Topic: Electrophysiology

Abstract

Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis.

Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
Background
Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown.
Objectives
This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis.
Methods
MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding.
Results
This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant.
Conclusions
This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:273-285
Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
J Am Coll Cardiol: 27 Jan 2020; 75:273-285 | PMID: 31976865
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Abstract

Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.

Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Aims
To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin.
Methods and results
We conducted a real-world nationwide retrospective cohort study using Taiwan\'s National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77-0.93; P < 0.001]. Sub-analyses revealed that each NOAC, namely dabigatran (aHR = 0.88, 95% CI = 0.78-0.99; P = 0.027), rivaroxaban (aHR = 0.81, 95% CI = 0.72-0.90; P < 0.001), and apixaban (aHR = 0.67, 95% CI = 0.52-0.87; P = 0.003), had a reduced fracture risk. Analyses including all eligible patients, without propensity score matching, generated similar results.
Conclusion
Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 31 Jan 2020; epub ahead of print
Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006423
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Abstract

Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study.

Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Aims
Atrial fibrillation (AF) confers higher risk of mortality and morbidity, but the long-term impact of physical activity (PA) and cardiorespiratory fitness (CRF) on outcomes in AF patients is unknown. We, therefore, examined the prospective associations of PA and estimated CRF (eCRF) with all-cause mortality, cardiovascular disease (CVD) mortality, morbidity and stroke in individuals with AF.
Methods and results
We followed 1117 AF patients from the HUNT3 study in 2006-08 until first occurrence of the outcomes or end of follow-up in November 2015. We used Cox proportional hazard regression to examine the prospective associations of self-reported PA and eCRF with the outcomes. Atrial fibrillation patients meeting PA guidelines had lower risk of all-cause [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.75] and CVD mortality (HR 0.54, 95% CI 0.34-0.86) compared with inactive patients. The respective HRs for CVD morbidity and stroke were 0.78 (95% CI 0.58-1.04) and 0.70 (95% CI 0.42-1.15). Each 1-metabolic equivalent task (MET) higher eCRF was associated with a lower risk of all-cause (HR 0.88, 95% CI 0.81-0.95), CVD mortality (HR 0.85, 95% CI 0.76-0.95), and morbidity (HR 0.88, 95% CI 0.82-0.95).
Conclusion
Higher PA and CRF are associated with lower long-term risk of CVD and all-cause mortality in individuals with AF. The findings support a role for regular PA and improved CRF in AF patients, in order to combat the elevated risk for mortality and morbidity.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 10 Feb 2020; epub ahead of print
Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Eur Heart J: 10 Feb 2020; epub ahead of print | PMID: 32047884
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Abstract

Alcohol Abstinence in Drinkers with Atrial Fibrillation.

Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
Background
Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear.
Methods
We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week \"blanking period\") and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up.
Results
Of 140 patients who underwent randomization (85% men; mean [±SD] age, 62±9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8±7.7 to 2.1±3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4±6.9 to 13.2±6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P = 0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P = 0.01).
Conclusions
Abstinence from alcohol reduced arrhythmia recurrences in regular drinkers with atrial fibrillation. (Funded by the Government of Victoria Operational Infrastructure Support Program and others; Australian New Zealand Clinical Trials Registry number, ACTRN12616000256471.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:20-28
Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
N Engl J Med: 01 Jan 2020; 382:20-28 | PMID: 31893513
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Abstract

Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Aims
As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings.
Methods and results
Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set.
Conclusion
Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 28 Jan 2020; epub ahead of print
Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Eur Heart J: 28 Jan 2020; epub ahead of print | PMID: 31995195
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Abstract

Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation.

