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Direct oral anticoagulants (DOACs) have partial renal clearance and generally require dosage adjustments based on renal function. While current US and European guidance recommends dose adjustments in patients with moderate chronic kidney disease (CKD), it is unclear how often this is done appropriately in routine clinical practice. We examined rates of appropriate and inappropriate dosing in patients with atrial fibrillation (AF) and moderate CKD, as determined by creatinine clearance (CrCl) of 30–50 mL/min calculated with the Cockcroft–Gault formula. Descriptive statistics were used to describe the rate of appropriate and inappropriate dosing as well as event rates. Among 1134 patients (8.5% of the overall ORBIT-AF II registry) with AF and CrCl 30–50 mL/min, the median age was 82 (25th, 75th percentile: 78, 86), 38% were male, and the median CHA2DS2VASC score was 4 (25th, 75th percentile: 4, 5). At baseline, more than one-third (34%) of patients with moderate CKD were inappropriately dosed with DOACs. When evaluating the specific prescribed doses in those with moderate CKD, 15% (N = 170/1134) were underdosed, 66% (743/1134) were appropriately dosed, and 20% (N = 221/1134) were overdosed. There were no significant differences in comorbid medical conditions between patients with moderate CKD who were appropriately and inappropriately dosed with a DOAC. In routine clinical practice, prescribing of DOACs in patients with AF with moderate CKD is often inconsistent with drug labeling, with up to one-third of patients being inappropriately dosed.

Objective We designed an automatic, computationally efficient, and interpretable algorithm for detecting ventricular ectopic beats in long-term, single-lead electrocardiogram recordings. Methods We built five simple, interpretable, and computationally efficient features from each cardiac cycle, including a novel morphological feature which described the distance to the median beat in the recording. After an unsupervised subject-specific normalization procedure, we trained an ensemble binary classifier using the AdaBoost algorithm Results After our classifier was trained on subset DS1 of the Massachusetts Institute of Technology-Beth Israel Hospital (MIT-BIH) Arrhythmia database, our classifier obtained an F1 score of 94.35% on subset DS2 of the same database. The same classifier achieved F1 scores of 92.06% on the St. Petersburg Institute of Cardiological Technics (INCART) 12-lead Arrhythmia database and 91.40% on the MIT-BIH Long-term database. A phenotype-specific analysis of model performance was afforded by the annotations included in the St. Petersburg INCART Arrhythmia database Conclusion The five features this novel algorithm employed allowed our ventricular ectopy detector to obtain high precision on previously unseen subjects and databases Significance Our ventricular ectopy detector will be used to study the relationship between premature ventricular contractions and adverse patient outcomes such as congestive heart failure and death.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date. Design COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771). Conclusion In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society describes the current status of mobile health (“mHealth”) technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored.

Background: Ablation reduces atrial fibrillation (AF) burden and improves health-related quality of life. The relationship between ablation, healthcare utilization, and AF type (paroxysmal AF [PAF] vs persistent AF [PsAF]) remains unclear. Objective: To compare changes in AF-related healthcare utilization and costs from preablation to postablation among patients with PAF and PsAF. Methods: Patients (2794 PAF, 1909 PsAF) undergoing ablation (2016–2018) were identified using the Optum database. Outcomes included inpatient admissions, emergency department (ED) visits, office visits, cardioversion, and antiarrhythmic drug (AAD) use. Costs (2018 US$) and outcomes were compared for the year before/after ablation using the McNemar test and Wilcoxon signed rank test. Results: Compared to PAF patients, PsAF patients were older (68.6 ± 9.0 years vs 67.4 ± 9.9 years, P < .0001), were less commonly female (36.3% vs 44.1%, P < .0001), and more commonly had a CHA2DS2-VASc ≥ 3(71.2% vs 62.7%, P < .0001). The 12-month postablation costs were lower for AF-specific inpatient admissions (PAF -28%, PsAF -33%), ED visits (PAF -76%, PsAF -70%), AAD prescription fills (PAF -25%, PsAF -7%), and cardioversions (PAF -59%, PsAF -55%) as compared to 12 months before ablation. Although these reductions were observed for both PAF and PsAF patients, absolute costs remained higher for PsAF. Total AF costs were higher during the 1 year after ablation vs before ablation (PAF: 11%, P < .0001; PsAF: 10%, P < .0001) owing to repeat ablation. However, in the 18-month follow-up analysis, postablation costs were overall reduced (PAF: 35%, P < .0001; PsAF: 34%, P < .0001), despite including costs from repeat ablation. Conclusion: Significant reductions in healthcare utilization and costs were observed among PAF and PsAF patients undergoing ablation. These data suggest a strategy of earlier ablation may reduce long-term healthcare utilization and costs.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/ Heart Rhythm Society/ European Heart Rhythm Association/ Asia Pacific Heart Rhythm Society describes the current status of mobile health ("mHealth") technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored. Varma, N (corresponding author), Cleveland Clin, Cleveland, OH 44106 USA. varman@ccf.org

INTRODUCTION Cryoballoon ablation (CBA) is an alternative to radiofrequency ablation (RFA) for ablation of atrial fibrillation (AF) and real-world comparisons of this strategy are lacking. As such, we sought to compare patient and periprocedural characteristics and outcomes of CBA versus RFA in the Get With the Guidelines AFIB Registry. METHODS Categorical variables were compared via the χ2 test and continuous variables were compared via the Wilcoxon rank-sum test. Adjusted analyses were performed using overlap weighting of propensity scores. RESULTS A total of 5247 (1465 CBA, 3782 RFA) ablation procedures were reported from 33 sites. Those undergoing CBA more often had paroxysmal AF (60.0% vs. 48.8%) and no prior AF ablation (87.5% vs. 73.8%). CHA2 DS2 -VASc scores were similar. Among de novo ablations, most ablations involved intracardiac echocardiography and electroanatomic mapping, but both were less common with CBA (87.3% vs. 93.9%, p

Catheter ablation is superior to antiarrhythmic therapy for the reduction of symptomatic atrial fibrillation (AF), recurrence, and burden. The possibility of a true ‘rhythm’ control strategy with catheter ablation has re-opened the debate on rate vs. rhythm control and the subsequent impact on stroke risk. Some observation studies suggest that successful AF catheter ablation and maintenance of sinus rhythm are associated with a decrease in stroke risk, while the CABANA trial had demonstrated no apparent reduction. Other observational studies have demonstrated increased stroke risk when oral anticoagulation (OAC) is discontinued after catheter ablation. When and in whom OAC can be discontinued after ablation will need to be determined in properly conducted randomized control trials. In this review article, we discuss our current understanding of the interactions between AF, stroke, and anticoagulation following catheter ablation. Specifically, we discuss the evidence for the long-term anticoagulation following successful catheter ablation, the potential for OAC discontinuation with restoration of sinus rhythm, and novel approaches to anticoagulation management post-ablation.

