Liverpool Heart and Chest Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

CV Cardiovascular CYP Cytochrome P (CYP) Unfractionated heparin ULN Upper limit of normal VENTURE-AF Active-controlled multi-center study with blind-adjudication designed to evaluate the safety of uninterrupted Rivaroxaban and uninterrupted vitamin K antagonists in subjects undergoing catheter ablation for non-valvular Atrial Fibrillation VHD Valvular heart disease VKA Vitamin K antagonist VTE Venous thromboembolic event WOEST What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary stenting X-VeRT Explore the efficacy and safety of once daily oral rivaroxaban for the prevention of cardiovascular events in patients with non-valvular atrial fibrillation scheduled for cardioversion a SmPC: 110 mg BID if age > _80 years, concomitant verapamil (both based on pharmacokinetics/pharmacodynamics analyses; not studied in this setting). b Not specifically studied, follow-up data available up to 12 months in phase III trial. c SmPc: 20 mg QD in patients at high risk of recurrence. 2021 EHRA Practical Guide on the use of NOACs AF, atrial fibrillation; CrCl, creatinine clearance; INR, international normalized ratio; NOAC, non-vitamin K antagonist oral anticoagulant; NSAID, non-steroidal anti-inflammatory drug; TIA, transient ischaemic attack; VKA, vitamin K antagonist. For frequency of visits: see Figure 3.

The American Society of Anesthesiologists (ASA) physical status is a tool commonly used to classify a patient's physical fitness before surgery. Since its introduction in 1941 it has undergone very few modifications to improve its reliability and to eliminate subjectivity, despite vast changes in both surgical and anaesthetic technique. We present the history of the ASA physical status and review the literature on its applicability to contemporary anaesthetic practice.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) prevent sudden death from cardiac causes in selected patients but require the use of transvenous lead systems. To eliminate the need for venous access, we designed and tested an entirely subcutaneous ICD system. METHODS: First, we conducted two short-term clinical trials to identify a suitable device configuration and assess energy requirements. We evaluated four subcutaneous ICD configurations in 78 patients who were candidates for ICD implantation and subsequently tested the best configuration in 49 additional patients to determine the subcutaneous defibrillation threshold in comparison with that of the standard transvenous ICD. Then we evaluated the long-term use of subcutaneous ICDs in a pilot study, involving 6 patients, which was followed by a trial involving 55 patients. RESULTS: The best device configuration consisted of a parasternal electrode and a left lateral thoracic pulse generator. This configuration was as effective as a transvenous ICD for terminating induced ventricular fibrillation, albeit with a significantly higher mean (+/-SD) energy requirement (36.6+/-19.8 J vs. 11.1+/-8.5 J). Among patients who received a permanent subcutaneous ICD, ventricular fibrillation was successfully detected in 100% of 137 induced episodes. Induced ventricular fibrillation was converted twice in 58 of 59 patients (98%) with the delivery of 65-J shocks in two consecutive tests. Clinically significant adverse events included two pocket infections and four lead revisions. After a mean of 10+/-1 months, the device had successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. CONCLUSIONS: In small, nonrandomized studies, an entirely subcutaneous ICD consistently detected and converted ventricular fibrillation induced during electrophysiological testing. The device also successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. (ClinicalTrials.gov numbers, NCT00399217 and NCT00853645.)

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Description: This update of the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding (UGIB) refines previous important statements and presents new clinically relevant recommendations. Methods: An international multidisciplinary group of experts developed the recommendations. Data sources included evidence summarized in previous recommendations, as well as systematic reviews and trials identified from a series of literature searches of several electronic bibliographic databases from inception to April 2018. Using an iterative process, group members formulated key questions. Two methodologists prepared evidence profiles and assessed quality (certainty) of evidence relevant to the key questions according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Group members reviewed the evidence profiles and, using a consensus process, voted on recommendations and determined the strength of recommendations as strong or conditional. Recommendations: Preendoscopic management: The group suggests using a Glasgow Blatchford score of 1 or less to identify patients at very low risk for rebleeding, who may not require hospitalization. In patients without cardiovascular disease, the suggested hemoglobin threshold for blood transfusion is less than 80 g/L, with a higher threshold for those with cardiovascular disease. Endoscopic management: The group suggests that patients with acute UGIB undergo endoscopy within 24 hours of presentation. Thermocoagulation and sclerosant injection are recommended, and clips are suggested, for endoscopic therapy in patients with high-risk stigmata. Use of TC-325 (hemostatic powder) was suggested as temporizing therapy, but not as sole treatment, in patients with actively bleeding ulcers. Pharmacologic management: The group recommends that patients with bleeding ulcers with high-risk stigmata who have had successful endoscopic therapy receive high-dose proton-pump inhibitor (PPI) therapy (intravenous loading dose followed by continuous infusion) for 3 days. For these high-risk patients, continued oral PPI therapy is suggested twice daily through 14 days, then once daily for a total duration that depends on the nature of the bleeding lesion. Secondary prophylaxis: The group suggests PPI therapy for patients with previous ulcer bleeding who require antiplatelet or anticoagulant therapy for cardiovascular prophylaxis.

Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.

Atrial fibrillation (AF) is the most common cardiac arrhythmia despite substantial efforts to understand the pathophysiology of the condition and develop improved treatments. Identifying the underlying causative mechanisms of AF in individual patients is difficult and the efficacy of current therapies is suboptimal. Consequently, the incidence of AF is steadily rising and there is a pressing need for novel therapies. Research has revealed that defects in specific molecular pathways underlie AF pathogenesis, resulting in electrical conduction disorders that drive AF. The severity of this so-called electropathology correlates with the stage of AF disease progression and determines the response to AF treatment. Therefore, unravelling the molecular mechanisms underlying electropathology is expected to fuel the development of innovative personalized diagnostic tools and mechanism-based therapies. Moreover, the co-creation of AF studies with patients to implement novel diagnostic tools and therapies is a prerequisite for successful personalized AF management. Currently, various treatment modalities targeting AF-related electropathology, including lifestyle changes, pharmaceutical and nutraceutical therapy, substrate-based ablative therapy, and neuromodulation, are available to maintain sinus rhythm and might offer a novel holistic strategy to treat AF. Atrial fibrillation (AF) is the most common cardiac arrhythmia and is increasing in prevalence as populations age. This Primer provides an overview of AF epidemiology, the mechanisms underlying electropathology in AF, and the diagnostic approaches and treatments, and highlights important directions to improve understanding and management of AF in co-creation with patients.

The consensus of the Asia Pacific Heart Rhythm Society (APHRS) on stroke prevention in atrial fibrillation (AF) has been published in 2017 which provided useful clinical guidance for cardiologists, neurologists, geriatricians, and general practitioners in the Asia-Pacific region. In these years, many important new data regarding stroke prevention in AF were reported. The practice guidelines subcommittee members comprehensively reviewed updated information on stroke prevention in AF, and summarized them in this 2021 focused update of the 2017 consensus guidelines of the APHRS on stroke prevention in AF. We highlighted and focused on several issues, including the importance of the AF Better Care pathway, the advantages of non-vitamin K antagonist oral anticoagulants (NOACs) for Asians, the considerations of use of NOACs for Asian AF patients with single one stroke risk factor beyond gender, the role of lifestyle factors on stroke risk, the use of oral anticoagulants during the "coronavirus disease 2019" pandemic, etc. We fully realize that there are gaps, unaddressed questions, and many areas of uncertainty and debate in the current knowledge of AF, and the physician's decision remains the most important factor in the management of AF.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing these systems has been based primarily on observational studies. METHODS: We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks. RESULTS: A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12). CONCLUSIONS: In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).