Guo Y, Lane DA, Wang L, Zhang H, ... Lip GYH,
Background
Current management of patients with atrial fibrillation (AF) is limited by low detection of AF, non-adherence to guidelines, and lack of consideration of patients\' preferences, thus highlighting the need for a more holistic and integrated approach to AF management.
Objective
The objective of this study was to determine whether a mobile health (mHealth) technology-supported AF integrated management strategy would reduce AF-related adverse events, compared with usual care.
Methods
This is a cluster randomized trial of patients with AF older than 18 years of age who were enrolled in 40 cities in China. Recruitment began on June 1, 2018 and follow-up ended on August 16, 2019. Patients with AF were randomized to receive usual care, or integrated care based on a mobile AF Application (mAFA) incorporating the ABC (Atrial Fibrillation Better Care) Pathway: A, Avoid stroke; B, Better symptom management; and C, Cardiovascular and other comorbidity risk reduction. The primary composite outcome was a composite of stroke/thromboembolism, all-cause death, and rehospitalization. Rehospitalization alone was a secondary outcome. Cardiovascular events were assessed using Cox proportional hazard modeling after adjusting for baseline risk.
Results
There were 1,646 patients allocated to mAFA intervention (mean age, 67.0 years; 38.0% female) with mean follow-up of 262 days, whereas 1,678 patients were allocated to usual care (mean age, 70.0 years; 38.0% female) with mean follow-up of 291 days. Rates of the composite outcome of \'ischemic stroke/systemic thromboembolism, death, and rehospitalization\' were lower with the mAFA intervention compared with usual care (1.9% vs. 6.0%; hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.22 to 0.67; p < 0.001). Rates of rehospitalization were lower with the mAFA intervention (1.2% vs. 4.5%; HR: 0.32; 95% CI: 0.17 to 0.60; p < 0.001). Subgroup analyses by sex, age, AF type, risk score, and comorbidities demonstrated consistently lower HRs for the composite outcome for patients receiving the mAFA intervention compared with usual care (all p < 0.05).
Conclusions
An integrated care approach to holistic AF care, supported by mHealth technology, reduces the risks of rehospitalization and clinical adverse events. (Mobile Health [mHealth] technology integrating atrial fibrillation screening and ABC management approach trial; ChiCTR-OOC-17014138).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534
Guo Y, Lane DA, Wang L, Zhang H, ... Lip GYH,
J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534 | PMID: 32241367
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Abstract

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Pallisgaard JL, Hansen ML
Aims
Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer.
Methods and results
A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively.
Conclusion
In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 06 Feb 2020; epub ahead of print
Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Pallisgaard JL, Hansen ML
Eur Heart J: 06 Feb 2020; epub ahead of print | PMID: 32030399
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Abstract

Oral Anticoagulation and Cardiovascular Outcomes in Patients With Atrial Fibrillation and End-Stage Renal Disease.

Pokorney SD, Black-Maier E, Hellkamp AS, Friedman DJ, ... Peterson ED, Piccini JP
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.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Mar 2020; 75:1299-1308
Pokorney SD, Black-Maier E, Hellkamp AS, Friedman DJ, ... Peterson ED, Piccini JP
J Am Coll Cardiol: 23 Mar 2020; 75:1299-1308 | PMID: 32192656
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Abstract

Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus: Insights from the DECLARE-TIMI 58 Trial.

Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD

Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes and its related comorbidities including hypertension, obesity, and heart failure (HF). SGLT2i have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2DM). We therefore investigated whether SGLT2i may also reduce the risk of AF/AFL.DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin versus placebo in 17160 patients with T2DM and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1,116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using the MedDRA Preferred Terms (\"atrial fibrillation\", \"atrial flutter\").Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events, 7.8 versus 9.6 events per 1000 patient-years, hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, No AF/AFL: HR 0.81, 95% CI 0.67-0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.83, 95% CI 0.66-1.04) versus MRF (HR 0.78, 95% CI 0.62-0.99; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55-1.11, No HF: HR 0.81, 95% CI 0.68-0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, HbA1c, body mass index, blood pressure, or eGFR (all P-INT>0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, P=0.005).Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with T2DM. This effect was consistent regardless of the patients\' prior history of AF, ASCVD, or HF.URL: https://clinicaltrials.gov Unique Identifier: NCT01730534.



Circulation: 26 Jan 2020; epub ahead of print
Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983236
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Abstract

Atrial Fibrillation: JACC Council Perspectives.

Chung MK, Refaat M, Shen WK, Kutyifa V, ... Lakkireddy DR,

Atrial fibrillation (AF) is an increasingly prevalent arrhythmia; its pathophysiology and progression are well studied. Stroke and bleeding risk models have been created and validated. Decision tools for stroke prophylaxis are evolving, with better options at hand. Utilization of various diagnostic tools offer insight into AF burden and thromboembolic risk. Rate control, rhythm control, and stroke prophylaxis are the cornerstones of AF therapy. Although antiarrhythmic drugs are useful, AF ablation has become a primary therapeutic strategy. Pulmonary vein isolation is the cornerstone of AF ablation, and methods to improve ablation safety and efficacy continue to progress. Ablation of nonpulmonary vein sites is increasingly being recognized as an important strategy for treating nonparoxysmal AF. Several new ablation techniques and technologies and stroke prophylaxis are being explored. This is a contemporary review on the prevalence, pathophysiology, risk prediction, prophylaxis, treatment options, new insights for optimizing treatment outcomes, and emerging concepts of AF.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 13 Apr 2020; 75:1689-1713
Chung MK, Refaat M, Shen WK, Kutyifa V, ... Lakkireddy DR,
J Am Coll Cardiol: 13 Apr 2020; 75:1689-1713 | PMID: 32273035
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Abstract