The Micra transcatheter pacemaker is a safe and effective alternative to transvenous permanent pacemakers (TV-PPMs). However, the safety profile and mortality outcomes of Micra implantation in patients deemed poor candidates for TV-PPM are incompletely understood.The purpose of this study was to evaluate safety and all-cause mortality in patients undergoing Micra implantation stratified by whether they were precluded for therapy with a TV-PPM.Patients from the Micra clinical trials were divided into groups on the basis of whether the implanter considered the patient to be precluded from receiving a TV-PPM. Micra groups were compared with one another as well as with a historical cohort of patients who received a single-chamber TV-PPM.A total of 2817 patients underwent a Micra implantation attempt, of whom 546 (19%) patients deemed ineligible for TV-PPM implantation for reasons such as venous access issues or prior device infections. Both acute mortality (2.75% vs 1.32%; P=.022) and total mortality at 36 months (38.1% vs 20.6%; P.001) were significantly higher in the precluded group than in the nonprecluded group. Mortality was similar among nonprecluded patients and patients implanted with a TV-PPM. The major complication rate through 36 months was similar between the 2 Micra groups (3.81% vs 4.30%; P=.40).All-cause mortality is higher in Micra patients deemed ineligible for TV-PPM implantation than in nonprecluded Micra patients and those who received a TV-PPM, in part related to a higher incidence of chronic comorbidities in these patients. The overall major complication rate was low and did not differ by preclusion status.Micra Post-Approval Registry ClinicalTrials.gov identifier: NCT02536118; Micra Continued Access Study ClinicalTrials.gov identifier: NCT02488681; Micra Transcatheter Pacing Study ClinicalTrials.gov identifier: NCT02004873; Medtronic Product Surveillance Registry ClinicalTrials.gov identifier: NCT01524276.

BACKGROUND Leadless pacemakers (LPs) provide ventricular pacing without the risks associated with transvenous leads and device pockets. LPs are appealing for patients who need pacing, but do not need defibrillator or cardiac resynchronization therapy. Most implanted LPs provide right ventricular pacing without atrioventricular synchrony (VVIR mode). The Mode Selection Trial in Sinus Node Dysfunction (MOST) showed similar outcomes in patients randomized to dual-chamber (DDDR) versus ventricular pacing (VVIR). We compared outcomes by pacing mode in LP-eligible patients from MOST. METHODS Patients enrolled in the MOST study with an left ventricular ejection fraction (LVEF) >35%, QRS duration (QRSd)

This study sought to determine the indications, characteristics, and outcomes of cardiovascular implantable electronic device (CIED) surgery in patients with LVAD.Many patients with a left ventricular assist device (LVAD) will require implantable cardioverter-defibrillator generator change or device revision or are candidates for de novo implantable cardioverter-defibrillator implantation following LVAD implantation.We performed an observational retrospective study of all LVAD recipients who subsequently underwent CIED surgery at Duke University Hospital from 2009 to 2019.A total of 159 patients underwent CIED surgery following LVAD implantation, including generator change (n = 93), device revision (n = 38), and de novo implant (n = 28). The median (interquartile range) time from LVAD implantation to CIED surgery was 18.1 months (5.5 to 35.1 months). Pre-operative risk for infection was elevated in the overall cohort with a median (interquartile range) Prevention of Arrhythmia Device Infection Trial (PADIT) score of 7.0 (5.0 to 9.0). Pocket hematoma occurred in 21 patients (13.2%) following CIED surgery. Antimicrobial envelops were used in 43 patients (27%). Device infection due to CIED surgery occurred in 5 (3.1%) patients and occurred only in patients who developed post-operative pocket hematoma (p 0.001). Mortality at 1 year following CIED surgery was 20% (n = 32).CIED surgery following LVAD implantation is associated with an increased risk for pocket hematoma and CIED infection. Further studies are needed to determine the risk-benefit ratio of CIED surgery in patients with LVADs.

Background Although there are considerable data on the safety of cryoablation, data on the rare but severe complication of atrioesophageal fistula (AEF) following cryoballoon ablation are limited. Objective To report the global, user-reported incidence of AEF associated with cryoballoon ablation for the treatment of atrial fibrillation using Medtronic’s complaint database. Methods User-reported cryoballoon ablation complications occurring between July 1, 2009, and March 31, 2019, were reviewed to identify cases of AEF. A global event rate of AEF was calculated by dividing the event count by total catheter utilization over the same period. Data on symptoms and patient sequalae were reported as available. Results More than 500,000 Arctic Front cryoballoon catheters (Arctic Front, Arctic Front Advance, Arctic Front Advance ST, and Arctic Front Advance Pro; Medtronic, Inc) were distributed globally during the 9.75-year study period. During this time, 18 confirmed AEF, 1 suspected AEF, and 1 pericardial esophageal fistula were identified; therefore, global incidence of AEF associated with the Arctic Front family of ablation catheters was 0.00396%. Patients most commonly presented with fever (88.2%), and initial symptoms were reported a median of 21 (interquartile range: 4–30) days after the ablation. Although rare, the development of an AEF resulted in death in 68.8% (11/16) of patients with known outcomes. Conclusions AEF is a possible but rare complication of cryoballoon ablation with a reported frequency of 1 in every 25,000 patients treated. Awareness of the prevalence and manifestation of AEF associated with cryoballoon ablation is critical for early identification and treatment of this complication., Graphical abstract