BACKGROUND: At the beginning of June 2020, there were nearly 7 million reported cases of coronavirus disease 2019 (COVID-19) worldwide and over 400,000 deaths in people with COVID-19. The objective of this study was to determine associations between comorbidities listed in the Charlson comorbidity index and mortality among patients in the United States with COVID-19. METHODS AND FINDINGS: A retrospective cohort study of adults with COVID-19 from 24 healthcare organizations in the US was conducted. The study included adults aged 18-90 years with COVID-19 coded in their electronic medical records between January 20, 2020, and May 26, 2020. Results were also stratified by age groups (<50 years, 50-69 years, or 70-90 years). A total of 31,461 patients were included. Median age was 50 years (interquartile range [IQR], 35-63) and 54.5% (n = 17,155) were female. The most common comorbidities listed in the Charlson comorbidity index were chronic pulmonary disease (17.5%, n = 5,513) and diabetes mellitus (15.0%, n = 4,710). Multivariate logistic regression analyses showed older age (odds ratio [OR] per year 1.06; 95% confidence interval [CI] 1.06-1.07; p < 0.001), male sex (OR 1.75; 95% CI 1.55-1.98; p < 0.001), being black or African American compared to white (OR 1.50; 95% CI 1.31-1.71; p < 0.001), myocardial infarction (OR 1.97; 95% CI 1.64-2.35; p < 0.001), congestive heart failure (OR 1.42; 95% CI 1.21-1.67; p < 0.001), dementia (OR 1.29; 95% CI 1.07-1.56; p = 0.008), chronic pulmonary disease (OR 1.24; 95% CI 1.08-1.43; p = 0.003), mild liver disease (OR 1.26; 95% CI 1.00-1.59; p = 0.046), moderate/severe liver disease (OR 2.62; 95% CI 1.53-4.47; p < 0.001), renal disease (OR 2.13; 95% CI 1.84-2.46; p < 0.001), and metastatic solid tumor (OR 1.70; 95% CI 1.19-2.43; p = 0.004) were associated with higher odds of mortality with COVID-19. Older age, male sex, and being black or African American (compared to being white) remained significantly associated with higher odds of death in age-stratified analyses. There were differences in which comorbidities were significantly associated with mortality between age groups. Limitations include that the data were collected from the healthcare organization electronic medical record databases and some comorbidities may be underreported and ethnicity was unknown for 24% of participants. Deaths during an inpatient or outpatient visit at the participating healthcare organizations were recorded; however, deaths occurring outside of the hospital setting are not well captured. CONCLUSIONS: Identifying patient characteristics and conditions associated with mortality with COVID-19 is important for hypothesis generating for clinical trials and to develop targeted intervention strategies.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December of 2019 in the city of Wuhan, China. Since the outbreak, various reports detail its symptoms and outcomes, primarily focusing on respiratory complications. However, reports are emerging of the virus' effects systemically, including that of the nervous system. A review of all current published literature was conducted, and we report that headache and anosmia were common neurological manifestations of SARS-CoV-2. Less common symptoms include seizure, stroke and isolated cases of Guillain-Barre syndrome. Further research is now warranted to precisely determine the relationship between those patients developing neurological sequelae, their clinical state and any subsequent morbidity and mortality.

OBJECTIVE: The 'Atrial fibrillation Better Care' (ABC) pathway has been recently proposed as a holistic approach for the comprehensive management of patients with atrial fibrillation (AF). We performed a systematic review of current evidence for the use of the ABC pathway on clinical outcomes. METHODS AND RESULTS: We performed a systematic review and meta-analysis according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed and EMBASE were searched for studies reporting the prevalence of ABC-pathway-adherent management in AF patients, and its impact on clinical outcomes (all-cause death, cardiovascular death, stroke, and major bleeding). Meta-analysis of odds ratio (OR) was performed with random-effects models; subgroup analysis and meta-regression were performed to account for heterogeneity. Among the eight studies included, we found a pooled prevalence of ABC-adherent management of 21% (95% confidence interval, CI: 13-34%), with a high grade of heterogeneity, explained by the increasing adherence to each ABC criterion. Patients treated according to the ABC pathway showed a lower risk of all-cause death (OR: 0.42; 95% CI: 0.31-0.56), cardiovascular death (OR: 0.37; 95% CI: 0.23-0.58), stroke (OR: 0.55; 95% CI: 0.37-0.82) and major bleeding (OR: 0.69; 95% CI: 0.51-0.94), with moderate heterogeneity. Prevalence of comorbidities was moderators of heterogeneity for all-cause and cardiovascular death, while longer follow-up was associated with increased effectiveness for all outcomes. CONCLUSION: Adherence to the ABC pathway was suboptimal, being adopted in one in every five patients. Adherence to the ABC pathway was associated with a reduction in the risk of major adverse outcomes.