Integrated management of atrial fibrillation in primary care: results of the ALL-IN cluster randomized trial.

van den Dries CJ, van Doorn S, Rutten FH, Oudega R, ... Hoes AW, Geersing GJ
Aims
To evaluate whether integrated care for atrial fibrillation (AF) can be safely orchestrated in primary care.
Methods and results
The ALL-IN trial was a cluster randomized, open-label, pragmatic non-inferiority trial performed in primary care practices in the Netherlands. We randomized 26 practices: 15 to the integrated care intervention and 11 to usual care. The integrated care intervention consisted of (i) quarterly AF check-ups by trained nurses in primary care, also focusing on possibly interfering comorbidities, (ii) monitoring of anticoagulation therapy in primary care, and finally (iii) easy-access availability of consultations from cardiologists and anticoagulation clinics. The primary endpoint was all-cause mortality during 2 years of follow-up. In the intervention arm, 527 out of 941 eligible AF patients aged ≥65 years provided informed consent to undergo the intervention. These 527 patients were compared with 713 AF patients in the control arm receiving usual care. Median age was 77 (interquartile range 72-83) years. The all-cause mortality rate was 3.5 per 100 patient-years in the intervention arm vs. 6.7 per 100 patient-years in the control arm [adjusted hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.37-0.82]. For non-cardiovascular mortality, the adjusted HR was 0.47 (95% CI 0.27-0.82). For other adverse events, no statistically significant differences were observed.
Conclusion
In this cluster randomized trial, integrated care for elderly AF patients in primary care showed a 45% reduction in all-cause mortality when compared with usual care.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 28 Feb 2020; epub ahead of print
van den Dries CJ, van Doorn S, Rutten FH, Oudega R, ... Hoes AW, Geersing GJ
Eur Heart J: 28 Feb 2020; epub ahead of print | PMID: 32112556
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Abstract

Simultaneous Endocardial and Epicardial Delineation of 3D Reentrant Ventricular Tachycardia.

Tung R, Raiman M, Liao H, Zhan X, ... Xue Y, Wu S
Background
Mechanisms of scar-related ventricular tachycardia (VT) are largely based on computational and animal models that portray a 2-dimensional view.
Objectives
The authors sought to delineate the human VT circuit with a 3-dimensional perspective from recordings obtained by simultaneous endocardial and epicardial mapping.
Methods
High-resolution mapping was performed during 97 procedures in 89 patients with structural heart disease. Circuits were characterized by systematic isochronal analysis to estimate the dimensions of the isthmus and extent of the exit region recorded on both myocardial surfaces.
Results
A total of 151 VT morphologies were mapped, of which 83 underwent simultaneous endocardial and epicardial mapping; 17% of circuits activated in a 2-dimensional plane, restricted to 1 myocardial surface. Three-dimensional activation patterns with nonuniform transmural propagation were observed in 61% of circuits with only 4% showing transmurally uniform activation, and 18% exhibiting focal activation patterns consistent with mid-myocardial reentry. The dimensions of the central isthmus were 17 mm (12 to 28 mm) × 10 mm (9 to 19 mm) with 55% exhibiting a minimal dimension of <1.5 cm. QRS activation was transmural in 63% and located 43 mm (34 to 52 mm) from the central isthmus. On the basis of 6 proposed definitions for epicardial VT, the prevalence of an epicardial circuit ranged from 21% to 80% in ischemic cardiomyopathy and 28% to 77% in nonischemic cardiomyopathy.
Conclusions
A 2D perspective oversimplifies the electrophysiological circuit responsible for reentrant human VT and simultaneous endocardial and epicardial mapping facilitates inferences about mid-myocardial activation. Intricate activation patterns are frequently observed on both myocardial surfaces, and the epicardium is functionally involved in the majority of circuits. Human reentry may exist within isthmus dimensions smaller than 1 cm, whereas QRS activation is often transmural and remote from the critical isthmus target. A 3-dimensional perspective of the VT circuit may enhance the precision of ablative therapy and may support a greater role for adjunctive strategies and technology to address arrhythmogenic tissue harbored in the mid-myocardium and subepicardium.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Mar 2020; 75:884-897
Tung R, Raiman M, Liao H, Zhan X, ... Xue Y, Wu S
J Am Coll Cardiol: 02 Mar 2020; 75:884-897 | PMID: 32130924
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Abstract

Comparison of Atrial Remodeling Caused by Sustained Atrial Flutter Versus Atrial Fibrillation.