BACKGROUND: In the Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) trial, catheter ablation reduced the risk of death and heart failure (HF) hospitalization in patients with atrial fibrillation and HF by 40%. OBJECTIVES: The study aimed to assess the generalizability of CASTLE-AF to routine clinical practice. METHODS: Using a large US administrative database, we identified 289,831 patients with atrial fibrillation and HF treated with ablation (n = 7465) or medical therapy alone (n = 282,366) from January 1, 2008, through August 31, 2018. Patients were divided into 3 groups on the basis of trial eligibility: (1) eligible for CASTLE-AF, (2) failing to meet the inclusion criteria, and (3) meeting at least 1 of the exclusion criteria. Propensity score overlap weighting was used to balance ablated and drug-treated patients on 90 baseline characteristics. Cox proportional hazards regression was used to compare ablation with medical therapy for the primary outcome of a composite end point of all-cause mortality and HF hospitalization. RESULTS: Only 7.8% of patients would have been eligible for the trial; 91.0% failed to meet the trial inclusion criteria;and 15.5% met the exclusion criteria. Ablation was associated with a lower risk of the primary outcome in the overall cohort (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.76–0.87; P < .001), in the trial-eligible cohort (HR 0.82; 95% CI 0.70–0.96; P = .01), and in patients who failed to meet inclusion criteria (HR 0.79; 95% CI 0.73–0.86; P < .001) but not in patients who met the exclusion criteria (HR 0.97; 95% CI 0.81–1.17). The relative risk reduction was consistent regardless of whether patients had HF with reduced left ventricular ejection fraction. CONCLUSION: The benefit associated with ablation appears to be more modest in practice than that reported in the CASTLE-AF trial.

The infection caused by severe acute respiratory syndrome coronavirus-2, or COVID-19, can result in myocardial injury, heart failure, and arrhythmias. In addition to the viral infection itself, investigational therapies for the infection can interact with the cardiovascular system. As cardiologists and cardiovascular service lines will be heavily involved in the care of patients with COVID-19, our division organized an approach to manage these complications, attempting to balance resource utilization and risk to personnel with optimal cardiovascular care. The model presented can provide a framework for other institutions to organize their own approaches and can be adapted to local constraints, resource availability, and emerging knowledge.

BackgroundCardioversion is common among patients with atrial fibrillation (AF). We hypothesised that novel oral anticoagulants (NOAC) used in clinical practice resulted in similar rates of stroke compared with vitamin K antagonists (VKA) for cardioversion.MethodsUsing the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, patients with AF who had a cardioversion, follow-up data and an AF diagnosis within 6 months of enrolment were identified retrospectively. Clinical outcomes were compared for patients receiving a NOAC or VKA for 1 year following cardioversion.ResultsAmong 13 004 patients with AF, 2260 (17%) underwent cardioversion. 1613 met the inclusion criteria for this analysis. At the time of cardioversion, 283 (17.5%) were receiving a VKA and 1330 (82.5%) a NOAC. A transoesophageal echocardiogram (TOE) was performed in 403 (25%) cardioversions. The incidence of stroke/transient ischaemic attack (TIA) at 30 days was the same for patients having (3.04 per 100 patient-years) or not having (3.04 per 100 patient-years) a TOE (p=0.99). There were no differences in the incidence of death (HR 1.19, 95% CI 0.62 to 2.28, p=0.61), cardiovascular hospitalisation (HR 1.02, 95% CI 0.76 to 1.35, p=0.91), stroke/TIA (HR 1.18, 95% CI 0.30 to 4.74, p=0.81) or bleeding-related hospitalisation (HR 1.29, 95% CI 0.66 to 2.52, p=0.45) at 1 year for patients treated with either a NOAC or VKA.ConclusionsCardioversion was a low-risk procedure for patients treated with NOAC, and there were statistically similar rates of stroke/TIA 30 days after cardioversion as for patients treated with VKA. There were no statically significant differences in death, stroke/TIA or major bleeding at 1 year among patients treated with NOAC compared with VKA after cardioversion.

This study identified factors associated with risk for cardiac perforation in the setting of atrial fibrillation (AF) ablation in contemporary clinical practice.Cardiac perforation is an uncommon but potentially fatal complication of AF ablation. An improved understanding of factors associated with cardiac perforation could facilitate improvements in procedural safety.Logistic regression models were used to assess predictors of cardiac perforation among Medicare beneficiaries who underwent AF ablation from July 1, 2013 and December 31, 2017. Cardiac perforation was defined as a diagnosis of hemopericardium, cardiac tamponade, or pericardiocentesis, within 30 days of AF ablation.Of 102,398 patients who underwent AF ablation, 0.61% (n = 623) experienced cardiac perforation as a procedural complication. Rates of cardiac perforation decreased over time. In adjusted analyses of the overall population, female sex (odds ratio [OR]: 1.34; 95% confidence interval [CI]: 1.14 to 1.58; p = 0.0004), obesity (OR: 1.35; 95% CI: 1.09 to 1.68; p = 0.0050), and absence of intracardiac echocardiography (ICE) (OR: 4.85; 95% CI: 4.11 to 5.71; p 0.0001) were associated with increased risk for cardiac perforation, whereas previous cardiac surgery (OR: 0.14; 95% CI: 0.07 to 0.26; p 0.0001) was associated with a lower risk for perforation. Patient risk factors for cardiac perforation were identical in the subset of patients in whom ICE was used (n = 76,134). A risk score was generated with the following point assignments: female sex (1 point); obesity (1 point); nonuse of ICE (5 points); and previous cardiac surgery (-6 points).Cardiac perforation is a rare complication of AF ablation; incidence has decreased over time. One of the strongest predictors of cardiac perforation in the contemporary era is a modifiable factor, use of intraprocedural ICE.

