPA achieved 58% (22 of 38) freedom from the primary end point. There was a significantly higher reduction in antiarrhythmic drug usage postablation after GPA than after PVI (55.5% vs 36%; P = .05). Patients were referred for redo ablation procedures in 31% (16 of 52) after GPA and 24% (12 of 50) after PVI (P = .53). CONCLUSION: GPA did not prevent atrial arrhythmias more than PVI. However, less radiofrequency ablation was delivered to achieve a higher reduction in antiarrhythmic drug usage with GPA than with PVI.

RETRO-MAPPING: A New Approach to Activation Mapping in Persistent Atrial Fibrillation Reveals Evidence of Spatiotemporal Stability.

[Figure: see text].

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

BACKGROUND: Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients. METHODS AND RESULTS: One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms). CONCLUSIONS: During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

Targeting the ectopy-triggering ganglionated plexuses without pulmonary vein isolation prevents atrial fibrillation.

BACKGROUND: Ganglionated plexuses (GPs) are implicated in atrial fibrillation (AF). Endocardial high-frequency stimulation (HFS) delivered within the local atrial refractory period can trigger ectopy and AF from specific GP sites (ET-GP). The aim of this study was to understand the role of ET-GP ablation in the treatment of AF. METHODS: Patients with paroxysmal AF indicated for ablation were recruited. HFS mapping was performed globally around the left atrium to identify ET-GP. ET-GP was defined as atrial ectopy or atrial arrhythmia triggered by HFS. All ET-GP were ablated, and PVs were left electrically connected. Outcomes were compared with a control group receiving pulmonary vein isolation (PVI). Patients were followed-up for 12 months with multiple 48-h Holter ECGs. Primary endpoint was ≥30 s AF/atrial tachycardia in ECGs. RESULTS: In total, 67 patients were recruited and randomized to ET-GP ablation (n = 39) or PVI (n = 28). In the ET-GP ablation group, 103 ± 28 HFS sites were tested per patient, identifying 21 ± 10 (20%) GPs. ET-GP ablation used 23.3 ± 4.1 kWs total radiofrequency (RF) energy per patient, compared with 55.7 ± 22.7 kWs in PVI (p = <.0001). Duration of procedure was 3.7 ± 1.0 and 3.3 ± 0.7 h in ET-GP ablation group and PVI, respectively (p = .07). Follow-up at 12 months showed that 61% and 49% were free from ≥30 s of AF/AT with PVI and ET-GP ablation respectively (log-rank p = .27). CONCLUSIONS: It is feasible to perform detailed global functional mapping with HFS and ablate ET-GP to prevent AF. This provides direct evidence that ET-GPs are part of the AF mechanism. The lower RF requirement implies that ET-GP targets the AF pathway more specifically.

How achievable are COVID-19 clinical trial recruitment targets? A UK observational cohort study and trials registry analysis.

OBJECTIVES: To analyse enrolment to interventional trials during the first wave of the COVID-19 pandemic in England and describe the barriers to successful recruitment in the circumstance of a further wave or future pandemics. DESIGN: We analysed registered interventional COVID-19 trial data and concurrently did a prospective observational study of hospitalised patients with COVID-19 who were being assessed for eligibility to one of the RECOVERY, C19-ACS or SIMPLE trials. SETTING: Interventional COVID-19 trial data were analysed from the clinicaltrials.gov and International Standard Randomized Controlled Trial Number databases on 12 July 2020. The patient cohort was taken from five centres in a respiratory National Institute for Health Research network. Population and modelling data were taken from published reports from the UK government and Medical Research Council Biostatistics Unit. PARTICIPANTS: 2082 consecutive admitted patients with laboratory-confirmed SARS-CoV-2 infection from 27 March 2020 were included. MAIN OUTCOME MEASURES: Proportions enrolled, and reasons for exclusion from the aforementioned trials. Comparisons of trial recruitment targets with estimated feasible recruitment numbers. RESULTS: Analysis of trial registration data for COVID-19 treatment studies enrolling in England showed that by 12 July 2020, 29 142 participants were needed. In the observational study, 430 (20.7%) proceeded to randomisation. 82 (3.9%) declined participation, 699 (33.6%) were excluded on clinical grounds, 363 (17.4%) were medically fit for discharge and 153 (7.3%) were receiving palliative care. With 111 037 people hospitalised with COVID-19 in England by 12 July 2020, we determine that 22 985 people were potentially suitable for trial enrolment. We estimate a UK hospitalisation rate of 2.38%, and that another 1.25 million infections would be required to meet recruitment targets of ongoing trials. CONCLUSIONS: Feasible recruitment rates, study design and proliferation of trials can limit the number, and size, that will successfully complete recruitment. We consider that fewer, more appropriately designed trials, prioritising cooperation between centres would maximise productivity in a further wave.