Pulsed field ablation (PFA) is an emerging technology for the treatment of atrial fibrillation (AF), for which pre-clinical and early-stage clinical data are suggestive of some degree of preferentiality to myocardial tissue ablation without damage to adjacent structures. Here in the MANIFEST-17K study we assessed the safety of PFA by studying the post-approval use of this treatment modality. Of the 116 centers performing post-approval PFA with a pentaspline catheter, data were received from 106 centers (91.4% participation) regarding 17,642 patients undergoing PFA (mean age 64, 34.7% female, 57.8% paroxysmal AF and 35.2% persistent AF). No esophageal complications, pulmonary vein stenosis or persistent phrenic palsy was reported (transient palsy was reported in 0.06% of patients; 11 of 17,642). Major complications, reported for ~1% of patients (173 of 17,642), were pericardial tamponade (0.36%; 63 of 17,642) and vascular events (0.30%; 53 of 17,642). Stroke was rare (0.12%; 22 of 17,642) and death was even rarer (0.03%; 5 of 17,642). Unexpected complications of PFA were coronary arterial spasm in 0.14% of patients (25 of 17,642) and hemolysis-related acute renal failure necessitating hemodialysis in 0.03% of patients (5 of 17,642). Taken together, these data indicate that PFA demonstrates a favorable safety profile by avoiding much of the collateral damage seen with conventional thermal ablation. PFA has the potential to be transformative for the management of patients with AF.

BACKGROUND: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. METHODS: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: -VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

Atrial fibrillation (AF) is highly prevalent with a lifetime risk of about 1 in 3-5 individuals after the age of 45 years. Between 2010 and 2019, the global prevalence of AF has risen markedly from 33.5 million to 59 million individuals living with AF. Early detection of AF and implementation of appropriate treatment could reduce the frequency of complications associated with AF. International AF management guidelines recommend opportunistic and systematic screening for AF, but additional data are needed. Digital approaches and pathways have been proposed for early detection and for the transition to early AF management. Mobile health (mHealth) devices provide an opportunity for digital screening and should be part of novel models of care delivery based on integrated AF care pathways. For a broad implementation of mHealth-based, integrated care for patients with chronic diseases as AF, further high quality evidence is necessary. In this review, we present an overview of the present data on epidemiology, screening techniques, and the contribution of digital health solutions to the integrated management of AF. We also provide a systemic review on current data of digital and integrated AF management.

The number of cardiac implantable electronic device (CIED) implantations has increased over recent years1,2 as a result of population growth, increasing life expectancy, adoption of guidelines, and better access to healthcare. Transvenous lead extraction (TLE), as a part of an overall lead management strategy, has also been increasing, not only as a consequence of this growth, but also because of increasing rates of infection,3 lead failure, awareness of indications for lead management, and development of extraction tools. Clinical research is essential for understanding efficacy and risks of TLE, which has important implications regarding decision-making and therapeutic strategies in patients who are candidates for this procedure. Data on TLE have mainly come from retrospective series, with variable reporting of endpoints. Recently, the ELECTRa registry conducted by the European Heart Rhythm Association (EHRA), has reported the largest prospective experience on lead extraction published to date in 3555 patients recruited from 19 European countries.4 There remain unresolved issues, which is a strong incentive for conducting further specifically-designed clinical trials to answer important questions in this area. In addition to clinical studies, national registries are potentially useful for evaluating epidemiology of TLE as well as for quality control and understanding resource implications. Standardization of definitions and reporting of parameters are paramount in order to analyse, compare, and pool data for scientific purposes. Expert consensus statements on lead extraction have been published by the Heart Rhythm Society (HRS) in 20095 and 2017,6 and by EHRA in 2012.7 Experience from the ELECTRa registry has been valuable for identifying challenges faced with conducting scientific studies in this field, and provides a framework for future endeavours. This writing group has been commissioned by EHRA to provide recommendations for designing scientific studies, reports and registries relating to lead extraction. In order to clarify the indications for lead extraction the following definitions are proposed (see Table 1). CIED-related infection types CIED, cardiac implantable electronic device. This was the most frequent indication for TLE in the ELECTRa registry amounting to 52.8% (of which approximately two-thirds were local infections).4 Several entities exist, which should be specified. This is defined as an infection limited to the generator pocket or along the lead course. It is clinically associated with local signs of inflammation, including erythema, warmth, fluctuance, wound dehiscence, tenderness, or purulent drainage, with