Objectives The goal of this study was to assess the utility of transvenous lead extraction for cardiovascular implantable electronic device (CIED) infection in patients with a left ventricular assist device (LVAD). Background The utility of transvenous lead extraction for the management CIED infection in patients with a durable LVAD has not been well described. Methods Clinical and outcomes data were collected retrospectively among patients who underwent lead extraction for CIED infection after LVAD implantation at Duke University Hospital. Results Overall, 27 patients (n = 6 HVAD; n = 15 HeartMate II; n = 6 Heartmate III) underwent lead extraction for infection. Median (interquartile range) time from LVAD implantation to infection was 6.1 (2.5, 14.9) months. Indications included endocarditis (n = 16), bacteremia (n = 9), and pocket infection (n = 2). Common pathogens were Staphylococcus aureus (n = 10), coagulase-negative staphylococci (n = 7), and Enterococcus faecalis (n = 3). Sixty-eight leads were removed, with a median lead implant time of 5.7 (3.6, 9.2) years. Laser sheaths were used in all procedures, with a median laser time of 35.0 (17.5, 85.5) s. Mechanical cutting tools were required in 11 (40.7%) and femoral snaring in 4 (14.8%). Complete procedural success was achieved in 25 (93.6%) patients and clinical success in 27 (100%). No procedural failures or major adverse events occurred. Twenty-one patients (77.8%) were alive without persistent endovascular infection 1 year after lead extraction. Most were treated with oral suppressive antibiotics after extraction (n = 23 [82.5%]). Persistent infection after extraction occurred in 4 patients and was associated with 50% 1-year mortality. Conclusions Transvenous lead extraction for LVAD-associated CIED infection can be performed safely with low rates of persistent infection and 1-year mortality.

Aims To determine the extent of shared decision-making (SDM), during selection of oral anticoagulant (OAC) and rhythm control treatments, in patients with newly diagnosed atrial fibrillation (AF). Methods and results We evaluated survey data from 1006 patients with new-onset AF enrolled at 56 US sites participating in the SATELLITE substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II). Patients completed surveys at enrolment and at 6-month follow-up. Patients were asked about who made their AF treatment decisions. Shared decision-making was classified as one that the patient felt was an autonomous decision or a shared decision with their healthcare provider (HCP). Approximately half of patients reported that their OAC treatment decisions were made entirely by their HCP. Compared with those reporting no SDM, patients reporting SDM for OAC were more often female (47.2% vs. 38.4%), while patients reporting SDM for rhythm control were more often male (62.2% vs. 57.6%). The most important factors cited by patients during decision-making for OAC were reducing stroke and bleeding risk, and their HCP’s recommendations. After adjustment, patients with self-reported understanding of OAC, and rhythm control options, had higher odds of having participated in SDM [odds ratio (OR) 2.54, confidence interval (CI): 1.75–3.68 and OR 2.36, CI: 1.50–3.71, both P ≤ 0.001, respectively]. Conclusion Shared decision-making is not widely implemented in contemporary AF practice. Patient understanding about available therapeutic options is associated with a more than a two-fold higher likelihood of SDM, and may be a potential target for future interventions.

Background Obstructive sleep apnea (OSA) is a known risk factor for atrial fibrillation (AF). However, it remains unclear whether OSA is independently associated with worse cardiovascular and neurological outcomes in patients with AF. Methods We used the ORBIT-AF I and ORBIT-AF II to conduct a retrospective cohort study of 22,760 patients with AF with and without OSA. Adjusted multivariable Cox proportional hazards models was used to determine whether OSA was associated with increased risk for major adverse cardiac and neurologic events (MACNEs) (cardiovascular death, myocardial infarction, stroke/transient ischemic attack/non–central nervous system embolism (stroke/SE), and new-onset heart failure], combined and individually. Results A total of 4,045 (17.8%) patients had OSA at baseline. Median follow-up time was 1.5 (interquartile range: 1-2.2) years, and 1,895 patients experienced a MACNE. OSA patients were younger (median [interquartile range] 68 [61-75] years vs 74 [66-81] years), were more likely male (70.7% vs 55.3%), and had increased body mass index (median 34.6 kg/m2 [29.8-40.2] vs 28.7 kg/m2 [25.2-33.0]). Those with OSA had a higher prevalence of concomitant comorbidities such as diabetes, chronic obstructive pulmonary disease, and heart failure. OSA patients had higher use of antithrombotic therapy. After adjustment, the presence of OSA was significantly associated with MACNE (hazard ratio: 1.16 [95% CI: 1.03-1.31], P = .011). OSA was also an independent risk factor for stroke/SE beyond the CHA2DS2-VASc risk factors (HR: 1.38 [95% CI 1.12-1.70], P = .003) but not cardiovascular death, myocardial infarction, new-onset heart failure, or major bleeding. Conclusions Among patients with AF, OSA is an independent risk factor for MACNE and, more specifically, stroke/SE.

COVID-19 is a syndrome that includes more than just isolated respiratory disease, as severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) also interacts with the cardiovascular, nervous, renal, and immune system at multiple levels, increasing morbidity in patients with underlying cardiometabolic conditions and inducing myocardial injury or dysfunction. Emerging evidence suggests that patients with the highest rate of morbidity and mortality following SARS-CoV2 infection have also developed a hyperinflammatory syndrome (also termed cytokine release syndrome). We lay out the potential contribution of a dysfunction in autonomic tone to the cytokine release syndrome and related multiorgan damage in COVID-19. We hypothesize that a cholinergic anti-inflammatory pathway could be targeted as a therapeutic avenue. Graphical Abstract .

Introduction Lead dysfunction can lead to serious consequences including failure to treat ventricular tachycardia or fibrillation (VT/VF). The incidence and mechanisms of lead dysfunction following left ventricular assist device (LVAD) implantation are not well-described. We sought to determine the incidence, mechanisms, timing, and complications of right ventricular lead dysfunction requiring revision following LVAD implantation. Methods Retrospective observational chart review of all LVAD recipients with pre-existing implantable cardioverter-defibrillator (ICD) from 2009 to 2018 was performed including device interrogation reports, laboratory and imaging data, procedural reports, and clinical outcomes. Results Among 583 patients with an ICD in situ undergoing LVAD implant, the median (interquartile range) age was 62.5 (15.7) years, 21% were female, and the types of LVADs included HeartWare HVAD (26%), HeartMate II (52%), and HeartMate III (22%). Right ventricular lead revision was performed in 38 patients (6.5%) at a median (25th, 75th) of 16.4 (3.6, 29.2) months following LVAD. Mechanisms of lead dysfunction included macrodislodgement (n = 4), surgical lead injury (n = 4), recall (n = 3), insulation failure (n = 8) or conductor fracture (n = 7), and alterations in the lead-myocardial interface (n = 12). Undersensing requiring revision occurred in 22 (58%) cases. Clinical sequelae of undersensing included failure to detect VT/VF (n = 4) and pacing-induced torsade de pointes (n = 1). Oversensing occurred in 12 (32%) and sequelae included inappropriate antitachycardia pacing ([ATP], n = 8), inappropriate ICD shock (n = 6), and ATP-induced VT (n = 1). Conclusion The incidence of right ventricular lead dysfunction following LVAD implantation is significant and has important clinical sequelae. Physicians should remain vigilant for lead dysfunction after LVAD surgery and test lead function before discharge.