Guichard JB, Naud P, Xiong F, Qi X, ... Da Costa A, Nattel S
Background
Atrial flutter (AFL) and atrial fibrillation (AF) are associated with AF-promoting atrial remodeling, but no experimental studies have addressed remodeling with sustained AFL.
Objectives
This study aimed to define the atrial remodeling caused by sustained atrial flutter (AFL) and/or atrial fibrillation (AF).
Methods
Intercaval radiofrequency lesions created a substrate for sustained isthmus-dependent AFL, confirmed by endocavity mapping. Four groups (6 dogs per group) were followed for 3 weeks: sustained AFL; sustained AF (600 beats/min atrial tachypacing); AF superimposed on an AFL substrate (AF+AFLs); sinus rhythm (SR) with an AFL substrate (SR+AFLs; control group). All dogs had atrioventricular-node ablation and ventricular pacemakers at 80 beats/min to control ventricular rate.
Results
Monitoring confirmed spontaneous AFL maintenance >99% of the time in dogs with AFL. At terminal open-chest study, left-atrial (LA) effective refractory period was reduced similarly with AFL, AF+AFLs and AF, while AF vulnerability to extrastimuli increased in parallel. Induced AF duration increased significantly in AF+AFLs and AF, but not AFL. Dogs with AF+AFLs had shorter cycle lengths and substantial irregularity versus dogs with AFL. LA volume increased in AF+AFLs and AF, but not dogs with AFL, versus SR+AFLs. Optical mapping showed significant conduction slowing in AF+AFLs and AF but not AFL, paralleling atrial fibrosis and collagen-gene upregulation. Left-ventricular function did not change in any group. Transcriptomic analysis revealed substantial dysregulation of inflammatory and extracellular matrix-signaling pathways with AF and AF+ALs but not AFL.
Conclusions
Sustained AFL causes atrial repolarization changes like those in AF but, unlike AF or AF+AFLs, does not induce structural remodeling. These results provide novel insights into AFL-induced remodeling and suggest that early intervention may be important to prevent irreversible fibrosis when AF intervenes in a patient with AFL.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jul 2020; 76:374-388
Guichard JB, Naud P, Xiong F, Qi X, ... Da Costa A, Nattel S
J Am Coll Cardiol: 27 Jul 2020; 76:374-388 | PMID: 32703507
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Abstract

A Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights from Patients at Risk Long-Term Monitored with Implantable Loop Recorder.

Diederichsen SZ, Haugan KJ, Kronborg C, Graff C, ... Brandes A, Svendsen JH

Stroke is an increasing health problem world-wide. Atrial fibrillation (AF) is a major risk factor for stroke, and the attention towards AF screening is rising, while new monitoring-technologies emerge. We aimed to evaluate the performance of a large panel of screening strategies and to assess population characteristics associated with diagnostic yield.Persons with stroke risk factors but without AF were recruited from the general population to undergo screening with implantable loop recorder (ILR). New-onset AF lasting ≥6 min was adjudicated by senior cardiologists. After continuous monitoring for >3 years complete day-to-day heart rhythm datasets were reconstructed for every participant, including exact time of onset and termination of all AF episodes. Random sampling was applied to assess the sensitivity and negative predictive value (NPV) of screening with various simulated screening strategies compared to ILR. The yield across strategies and population subgroups was compared using non-parametric tests.The rhythm datasets comprised 590 participants enduring a total of 659,758 days of continuous monitoring and 20,110 AF episodes. In this data, a single 10-sec ECG yielded a sensitivity (and NPV) of 1.5% (66%) for AF detection, increasing to 8.3% (67%) for twice-daily 30-sec ECGs during 14 days, and to 11% (68%), 13% (68%), 15% (69%), 21% (70%), and 34% (74%) for a single 24-h, 48-h, 72-h, 7-day, or 30-day continuous monitoring, respectively. AF detection further improved when subsequent screenings were performed, or when the same monitoring-duration was spread over several periods as compared to a single period (e.g. three 24-h monitorings vs. one 72-h monitoring), p<0.0001 for all comparisons. The sensitivity was consistently higher among participants with age ≥75 years, male sex, CHADS2 score >2, or brain natriuretic peptide (NT-proBNP) ≥40 pmol/L, and among participants with underlying ≥24-h AF episodes compared to shorter AF, p<0.0001 for all screening strategies.In screening for AF among participants with stroke risk factors, the diagnostic yield increased with duration, dispersion and number of screenings, although all strategies had low yield compared to ILR. The sensitivity was higher among participants who were older, males, or had higher NT-proBNP.URL: https://clinicaltrials.gov Unique Identifier: NCT02036450.