negative blood cultures.8–10 This entity should be differentiated from superficial incisional Infection, which involves only skin and subcutaneous tissue without communication with the pocket (and may not require lead extraction). This is a chronic process whereby the device and/or lead(s) are exposed through the skin, with or without local signs of infection (the device should however be considered infected, whatever the mechanism for erosion). Very often the erosion is preceded by the adherence of the skin on the device with a concomitant browning and thinning of the skin. Erosion is usually indicative of infection. Blood cultures are negative, and some of these patients are asymptomatic, while others complain of local pain. In presence of positive blood cultures with or without systemic infection symptoms and signs. Local signs of pocket infection and positive blood cultures and lead or valvular vegetation(s). The 2015 European Society of Cardiology (ESC) modified Duke Criteria8 have been used to define endocarditis. It should be noted that these criteria are used to define valvular endocarditis. For CIED-related endocarditis, additional criteria might be considered, such as positive cultures of the extracted lead in case of negative blood cultures, presence of lead vegetations, and abnormal metabolic activity around the CIED generator and/or leads detected by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) or radiolabelled leucocytes single-photon-emission computed tomography/CT. Local signs of pocket infection and positive blood cultures, without lead or valvular vegetation(s). Bacteraemia with or without lead or valvular vegetation(s), and without local signs of pocket infection. Bacteraemia without an obvious source other than the CIED. After extraction, disappearance of bacteraemia is expected. In case of lead dysfunction, there is the option of abandoning the lead or extracting it (e.g. to reduce intravascular lead burden or regain access in the presence of venous occlusion). Lead dysfunction was the second most frequent reason for lead extraction in the ELECTRa registry, amounting to 38.1% of cases.4 Causes for lead dysfunction may be lead fracture or insulation failure resulting in issues with lead impedance, sensing or capture. In some cases, the electrical parameters may still be normal, but the integrity of the lead is clearly compromised (e.g. inside out cable externalization of Riata leads, radiological evidence of subclavian crush etc.). There are a variety of situations where a functional lead may no longer be required, with the option of either abandoning or extracting the lead. Examples are upgrades from a pacemaker to an implantable cardioverter-defibrillator (ICD), downgrading from dual- to single-chamber systems, lead recall with prophylactic revision, system relocation for radiotherapy, lack of device indication etc. These abandoned leads may be extracted to reduce the intravascular lead burden in order to avoid future issues (see Table 2). Definitions of terms for non-infected leads CIED, cardiac implantable electronic device. Leads may be functional but cause complications for which extraction may be indicated (e.g. thromboembolic events, superior vena cava syndrome, arrhythmias, perforation, lead-lead interaction etc.). If stenting is planned for treating stenosis in a vein with a transvenous lead, extraction is usually performed to avoid entrapment of the lead. Up to 25% of patients with transvenous leads develop some degree of stenosis,11 which may later hinder additional lead implantation (e.g. in case of upgrades). There are a number of different management strategies,12 which include tunnelling a contra-lateral lead across the chest, venoplasty, or lead extraction to provide a channel through which new leads can be implanted. There is evidence that magnetic resonance imaging (MRI) can be safely performed in patients implanted with non-conditional CIEDs, but abandoned or dysfunctional leads are considered to be contra-indications (even if an MRI-conditional device is implanted).13 Therefore, extraction of these leads may be performed in selected cases, with appropriate assessment of the risk and benefits of the lead extraction procedure, in order to allow access to MRI, when no other diagnostic alternatives to MRI are available. Some patients may have severe chronic pain attributed to lead insertion (e.g. due to a periosteal reaction), for which lead extraction may be performed. It is important to recognize that chronic pain may be a sign of an infection. A number of other rare indications for lead extraction exist, such as prophylactic extraction of leads that due to their design or their failure pose a potential future threat to the patient if left in place e.g. Accufix leads (Telectronics). Lead removal often includes a wide spectrum of tools and techniques, ranging from simple manual traction to multiple procedures and combined approaches (see Table 3). Definition of LE approaches, techniques and tools LE, lead extraction; RFA, radiofrequency ablation. Most lead extractions are performed using a percutaneous approach as it is less invasive. In specific situations (e.g. high-risk procedures or in case of very large vegetations), an open extraction with sternotomy and cardiopulmonary bypass may be preferred. Some centres perform hybrid approaches that combine percutaneous extraction with minimally invasive surgery or thoracoscopy. The various approaches for percutaneous TLE are detailed below. Most lead extraction procedures begin via the identical