Background Focal impulse and rotor modulation (FIRM) can cause slowing, organization, and occasionally termination of atrial fibrillation (AF), although results have been mixed. To further characterize changes in AF during rotor ablation, we quantified morphologic and temporal activation changes following FIRM. Methods In patients undergoing FIRM ablation for AF, we retrospectively analyzed coronary sinus bipolar EGMs before and after rotor ablation, including EGM activation frequency and regularity, dominant frequency (DF), and organizational index (OI). Changes in EGM waveform morphology were determined with recurrence quantification analysis (RQA) consisting of recurrence rate (RR), determinism (DET), laminarity (LAM), average diagonal line length (L), and trapping time (TT) using Wilcoxon signed‐rank testing. Results Overall, 36 rotors from 21 patients undergoing FIRM ablation were analyzed. All morphology RQA parameters demonstrated significant organization of atrial activation after rotor ablation (RR P = .03, DET P = .005, LAM P = .03, L P = .005, TT P = .009). The organizational index also showed a significant increase after rotor ablation (P = .01), and the change in OI correlated with changes in all morphology parameters. Of the rotors, 14/36 (39%) rotors showed organizational changes in all morphology parameters and OI, and an additional 5 rotors (19/36, 53%) showed organizational changes in 4 of 5 morphology parameters and OI. Conclusions Coronary sinus EGM waveform morphologies and activation patterns are significantly altered after FIRM ablation even when there is no fibrillatory slowing. RQA morphology analysis and organizational index may impart important information regarding underlying AF organization and may be useful in quantifying the acute response to ablation., We quantified changes in the morphologic and temporal activation patterns in left atrial electrograms before and after focal source/rotor ablation using FIRM. In our analysis, we found that coronary sinus electrogram waveform morphologies and activation patterns are significantly altered after FIRM ablation even when no fibrillatory rate slowing is clinically evident.

Background: In observational studies, case reports, and animal studies, amiodarone has been associated with incident cancer. Objective: The purpose of this study was to examine whether a dose–response relationship between amiodarone use and the risk of cancer could be ascertained in a large nationwide study cohort. Methods: Using nationwide registers, we included all Danish patients with atrial fibrillation (AF) treated with amiodarone from 1996 to 2014. Exposure was defined both by categories and as a continuous variable of the cumulative defined daily doses (cDDDs) of amiodarone. The associations between amiodarone cDDD and incident cancer, as well as organ-specific types of cancer (skin, liver, lung), were estimated using multivariable Cox regression models and reported as hazard ratios (HR) with 95% confidence intervals (CI) and using cubic restricted spline plots. Results: We included 18,503 patients with a median follow-up time of 8.1 years (interquartile range [IQR] 4.3–12.4). Median age was 70 years (IQR 63–77). A total of 2974 individuals developed cancer during follow-up. We found no association between increasing amiodarone exposure (cDDD 181–400 and cDDD >400) and the hazard of incident cancer (HR 0.95; 95% CI 0.87–1.04; and HR 1.01; 95% CI 0.92–1.10) with reference to patients with cDDD

Background Atrial fibrillation (AF) is common in patients with end-stage renal disease (ESRD). The impact of oral anticoagulation (OAC) in ESRD patients is uncertain. Objectives The purpose of this study was to describe patterns of OAC use in ESRD patients with AF and their associations with cardiovascular outcomes. Methods Using Medicare fee-for-service 5% claims data from 2007 to 2013, we analyzed treatment and outcomes in a cohort of patients with ESRD and AF. Prescription drug benefit information was used to determine the timing of OAC therapy. Cox proportional hazards modeling was used to compare outcomes including death, all-cause stroke, ischemic stroke, hemorrhagic stroke, and bleeding hospitalizations in ESRD patients treated with or without OAC. Results The cohort included 8,410 patients with AF and ESRD. A total of 3,043 (36.2%) patients were treated with OAC at some time during the study period. Propensity scores used to match 1,519 patients with AF and ESRD on OAC with 3,018 ESRD patients without OAC. Treatment with OAC was not associated with hospitalization for stroke (hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.23 to 1.35; p = 0.97) or death (HR: 1.02; 95% CI: 0.94 to 1.10; p = 0.62). OAC was associated with an increased risk of hospitalization for bleeding (HR: 1.26; 95% CI: 1.09 to 1.46; p = 0.0017) and intracranial hemorrhage (HR: 1.30; 95% CI: 1.07 to 1.59; p = 0.0094). Conclusions OAC utilization was low in patients with AF and ESRD. We found no association between OAC use and reduced risk of stroke or death. OAC use was associated with increased risks of hospitalization for bleeding or intracranial hemorrhage. Alternative stroke prevention strategies are needed in patients with ESRD and AF.

Catheter ablation has brought major advances in the management of patients with atrial fibrillation (AF). As evidenced by multiple randomized trials, AF catheter ablation can reduce the risk of recurrent AF and improve quality of life. In some studies, AF ablation significantly reduced cardiovascular hospitalizations. Despite the existing data on AF catheter ablation, numerous knowledge gaps remain concerning this intervention. This report is based on a recent virtual workshop convened by the National Heart, Lung, and Blood Institute to identify key research opportunities in AF ablation. We outline knowledge gaps related to emerging technologies, the relationship between cardiac structure and function and the success of AF ablation in patient subgroups in whom clinical benefit from ablation varies, and potential platforms to advance clinical research in this area. This report also considers the potential value and challenges of a sham ablation randomized trial. Prioritized research opportunities are identified and highlighted to empower relevant stakeholders to collaborate in designing and conducting effective, cost-efficient, and transformative research to optimize the use and outcomes of AF ablation.