Circulation: 01 Mar 2020; epub ahead of print
Diederichsen SZ, Haugan KJ, Kronborg C, Graff C, ... Brandes A, Svendsen JH
Circulation: 01 Mar 2020; epub ahead of print | PMID: 32114796
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Abstract

Apixaban versus Warfarin in Patients with Atrial Fibrillation and Advanced Chronic Kidney Disease.

Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, ... Wallentin L, Granger CB

Compared with the general population, patients with advanced chronic kidney disease (CKD) have a >10-fold higher burden of atrial fibrillation (AF). Limited data are available guiding the use of non-vitamin K antagonist oral anticoagulants in this population.We compared the safety of apixaban with warfarin in 269 patients with AF and advanced CKD (defined as creatinine clearance [CrCl] 25-30 mL/min) enrolled in ARISTOTLE. Cox proportional models were used to estimate hazard ratios (HRs) for major bleeding and major or clinically relevant non-major (CRNM) bleeding. We characterized the pharmacokinetic profile of apixaban by assessing differences in exposure using non-linear mixed effects models.Among patients with CrCl 25-30 mL/min, apixaban caused less major bleeding (HR 0.34, 95% confidence interval [CI] 0.14-0.80) and major or CRNM bleeding (HR 0.35, 95% CI 0.17-0.72) compared with warfarin. Patients with CrCl 25-30 mL/min randomized to apixaban demonstrated a trend towards lower rates of major bleeding when compared with those with CrCl >30 mL/min (p interaction=0.08) and major or CRNM bleeding (p interaction=0.05). Median daily steady state areas under the curve (AUCss) for apixaban 5 mg twice daily were 5512 ng/mL*hr and 3406 ng/mL*hr for patients with CrCl 25-30 mL/min or >30 mL/min, respectively. For apixaban 2.5 mg twice daily, the median exposure was 2780 ng/mL*hr for patients with CrCl 25-30 mL/min. The AUC values for patients with CrCl 25-30 mL/min fell completely within the ranges demonstrated for patients with CrCl >30 mL/min.Among patients with AF and CrCl 25-30 mL/min, apixaban caused less bleeding than warfarin, with even greater reductions in bleeding than in patients with CrCl >30 mL/min. We observed substantial overlap in the range of exposure to apixaban 5 mg twice daily for patients with or without advanced CKD, supporting conventional dosing in patients with CrCl 25-30 mL/min. Randomized controlled studies evaluating the safety and efficacy of apixaban are urgently needed in patients with advanced CKD, including those receiving dialysis.URL: https://ClinicalTrials.gov Unique Identifier: NCT00412984.



Circulation: 11 Mar 2020; epub ahead of print
Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, ... Wallentin L, Granger CB
Circulation: 11 Mar 2020; epub ahead of print | PMID: 32160801
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Abstract

Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A Scientific Statement From the American Heart Association.

Chung MK, Eckhardt LL, Chen LY, Ahmed HM, ... Trulock KM,

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with substantial morbidity, mortality, and healthcare use. Great strides have been made in stroke prevention and rhythm control strategies, yet reducing the incidence of AF has been slowed by the increasing incidence and prevalence of AF risk factors, including obesity, physical inactivity, sleep apnea, diabetes mellitus, hypertension, and other modifiable lifestyle-related factors. Fortunately, many of these AF drivers are potentially reversible, and emerging evidence supports that addressing these modifiable risks may be effective for primary and secondary AF prevention. A structured, protocol-driven multidisciplinary approach to integrate lifestyle and risk factor management as an integral part of AF management may help in the prevention and treatment of AF. However, this aspect of AF management is currently underrecognized, underused, and understudied. The purpose of this American Heart Association scientific statement is to review the association of modifiable risk factors with AF and the effects of risk factor intervention. Implementation strategies, care pathways, and educational links for achieving impactful weight reduction, increased physical activity, and risk factor modification are included. Implications for clinical practice, gaps in knowledge, and future directions for the research community are highlighted.