route of lead implantation, also known as venous entry or implant vein approaches. If the venous entry approach fails, or in the presence of free-floating leads, an internal jugular venous approach can be used, combining superior and femoral accesses.14 Extraction may be performed with femoral venous access as a primary strategy or as a bailout procedure, using specialized tools.15 When reporting data for lead extraction procedures, it is important to be specific regarding the tools and techniques used, as these will have a direct impact on outcome and also on costs. Often, a ‘stepwise’ approach is used whereby the operator transitions from simple to more complex strategies. Therefore, different tools and techniques may be used during a procedure, even for the same lead. In case of a stepwise approach, it is useful to report the sequence of techniques, which were employed for a given lead. Applying mild pulling force without the use of specialized tools (other than a standard stylet) was used in 27% of patients in the ELECTRa registry,4 and may be effective for leads with a short dwell time (i.e. time since implant <1–2 years). These are designed to improve tensile strength to facilitate traction and to stabilize leads. They may be used alone or in combination with other tools such as sheaths. These sheaths are designed for blunt dissection of fibrotic binding sites, using simple manual pushing/rotational force. They are most often composed of polypropylene, but metallic or Teflon (PTFE) sheaths are also available. They may be used alone or with handles that facilitate rotation, and most often with a locking stylet. When reporting use of powered sheaths, it is important to specify which type of tool was used, as their mechanism, efficacy and risk profiles may differ. They are used in conjunction with a locking stylet inserted into the lead, which builds a rail upon which the device is advanced. Rotational mechanical sheaths are currently hand powered and have a threaded tip which dissects adherent tissue.16,Electrosurgical sheaths use radiofrequency energy to dissect fibrous tissue but are now seldom used. Laser sheaths use laser energy delivered circumferentially along the tip of the sheath.17 As additional tools become available this list should be expanded accordingly. These are most often deployed via a femoral approach, and may consist of a single or double15 loop, which can be used for grasping free-floating lead extremities or the lead body (double loop design). These devices are usually introduced via a femoral approach to grasp free-floating lead extremities, but are seldom used today. These wires are used for grasping conductor cables or lumenless leads in order to be able to use an extraction sheath. These tools allow secure binding of locking stylets and the proximal components of the lead to facilitate extraction.18 In case of a vascular tear, these highly compliant balloons are filled with diluted contrast agents to stem bleeding while awaiting surgical bailout.19 Tools that are dedicated to other procedures may sometimes be used for lead extraction (e.g. for grasping leads), such as pigtail catheters, deflectable wires, deflectable catheters, bioptomes, deflectable sheaths etc. It is recommended to report the size of the tools used, as these may impact complications (e.g. bleeding at the venous entry site, collateral damage, etc.). However, it is important to realize that tool size may be labelled differently (e.g. mechanical sheath size usually refers to internal diameters, whereas laser sheath size refers to external diameter), and that use of outer sheaths will also impact tool size. To interpret studies, whether prospective randomized trials or retrospective studies, there must be clear and consistent definitions. Since many complications may occur after the patient leaves the procedural venue, appropriate follow-up should be performed. In addition, true informed consent requires each operator to know their own volumes and outcomes. This requires and able to report in a Definitions of a lead extraction, procedural and complications have been well in the and consensus on and used in the ELECTRa It will be the of this to with to the of A of the that the of lead extraction has which reporting of the and efficacy of lead extraction procedures to The removal of a lead is clearly different from a lead. To the clear definitions for and is not a lead extraction procedure, which have been in the and also in this When a the following definitions should be of a lead or lead using This entity includes removal of subcutaneous leads. A lead removal using simple traction techniques locking sheaths, or femoral extraction and leads were implanted with removal of at lead that has been implanted for more than or a lead of of implant the of specialized that is not as part of the implant and/or removal of a lead from a route other than the implant removal of may be considered as extraction For scientific it is important to of the as a as well as to data on of extraction of leads (e.g. in order to for leads, and for The of will very upon and can only be in case the follow-up is In case of leads, a CIED removal is even if a may be to consensus of In case of non-infected leads, clinical may be of lead tip on A list of definitions regarding and outcome is reported in Table Definitions for extraction procedures and implantable of leads and with the of or where there is by the number of of a of a lead that not impact the outcome of the procedure. This may be the tip or a part of the lead or the