Background Catheter ablation is an important rhythm control therapy in patients with atrial fibrillation (AF) with concomitant heart failure (HF). The objective of this study was to assess the comparative efficacy of AF ablation patients with ischemic vs nonischemic heart failure. Methods We conducted a retrospective, observational cohort study of patients with HF who underwent AF ablation. Outcomes were compared based on HF etiology and included in‐hospital events, symptoms (Mayo AF Symptom Inventory [MAFSI]), and functional status (New York Heart Association class) and freedom from atrial arrhythmias at 12 months. Results Among 242 patients (n = 70 [29%] ischemic, n = 172 [71%] nonischemic), patients with nonischemic cardiomyopathy were younger (mean age 64 ± 11.5 vs 69 ± 9.1, P = .002), more often female (36% vs 17%, P = .004), and had higher mean left‐ventricular ejection fraction (47% vs 42%, P = .0007). There were no significant differences in periprocedural characteristics, including mean procedure time (243 ± 74.2 vs 259 ± 81.8 minutes, P = .1) and nonleft atrial ablation (17% vs 20%, P = .6). All‐cause adverse events were similar in each group (15% vs 17%, P = .7). NYHA and MAFSI scores improved significantly at follow‐up and did not differ according to HF etiology (P = .5; P = .10‐1.00 after Bonferroni correction). There were no significant differences in freedom from recurrent atrial arrhythmia at 12‐months between ischemic (74%) and nonischemic patients (78%): adjusted RR 0.63, 95% confidence interval 0.33‐1.19. Conclusions Catheter ablation in patients with AF and concomitant heart failure leads to significant improvements in functional and symptom status without significant differences between patients with ischemic vs nonischemic HF etiology., Catheter ablation is an important rhythm control therapy in patients with atrial fibrillation (AF) with concomitant heart failure (HF). The objective of this study was to assess the comparative efficacy of AF ablation patients with ischemic versus nonischemic heart failure. We found that catheter ablation in patients with AF and concomitant heart failure leads to significant improvements in functional and symptom status without significant differences between patients with ischemic versus nonischemic HF etiology.

Amiodarone is the most effective antiarrhythmic drug (AAD) for atrial fibrillation (AF), but it has a high incidence of adverse effects.Using the ORBIT AF registry, patients with AF on amiodarone at enrollment, prescribed amiodarone during follow-up, or never on amiodarone were analyzed for the proportion treated with a guideline-based indication for amiodarone, the variability in amiodarone use across sites, and the outcomes (mortality, hospitalization, and stroke) among patients treated with amiodarone. Hierarchical logistic regression modeling with site-specific random intercepts compared rates of amiodarone use across 170 sites. A logistic regression model for propensity to receive amiodarone created a propensity-matched cohort. Cox proportional hazards modeling, stratified by matched pairs evaluated the association between amiodarone and outcomes.Among 6,987 AF patients, 867 (12%) were on amiodarone at baseline and 451 (6%) started on incident amiodarone during the 3-year follow-up. Use of amiodarone varied among sites from 3% in the lowest tertile to 21% in the highest (p0.0001). Among those treated, 32% had documented contraindications to other AADs or had failed another AAD in the past. Mortality, cardiovascular hospitalization, and stroke were similar among matched patients on and not on amiodarone at baseline, while incident amiodarone use in matched patients was associated with higher all-cause mortality (adjusted HR 2.06, 95% CI 1.35-3.16).Use of amiodarone among AF patients in community practice is highly variable. More than 2 out of 3 patients treated with amiodarone appeared to be eligible for a different AAD.

Objectives This study reports on the performance of a leadless ventricular pacemaker with automated, enhanced accelerometer-based algorithms that provide atrioventricular (AV) synchronous ...

Background Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described. Methods We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression. Results Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of “all eligible” GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]). Conclusions In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.

This collaborative statement from the International Society for Holter and Noninvasive Electrocardiology/Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society describes the current status of mobile health ("mHealth") technologies in arrhythmia management. The range of digital medical tools and heart rhythm disorders that they may be applied to and clinical decisions that may be enabled are discussed. The facilitation of comorbidity and lifestyle management (increasingly recognized to play a role in heart rhythm disorders) and patient self-management are novel aspects of mHealth. The promises of predictive analytics but also operational challenges in embedding mHealth into routine clinical care are explored.

Background Wait times for catheter ablation in patients with symptomatic atrial fibrillation (AF) may influence clinical outcomes. Objective This study examined the relationship between the duration from AF diagnosis to ablation, or diagnosis-to-ablation time (DAT), on the clinical response to catheter ablation in a large nationwide cohort of patients. Methods We identified patients with new atrial fibrillation (AF) who underwent catheter ablation between January 2014 and December 2017 using the IBM MarketScan databases. Cox proportional hazard models were used to estimate the strength of the association between DAT and the outcomes of AF recurrence and hospitalization at one year post-ablation. Results Among 11,143 AF patients who underwent ablation, the median age was 59 years, 31% were female and the median CHA2DS2-VASc score was 2. Median DAT was 5.5 (2.6, 13.1) months. At 1-year post-ablation, 10.0% (N=1,116) developed recurrent AF. For each year increase in DAT, the risk of AF recurrence increased by 20% after adjustment for baseline comorbidities and medications (hazard ratio (HR) 1.20, 95% CI 1.11-1.30). A longer DAT was associated with an increased risk of hospitalization (HR 1.08 per DAT year, 95% CI 1.02-1.15). DAT was a stronger predictor of AF recurrence post-ablation than traditional clinical risk factors, including age, prior heart failure, or renal failure. Conclusions Increasing duration between AF diagnosis and catheter ablation is associated with higher AF recurrence rates and all-cause hospitalization. Our findings are consistent with a growing body of evidence supporting the benefits of prioritizing early restoration of sinus rhythm.

