Estimating the sample size of sham-controlled randomized controlled trials using existing evidence [version 2; peer review: 2 approved].

Background: In randomized controlled trials (RCTs), the power is often 'reverse engineered' based on the number of participants that can realistically be achieved. An attractive alternative is planning a new trial conditional on the available evidence; a design of particular interest in RCTs that use a sham control arm (sham-RCTs). Methods: We explore the design of sham-RCTs, the role of sequential meta-analysis and  conditional planning in a systematic review of renal sympathetic denervation for patients with arterial hypertension. The main efficacy endpoint was mean change in 24-hour systolic blood pressure. We performed sequential meta-analysis to identify the time point where the null hypothesis would be rejected in a prospective scenario. Evidence-based conditional sample size calculations were performed based on fixed-effect meta-analysis. Results: In total, six sham-RCTs (981 participants) were identified. The first RCT was considerably larger (535 participants) than those subsequently published (median sample size of 80). All trial sample sizes were calculated assuming an unrealistically large intervention effect which resulted in low power when each study is considered as a stand-alone experiment. Sequential meta-analysis provided firm evidence against the null hypothesis with the synthesis of the first four trials (755 patients, cumulative mean difference -2.75 (95%CI -4.93 to -0.58) favoring the active intervention)). Conditional planning resulted in much larger sample sizes compared to those in the original trials, due to overoptimistic expected effects made by the investigators in individual trials, and potentially a time-effect association. Conclusions: Sequential meta-analysis of sham-RCTs can reach conclusive findings earlier and hence avoid exposing patients to sham-related risks. Conditional planning of new sham-RCTs poses important challenges as many surgical/minimally invasive procedures improve over time, the intervention effect is expected to increase in new studies and this violates the underlying assumptions. Unless this is accounted for, conditional planning will not improve the design of sham-RCTs

Invasive electrophysiological testing to predict and guide permanent pacemaker implantation after transcatheter aortic valve implantation: A meta-analysis.

BACKGROUND Atrioventricular conduction abnormalities after transcatheter aortic valve implantation (TAVI) are common. The value of electrophysiological study (EPS) for risk stratification of high-grade atrioventricular block (HG-AVB) and guidance of permanent pacemaker (PPM) implantation is poorly defined. OBJECTIVE The purpose of this study was to identify EPS parameters associated with HG-AVB and determine the value of EPS-guided PPM implantation after TAVI. METHODS We performed a systematic review and meta-analysis of studies investigating the value of EPS parameters for risk stratification of TAVI-related HG-AVB and for guidance of PPM implantation among patients with equivocal PPM indications after TAVI. RESULTS Eighteen studies (1230 patients) were eligible. In 7 studies, EPS was performed only after TAVI, whereas in 11 studies EPS was performed both before and after TAVI. Overall PPM implantation rate for HG-AVB was 16%. AV conduction intervals prolonged after TAVI, with the AH and HV intervals showing the largest magnitude of changes. Pre-TAVI HV >70 ms and the absolute value of the post-TAVI HV interval were associated with subsequent HG-AVB and PPM implantation with odds ratios of 2.53 (95% confidence interval [CI] 1.11-5.81; P = .04) and 1.10 (95% CI 1.03-1.17; P = .02; per 1-ms increase), respectively. In 10 studies, PPM was also implanted due to abnormal EPS findings in patients with equivocal PPM indications post-TAVI (typically new left bundle branch block or transient HG-AVB). Among them, the rate of long-term PPM dependency was 57%. CONCLUSION Selective EPS testing may assist in the risk stratification of post-TAVI HG-AVB and in the guidance of PPM implantation, especially in patients with equivocal PPM indications post-TAVI

Cardiovascular clinical trials in the era of a pandemic.

COVID-19 has reached pandemic levels in March 2020 and impacted public health with unpredictable consequences.1, 2 The conduct of clinical research in areas unrelated to COVID-19 has been disrupted and will be further affected. Researchers, trial participants and study personnel have to overcome challenges to sustain proper and safe conduct of clinical trials (i.e. logistical challenges, lower enrollment than expected, difficulties in follow-up and outcome assessment/adjudication, incomplete data collection, research funding prolongation)

Antidepressant treatment in patients following acute coronary syndromes: a systematic review and Bayesian meta-analysis.