when the part not the risk of perforation, events, of or cause of or where there is clinical by the number of to either procedural or clinical or the development of or Extraction procedures that by the number of Lead or extraction with removal of lead Lead or extraction where part of the lead in the body or of complications is more complex as patients may also be additional procedures at the time of extraction, such as (e.g. was the pocket due to the extraction or the In addition, can impact (e.g. the patient as a of the extraction or due to the that was the indication for the It is important that be reported as as to avoid The of the is less important to the patient than the the complications must be and list of complications is in Table clear definitions to and allow for a understanding of the risks of the procedure. As the and complications are defined by their time in to the and their from to the of a that or from the time patient the the patient leaves the This includes complications to the of the the of and and the to the that or following the to the that or after following the and during the are into or with on and must be and This reporting and the to quality and outcomes. increased in a specific must be and a performed. complications can be only if are of the to the procedure, which is or in or In addition, that or requires or of or that requires surgical to of the to the that requires or procedural to and not or the it life or cause are as standard reported for a This complications and to the procedure, and should be the follow-up should be for a longer (e.g. This allow for a better understanding of the to the indication for extraction (e.g. of and if an extraction approach has For patients extraction for a device infection have to a 25% extraction. In addition, data extraction for infection The quality of scientific or registry is by the quality of the As with there is a of to be and for the to the data will should be to with and and avoid are available. such is Data at and by a This is a secure that can be used to of this is that it and data can be A list of parameters are detailed (the of parameters will upon the of the and an of a case report is available on the etc.). and (e.g. open left Heart Association presence of as these may procedural for the CIED. for extraction. should be and leads of leads. of device and leads. The lead of the and each of these components can the of the It is important that these data are available for The of an extracted lead may be if the is in the using to avoid in data for and each lead to the specific As an the (e.g. leads, subcutaneous leads, leads, or may be for each lead. The and for the device and leads should be of implant of procedural and complications are to this of leads etc.). of of leads including leads, lead etc. at extraction (and the of leads, presence of vegetations, contrast lead etc. Blood etc. these parameters may and in order to with of blood cultures infection is and of procedure. or procedure. or hybrid or whether a cardiac is in or operator imaging of and and their of etc.). tools used in which order for each of tools in the superior vena cava etc.). performed during the (e.g. pocket venoplasty, lead with or without of the lead etc.). of extraction for each in failure in access site, type of device this may and complications bleeding and their If the of vascular or cardiac should be as have an impact on performed. Blood management (e.g. etc.). type of access of complications date and and of There are in evidence in the of lead extraction. Some of the are below. in case of devices a removal is the following have to be the of additional diagnostic tools in patients with Clinical of different strategies of and of and their a system to the risk of complications associated with percutaneous removal that will a of patients for an open surgical approach for CIED extraction is the of device with or device as management in local and systemic infection. of of whether open surgery is in patients with a and endocarditis, but without an or other indication for open surgery (e.g. is a size to be extracted by TLE, open surgical or pacemaker and leads a decision-making process when extraction. The issues are around clearly the risk associated with lead and whether the potential of lead extraction the risk of the procedure. In an of the Data patients removal of an or lead complications and than with a lead There are data on the lead burden that in venous access issues and superior vena cava syndrome, and consensus are on as to the of abandoned leads that extraction of more than leads on or leads through the issues with abandoned leads, such as are also not well of on leads are abandoned (e.g. of the lead is important since this has a on future follow-up and extraction For leads or and data is essential to with clinical to the and a recall is an to a with a device that are by the to the degree of by the The provides but are by national and use a different recall system to the the This is an by a to reduce a risk of or in the of associated with the use of a device that is on the whether associated with direct or should be reported and should be via a the of clinical registries for device and lead in with and such as the and Experience This will of lead and patient in Standardization of and data is important for this require such as the system proposed by the tools for prospective of CIED may improve the a registry to This will require and of from multiple as proposed by the and other the or provides a from which lead (and data can be It