Single Ectopy-Triggering Ganglionated Plexus Ablation Without Pulmonary Vein Isolation Prevents Atrial Fibrillation.

A 58-year-old woman with drug-refractory symptoms of paroxysmal atrial fibrillation (AF) was referred for AF ablation. A single site of ganglionated plexus triggering pulmonary vein ectopy and AF was ablated, without pulmonary vein isolation. This procedure led to long-term freedom from AF. (Level of Difficulty: Advanced.).

Evaluation of a new algorithm for tracking activation during atrial fibrillation using multipolar catheters in humans.

BACKGROUND: Conventional mapping techniques during atrial fibrillation (AF) are difficult to apply because of cycle length irregularity. Mapping studies are usually restricted to short durations of AF in limited regions because of the laborious manual annotation of local activation time (LAT). The purpose of this study was to test an automated algorithm to map activation during AF, with comparable accuracy to manual annotation. METHODS: Left atrial (LA) mapping was performed using a 20-pole double loop catheter (AFocusII) in 30-second data segments from 16 patients. The new algorithm (RETRO-Mapping) was designed to detect wavefront propagation between electrodes, and display activating wavefronts on a two-dimensional representation of the catheter. Activation patterns were validated against their bipolar electrograms and with isochronal maps. The mapping protocol was approved by the research ethics committee (13/LO1169 and 14/LO1367). RESULTS: During AF, uniform wavefront activation direction (mean ± SD, degrees) from manually constructed isochronal maps was comparable to RETRO-Propagation Map (RETRO-PM) and RETRO-Automated Direction (RETRO-AD): 1 ± 6.9 for RETRO-PM; and 2 ± 6.6 for RETRO-AD. There was no significant difference in activation direction assigned to 1373 uniform wavefronts during AF when comparing RETRO-PM with RETRO-AD (Bland-Altman mean difference: -0.1 degrees; limits of agreement: -8.0 to 8.3; 95% CI -0.4 to 0.2; (r = 0.01) R2 = < 0.005; P = .77). CONCLUSION: We have developed and validated a new technique to map activation during AF. This technique shows comparable accuracy to that of conventional isochronal mapping with careful manual adjustment of LAT.

Opposing alterations in anxiety and species-typical behaviours in serotonin transporter overexpressor and knockout mice.

Human gene association studies have produced conflicting findings regarding the relationship between the 5-HT transporter (5-HTT) and anxiety. In the present study genetically modified mice were utilised to examine the effects of changes in 5-HTT expression on anxiety. In addition, the influence of 5-HTT expression on two innate "species-typical" behaviours (burrowing and marble burying) and body weight was explored. Across a range of models, 5-HTT overexpressing mice displayed reduced anxiety-like behaviour whilst 5-HTT knockout mice showed increased anxiety-like behaviour, compared to wildtype controls. In tests of species-typical behaviour 5-HTT overexpressing mice showed some facilitation whilst 5-HTT knockout mice were impaired. Reciprocal effects were also seen on body weight, as 5-HTT overexpressors were lighter and 5-HTT knockouts were heavier than wildtype controls. These findings show that variation in 5-HTT gene expression produces robust changes in anxiety and species-typical behaviour. Furthermore, the data add further support to findings that variation of 5-HTT expression in the human population is linked to changes in anxiety-related personality traits.