Procedural and clinical outcomes of patients undergoing extraction or removal of azygous coils are not well characterized.Evaluate outcomes in patients who undergo device extraction with an azygous coil in situ.Patients undergoing extraction with an azygous coil in situ between May 2015 and January 2021 were included in this retrospective single-center analysis. Outcomes included procedural success, use of laser and mechanical cutting tools during the procedure, procedural complications, and mortality.We identified 2 patients undergoing device extraction with an azygous coil in situ with a dwell time greater than 12 months. The patients were male, aged 73 and 83 years. Both had a history of hypertension, atrial fibrillation, heart failure (ejection fractions15% and 20%), and cardiomyopathy (nonischemic and ischemic), and presented with an infection (case 1 with a single-chamber ICD and Staphylococcus aureus bacteremia, case 2 with a cardiac resynchronization therapy defibrillator pocket infection). The mean dwell time of all 6 leads extracted was 6.43 years (range 1.33-12.63 years), and the 2 azygous coils had dwell times of 1.33 and 6.04 years. In case 1, the azygous coil was inferior to the cardiac silhouette, while in case 2 it was superior. A 14F laser sheath was employed to remove both azygous coils. Both extractions were a complete procedural success in which all leads were removed completely without intraoperative complications.These cases demonstrate the variable courses of azygous coils, provide proof of concept that they can be removed safely, and illustrate that azygous coils can be removed with the same techniques that are commonly used to remove other types of leads.

Multiple class I and class IIa recommendations exist related to surgical ablation (SA) of atrial fibrillation (AF) in patients undergoing cardiac surgery.Examine temporal trends and predictors of SA for AF in a large US healthcare system.We retrospectively analyzed data from the Society for Thoracic Surgery (STS) Adult Cardiac Surgery Database for 21 hospitals in the Providence St. Joseph Health system. All patients with preoperative AF who underwent isolated coronary artery bypass graft (CABG) surgery, isolated aortic valve replacement (AVR), AVR with CABG surgery (AVR+CABG), isolated mitral valve repair or replacement (MVRr), and MVRr with CABG surgery (MVRr+CABG) from July 1, 2014, to March 31, 2020 were included. Temporal trends in SA were evaluated using the Cochran-Armitage trends test. A multilevel logistic regression model was used to examine patient-, hospital-, and surgeon-level predictors of SA.Among 3124 patients with preoperative AF, 910 (29.1%) underwent SA. This was performed most often in those undergoing isolated MVRr (n = 324, 44.8%) or MVRr+CABG (n = 75, 35.2%). Rates of SA increased over time and were highly variable between hospitals. Years since graduation from medical school for the primary operator was one of the few predictors of SA: odds ratio (95% confidence interval) = 0.71 (0.56-0.90) for every 10-year increase. Annual surgical (both hospital and operator) and AF catheter ablation volumes were not predictive of SA.Wide variability in rates of SA for AF exist, underscoring the need for greater preoperative collaboration between cardiologists, electrophysiologists, and cardiac surgeons.

Aims To determine whether the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) integrated risk tool predicts mortality, non-haemorrhagic stroke/systemic embolism, and major bleeding for up to 2 years after new-onset AF and to assess how this risk tool performs compared with CHA2DS2-VASc and HAS-BLED. Methods and results Potential predictors of events included demographic and clinical characteristics, choice of treatment, and lifestyle factors. A Cox proportional hazards model was identified for each outcome by least absolute shrinkage and selection operator methods. Indices were evaluated in comparison with CHA2DS2-VASc and HAS-BLED risk predictors. Models were validated internally and externally in ORBIT-AF and Danish nationwide registries. Among the 52 080 patients enrolled in GARFIELD-AF, 52 032 had follow-up data. The GARFIELD-AF risk tool outperformed CHA2DS2-VASc for all-cause mortality in all cohorts. The GARFIELD-AF risk score was superior to CHA2DS2-VASc for non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in internal validation and in the Danish AF cohort. In very low- to low-risk patients [CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)], the GARFIELD-AF risk score offered strong discriminatory value for all the endpoints when compared to CHA2DS2-VASc and HAS-BLED. The GARFIELD-AF tool also included the effect of oral anticoagulation (OAC) therapy, thus allowing clinicians to compare the expected outcome of different anticoagulant treatment decisions [i.e. no OAC, non-vitamin K antagonist (VKA) oral anticoagulants, or VKAs]. Conclusions The GARFIELD-AF risk tool outperformed CHA2DS2-VASc at predicting death and non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in overall as well as in very low- to low-risk group patients with AF. Clinical trial registration URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF: NCT01090362, ORBIT-AF I: NCT01165710; ORBIT-AF II: NCT01701817.

Background: Whether the amount of atrial fibrillation (AF) patients experience conveys important prognostic information beyond that provided by the diagnosis of AF is uncertain. The study objective was to assess the dose-response relationship between device-detected AF burden and subsequent cardiovascular outcomes. Methods: Among patients with paroxysmal AF who underwent cardiac implantable electronic device implantation (2010–2016), Merlin.net remote-monitoring data were linked to Medicare claims to assess the magnitude and strength of the associations between device-based AF burden (defined as a daily percentage of time spent in AF or maximal AF episode duration ascertained at baseline over 30 days) and key cardiovascular outcomes. Results: Among 39 710 patients (mean age 77.1±8.7 years, 60.7% male, and a mean CHA 2 DS 2 -VASc score 4.9±1.3), all-cause mortality at 1-year increased with baseline AF burden: 8.54% with AF burden 0%, 8.9% with AF burden 0% to 5%, and 10.9% with AF burden 5% to 98% ( P Conclusions: In paroxysmal AF, there is a clinically relevant dose-response relationship between increasing AF burden and rates of adverse outcomes at 1- and 3-years, including increasing risks of cardiovascular hospitalization, ischemic stroke, and mortality.