is well that the presence of a wide variety of extraction tools is of to patient as well as procedural of and efficacy of the different tools is as some devices (e.g. may be used as for studies are for with the of new tools for which data (e.g. There are a number of risk associated with lead extraction research may for which may with management There to be a lack of consensus regarding should be to become in lead extraction. There are that extracting a of leads in at procedures as a for with of procedures at each to However, it is to for the multiple available tools in a limited number of It has been in a with that of locking stylets and laser can provide an and may improve types of are also available using and which allow of parameters such as traction force at different may also provide a to for who have a research is however to that can improve and impact procedural number of that an operator is to provide and effective lead extraction, and there are no true to may provide that can of extraction tools and but their will be by the with which the There is some evidence that the of complications and are to the of a TLE and the experience of the This is by data of the where the for and centres was procedures The was different and centres with in centres However, there was no in The differentiated and centres on case over a and data are to that are associated with better patient which may have future implications. The of different or hybrid on procedural is a of potential scientific In a large retrospective TLE procedures on the of surgical or management of procedural it was that was if surgical or was performed in the than in an A European Heart Rhythm Association published in that most TLE procedures at that time were performed in a hybrid In the ELECTRa of the procedures were performed in an hybrid This might a in the of TLE centres or might be to the different centres in the data studies the of management in TLE should the for such procedures on endpoints. A further with lack of evidence is the impact of type local with or without on during Data from the ELECTRa registry an even types the centres with a use of local on TLE procedures not clearly specific but require in case the is not performed data to be and to clarify this There a strong to a scientific for lead extraction recommendations in patient patient consist but are not to very and patients potentially open extraction procedures (e.g. lead than or leads into or to these patient is the that the of such patients in single series, even in are to It is of to perform future studies on a data of multiple either in the of studies or a lead extraction registry pool but this is to in the In this a of data should be to allow for data multiple As lead extraction is a for a randomized clinical but questions the should and provide appropriate have published clinical on TLE and large which are to improve understanding in this However, many questions still remain regarding TLE, not only the limited number of randomized trials but also the lack of in reporting procedures and These unresolved issues have given a strong incentive for this consensus The recommendations are to and and are to clinical scientific guidelines, quality and The also in evidence lead extraction, with the to in scientific trials and is available at of The EHRA

BACKGROUND: Infections after placement of cardiac implantable electronic devices (CIEDs) are associated with substantial morbidity and mortality. There is limited evidence on prophylactic strategies, other than the use of preoperative antibiotics, to prevent such infections. METHODS: We conducted a randomized, controlled clinical trial to assess the safety and efficacy of an absorbable, antibiotic-eluting envelope in reducing the incidence of infection associated with CIED implantations. Patients who were undergoing a CIED pocket revision, generator replacement, or system upgrade or an initial implantation of a cardiac resynchronization therapy defibrillator were randomly assigned, in a 1:1 ratio, to receive the envelope or not. Standard-of-care strategies to prevent infection were used in all patients. The primary end point was infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence, or death, within 12 months after the CIED implantation procedure. The secondary end point for safety was procedure-related or system-related complications within 12 months. RESULTS: A total of 6983 patients underwent randomization: 3495 to the envelope group and 3488 to the control group. The primary end point occurred in 25 patients in the envelope group and 42 patients in the control group (12-month Kaplan-Meier estimated event rate, 0.7% and 1.2%, respectively; hazard ratio, 0.60; 95% confidence interval [CI], 0.36 to 0.98; P = 0.04). The safety end point occurred in 201 patients in the envelope group and 236 patients in the control group (12-month Kaplan-Meier estimated event rate, 6.0% and 6.9%, respectively; hazard ratio, 0.87; 95% CI, 0.72 to 1.06; P<0.001 for noninferiority). The mean (±SD) duration of follow-up was 20.7±8.5 months. Major CIED-related infections through the entire follow-up period occurred in 32 patients in the envelope group and 51 patients in the control group (hazard ratio, 0.63; 95% CI, 0.40 to 0.98). CONCLUSIONS: Adjunctive use of an antibacterial envelope resulted in a significantly lower incidence of major CIED infections than standard-of-care infection-prevention strategies alone, without a higher incidence of complications. (Funded by Medtronic; WRAP-IT ClinicalTrials.gov number, NCT02277990.).