AIMS The aim of this study is to investigate the effect of antidepressant therapy on mortality and cardiovascular outcomes in patients with acute coronary syndrome (ACS). METHODS AND RESULTS We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and performed a Bayesian random-effects meta-analysis of randomized controlled trials that investigated antidepressant pharmacotherapy in patients following ACS. The primary outcome was all-cause mortality. Secondary outcomes were repeat hospitalizations and recurrent myocardial infarctions (MIs). Ten randomized controlled trials with a total of 1935 patients qualified for inclusion. Selective serotonin reuptake inhibitors were investigated in six, bupropion in three, and mirtazapine in one trial. Placebo was used as control in eight trials. There was no difference in all-cause mortality [odds ratio (OR) 0.97, 95% credible interval (CrI) 0.66-1.42] and recurrent MI (OR 0.64, 95% CrI 0.40-1.02) between patients receiving antidepressants compared with controls, whereas antidepressant therapy was associated with less repeat hospitalizations (OR 0.62, 95% CrI 0.40-0.94). In patients with ACS and concomitant depression, antidepressants reduced the odds of recurrent MI compared with usual care/placebo (OR 0.45, 95% CrI 0.25-0.81). Extended funnel plots suggest robustness of the observations. CONCLUSIONS Antidepressants in patients following ACS have no effect on mortality but reduce repeat hospitalizations; in patients with depression, there is a reduced risk of recurrent MI with antidepressant therapy

Toward a novel semi‐invasive activation mapping tool for the diagnosis of supraventricular arrhythmias from the esophagus

Supraventricular arrhythmia diagnosis using the surface electrocardiogram (sECG) is often cumbersome due to limited atrial signal quality. In some instances, use of esophageal electrocardiography (eECG) may facilitate the diagnosis. Here, we present a novel approach to reconstruct cardiac activation maps from eECG recordings. Methods: eECGs and sECGs were recorded from 19 individuals using standard acquisition tools. From the recordings, algorithms were developed to estimate the esophageal ECG catheter's position and to reconstruct high‐resolution mappings of the cardiac electric activity projected in the esophagus over time. Results: Esophageal two‐dimensional activation maps were created for five healthy individuals and 14 patients suffering from different arrhythmias. The maps are displayed as time‐dependent contour plots, which not only show voltage over time as conventional ECGs, but also the location, direction, and projected propagation speed of the cardiac depolarization wavefront in the esophagus. Representative examples of sinus rhythm, atrial flutter, and ventricular pre‐excitation are shown. Conclusion: The methodology presented in this report provides a high‐resolution view of the cardiac electric field in the esophagus. It is the first step toward a threedimensional mapping system, which shall be able to reconstruct a three‐dimensional view of the cardiac activation from recordings within the esophagus

Discharge Location and Outcomes after Transcatheter Aortic Valve Implantation.

The relationship between discharge location and outcomes after transcatheter aortic valve implantation (TAVI) is largely unknown. Thus, the objective of this study was to investigate the impact of discharge location on clinical outcomes after TAVI. Between August 2007 and December 2018, consecutive patients undergoing transfemoral TAVI at Bern University Hospital were grouped according to discharge location. Clinical adverse events were adjudicated according to VARC-2 endpoint definitions. Of 1,902 eligible patients, 520 (27.3%) were discharged home, 945 (49.7%) were discharged to a rehabilitation clinic and 437 (23.0%) were transferred to another institution. Compared with patients discharged to a rehabilitation facility or another institution, patients discharged home were younger (80.8±6.5 vs. 82.9±5.4 and 82.8±6.4 years), less likely female (37.3% vs. 59.7% and 54.2%) and at lower risk according to STS-PROM (4.5±3.0% vs. 5.5±3.8% and 6.6±4.4%). At 1 year follow-up, patients discharged home had similar rates of all-cause mortality (HRadj 0.82; 95%CI 0.54-1.24), cerebrovascular events (HRadj 1.04; 95%CI 0.52-2.08) and bleeding complications (HRadj 0.93; 95%CI 0.61-1.41) compared to patients discharged to a rehabilitation facility. Patients discharged home or to rehabilitation were at lower risk for death (HRadj 0.37; 95%CI 0.24-0.56 and HRadj 0.44; 95%CI 0.32-0.60) and bleeding (HRadj 0.48; 95%CI 0.30-0.76 and HRadj 0.66; 95%CI 0.45-0.96) during the first year after hospital discharge compared to patients transferred to another institution. In conclusion, discharge location is associated with outcomes after TAVI with patients discharged home or to a rehabilitation facility having better clinical outcomes than patients transferred to another institution. Clinical Trial Registration: https://www.clinicaltrials.gov. NCT01368250