BACKGROUND Early results from the Micra investigational trial and Micra Post-Approval Registry (PAR) demonstrated excellent safety and device performance; however, outcomes based on anticoagulation (AC) status at implant have not been evaluated. OBJECTIVE The purpose of this study was to report implant characteristics, perforation rate, and vascular-related events based on perioperative oral AC strategy in patients undergoing Micra implant. METHODS We compared procedure characteristics, major complications, and vascular events, including pericardial effusion, stratified by any adverse event (including major complications, minor complications, and observations) or major complication only according to AC status in the Micra PAR. RESULTS Among 1795 patients with AC status available, 585 were not on AC, 795 had AC interrupted, and 415 had AC continued during Micra implant. Non-AC patients tended to be younger, with less history of atrial fibrillation and chronic obstructive pulmonary disease, and more history of dialysis than interrupted and continued patients. The implant success rate was similar for all groups (99.1%-99.8%). Through 30 days postimplant, the overall major complication rate was 3.1% for the non-AC group, 2.6% for the interrupted group, and 1.5% for the continued group. The combined rate for any vascular or pericardial effusion adverse event did not differ significantly among AC strategies (6.5%, 4.8%, and 3.6%, respectively). CONCLUSION Implant of Micra seems to be safe and feasible regardless of an interrupted or continued periprocedural oral AC strategy, with no increased risk of perforation or vascular complications.

ObjectiveIn patients with newly diagnosed atrial fibrillation (AF), do baseline risk factors and stroke prevention strategies account for the geographically diverse outcomes.DesignGlobal Anticoagulant Registry in the FIELD-Atrial Fibrillation is a prospective multinational non-interventional registry of patients with newly diagnosed AF (n=52 018 patients).SettingInvestigator sites (n=1317) were representative of the care settings/locations in each of the 35 participating countries. Treatment decisions were all determined by the local responsible clinicians.ParticipantsThe patients (18 years and over) with newly diagnosed AF had at least 1 investigator-determined stroke risk factor and patients were not required to meet specific thresholds of risk score for anticoagulant treatment.Main outcomes and measuresObserved 1-year event rates and risk-standardised rates were derived.ResultsRates of death, non-haemorrhagic stroke/systemic embolism and major bleeding varied more than three-to-four fold across countries even after adjustment for baseline factors and antithrombotic treatments. Rates of anticoagulation and antithrombotic treatment varied widely. Patients from countries with the highest rates of cardiovascular mortality and stroke were among the least likely to receive oral anticoagulants. Beyond anticoagulant treatment, variations in the treatment of comorbidities and lifestyle factors may have contributed to the variations in outcomes. Countries with the lowest healthcare Access and Quality indices (India, Ukraine, Argentina, Brazil) had the highest risk-standardised mortality.ConclusionThe variability in outcomes across countries for patients with newly diagnosed AF is not accounted for by baseline characteristics and antithrombotic treatments. Residual mortality rates were correlated with Healthcare Access and Quality indices. The findings suggest the management of patients with AF needs to not only address guideline indicated and sustained anticoagulation, but also the treatment of comorbidities and lifestyle factors.Trial registration numberNCT01090362.

BACKGROUND Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation. METHODS In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35. FINDINGS Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. INTERPRETATION The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. FUNDING Bayer.

Background : Post-operative AF (POAF) is the most common complication following cardiac surgery, occurring in 30% to 60% of patients undergoing bypass and/or valve surgery. POAF is associated with longer intensive care unit/hospital stays, increased healthcare utilization, and increased morbidity and mortality. Injection of botulinum toxin type A into the epicardial fat pads resulted in reduction of AF in animal models, and in 2 clinical studies of cardiac surgery patients, without new safety observations. Methods : The objective of NOVA is to assess the use of AGN-151607 (botulinum toxin type A) for prevention of POAF in cardiac surgery patients. This randomized, multi-site, placebo-controlled trial will study one-time injections of AGN-151607 125 U (25 U / fat pad) and 250 U (50 U / fat pad) or placebo during cardiac surgery in ∼330 participants. Primary endpoint: % of patients with continuous AF ≥ 30 s. Secondary endpoints include several measures of AF frequency, duration, and burden. Additional endpoints include clinically important tachycardia during AF, time to AF termination, and healthcare utilization. Primary and secondary efficacy endpoints will be assessed using continuous ECG monitoring for 30 days following surgery. All patients will be followed for up to 1 year for safety. Conclusion : The NOVA Study will test the hypothesis that injections of AGN-151607 will reduce the incidence of POAF and associated resource utilization. If demonstrated to be safe and effective, the availability of a one-time therapy for the prevention of POAF would represent an important treatment option for patients undergoing cardiac surgery.

Background: Older adults with atrial fibrillation (AF) are often treated with the shortest possible duration of antiplatelet/anticoagulant therapy after myocardial infarction (MI) or percutaneous coronary intervention (PCI) due to concern for bleeding. However, the risk of recurrent MI or PCI prompting antiplatelet therapy extension is unknown in this population. Methods: Using the National Cardiovascular Data Registry linked to Medicare claims, we described the cumulative incidence of recurrent MI or PCI over a median of 7-year follow-up for patients ≥65 years old with AF discharged alive after acute MI between 2008 and 2017. We used pharmacy fill data to describe the proportion of patients filling prescriptions for both oral anticoagulants and P2Y 12 inhibitors for ≥50% of the indicated duration after MI or PCI. Results: Of 187 622 older patients discharged alive after MI, 50 539 (26.9%) had AF. Over a median of 7-year follow-up in patients with AF, the cumulative incidence was 14.5% for recurrent MI, 12.1% for PCI, 7.9% for stroke, and 9.5% for bleeding hospitalization. Among 7998 patients with AF and recurrent MI or PCI, 1668 (20.9%) had >1 MI or PCI during follow-up. Assuming each MI or PCI should be followed by 6 months of P2Y 12 inhibitor therapy, patients with AF who had a recurrent MI/PCI had a median estimated indication for antiplatelet/anticoagulant treatment of 287 days (194, 358), but filled both P2Y 12 inhibitor and oral anticoagulant for a median of 0 days (0, 21). In this cohort, 12.2% of patients filled prescriptions for both a P2Y 12 inhibitor and oral anticoagulant for ≥50% of the indicated duration. Conclusions: Older adults with AF and MI have high incidences of downstream recurrent MI or PCI requiring extended antiplatelet/anticoagulant therapy durations, yet many appear to be under-treated. These results highlight the need for better thrombosis prevention strategies in this group of patients.