Radiofrequency ablation lesion assessment using optical coherence tomography – a proof‐of‐concept study

BACKGROUND Radiofrequency catheter ablation (RFA) is an effective treatment for atrial fibrillation. However, ablation lesions are usually only assessed functionally. The immediate effect of RFA on the tissue is not directly visualized. Optical coherence tomography (OCT) is an imaging technique that uses light to capture high-resolution images with histology-like quality. Therefore, it might be used for high-precision imaging of ablation lesions. METHODS AND RESULTS Radiofrequency ablation lesions (n = 25) were produced on the freshly excised left and right ventricular porcine endocardium. A Thermocool ST SF NAV ablation catheter (Biosense Webster Inc) and an EP-Shuttle ablation generator (Stockert GmbH) were used to produce ablation lesions with powers from 10 to 40 W (energies ranging from 100 Ws to 900 Ws). After ablation, the tissue was imaged with a swept source OCT system (at a wavelength of 1300 nm). Subsequently, the ablation lesions underwent the histological analysis. The ablation lesions could be visualized by OCT in all 17 samples with ablation powers ≥20 W, meanwhile, no lesion could be observed in the other eight samples with lower power (10 W). Lesion depths and lesion radiuses, as assessed by OCT, correlated well with those observed on the subsequent histological analysis (Spearman's r = 0.94, P < 0.001 and r = 0.84, P < 0.001). In addition, successful three-dimensional reconstructions of ablation lesions were performed. CONCLUSION OCT can provide a visual high-resolution assessment of ablation lesions

High incidence of diaphragmatic myopotential oversensing by a specific implantable cardioverter defibrillator.

INTRODUCTION Diaphragmatic myopotential oversensing (dMPO) by implantable cardioverter defibrillators (ICDs) is thought to be a rare condition that can be misdiagnosed as lead failure and lead to unnecessary lead replacement. We observed several cases of dMPO in patients with Sorin/LivaNova ICDs (MicroPort Sci.). We sought to systematically assess the incidence of dMPO in patients with Sorin/LivaNova ICDs. METHODS AND RESULTS A predefined number of 100 consecutive patients with Sorin/LivaNova ICDs were prospectively included in the device clinic of our center. Stored arrhythmia episodes were checked for spontaneous dMPO. In addition, we performed provocation maneuvers by Valsalva. At least one episode of spontaneous or provoked dMPO was seen in 12 (12%) of the 100 patients included in the study (86% males, median age: 66 years). Nine of 89 patients (10%) with true bipolar and 3 of 11 patients (27%) with integrated bipolar sensing configuration were affected. Spontaneous dMPO was observed in 7 of 58 patients (12%) with sensitivity programmed to 0.4 mV and in 2 of 42 patients (5%) with sensitivity programmed to 0.6 mV (not significant). In three patients, dMPO could be provoked with no spontaneous episodes recorded. In two nonpacemaker-dependent patients with a CRT-D, ventricular pacing was temporarily inhibited. No antitachycardia therapy was triggered by dMPO in any patient. CONCLUSIONS DMPO is frequent in patients with Sorin/LivaNova ICDs, especially with sensitivity programmed to 0.4 mV. It also frequently occurs with true bipolar sensing configuration. DMPO should not be misinterpreted as lead failure to avoid unnecessary lead replacement