Circulation: 08 Mar 2020:CIR0000000000000748; epub ahead of print
Chung MK, Eckhardt LL, Chen LY, Ahmed HM, ... Trulock KM,
Circulation: 08 Mar 2020:CIR0000000000000748; epub ahead of print | PMID: 32148086
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Abstract

Dexmedetomidine for reduction of atrial fibrillation and delirium after cardiac surgery (DECADE): a randomised placebo-controlled trial.

Turan A, Duncan A, Leung S, Karimi N, ... Sessler DI,
Background
Atrial fibrillation and delirium are common consequences of cardiac surgery. Dexmedetomidine has unique properties as sedative agent and might reduce the risk of each complication. This study coprimarily aimed to establish whether dexmedetomidine reduces the incidence of new-onset atrial fibrillation and the incidence of delirium.
Methods
A randomised, placebo-controlled trial was done at six academic hospitals in the USA. Patients who had had cardiac surgery with cardiopulmonary bypass were enrolled. Patients were randomly assigned 1:1, stratified by site, to dexmedetomidine or normal saline placebo. Randomisation was computer generated with random permuted block size 2 and 4, and allocation was concealed by a web-based system. Patients, caregivers, and evaluators were all masked to treatment. The study drug was prepared by the pharmacy or an otherwise uninvolved research associate so that investigators and clinicians were fully masked to allocation. Participants were given either dexmedetomidine infusion or saline placebo started before the surgical incision at a rate of 0·1 μg/kg per h then increased to 0·2 μg/kg per h at the end of bypass, and postoperatively increased to 0·4 μg/kg per h, which was maintained until 24 h. The coprimary outcomes were atrial fibrillation and delirium occurring between intensive care unit admission and the earlier of postoperative day 5 or hospital discharge. All analyses were intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT02004613 and is closed.
Findings
798 patients of 3357 screened were enrolled from April 17, 2013, to Dec 6, 2018. The trial was stopped per protocol after the last designated interim analysis. Among 798 patients randomly assigned, 794 were analysed, with 400 assigned to dexmedetomidine and 398 assigned to placebo. The incidence of atrial fibrillation was 121 (30%) in 397 patients given dexmedetomidine and 134 (34%) in 395 patients given placebo, a difference that was not significant: relative risk 0·90 (97·8% CI 0·72, 1·15; p=0·34). The incidence of delirium was non-significantly increased from 12% in patients given placebo to 17% in those given dexmedetomidine: 1·48 (97·8% CI 0·99-2·23). Safety outcomes were clinically important bradycardia (requiring treatment) and hypotension, myocardial infarction, stroke, surgical site infection, pulmonary embolism, deep venous thrombosis, and death. 21 (5%) of 394 patients given dexmedetomidine and 8 (2%) of 396 patients given placebo, had a serious adverse event as determined by clinicians. 1 (<1%) of 391 patients given dexmedetomidine and 1 (<1%) of 387 patients given placebo died.
Interpretation
Dexmedetomidine infusion, initiated at anaesthetic induction and continued for 24 h, did not decrease postoperative atrial arrhythmias or delirium in patients recovering from cardiac surgery. Dexmedetomidine should not be infused to reduce atrial fibrillation or delirium in patients having cardiac surgery.
Funding
Hospira Pharmaceuticals.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 17 Jul 2020; 396:177-185
Turan A, Duncan A, Leung S, Karimi N, ... Sessler DI,
Lancet: 17 Jul 2020; 396:177-185 | PMID: 32682483
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Abstract

Attenuation of Oxidative Injury with Targeted Expression of NOX2 shRNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium: A Novel Gene Therapy Approach to Atrial Fibrillation.

Yoo S, Pfenniger A, Hoffman J, Zhang W, ... Aistrup GL, Arora R

Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal as they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury, by causing upregulation of a constitutively active form of acetylcholine-dependent K current () - called- is an important mechanism underlying not only the genesis but also the perpetuation of electrical remodeling in the , fibrillating atrium.To understand the mechanism by which oxidative injury promotes the genesis and/or maintenance of AF, we performed targeted injection of NOX2 shRNA (followed by electroporation to facilitate gene delivery) in atria of normal dogs followed by rapid atrial pacing. We used in-vivo high density electrical mapping, isolation of atrial myocytes, whole-cell patch clamping, in-vitro tachypacing of atrial myocytes, lucigenin chemiluminescence assay, immunoblotting, real-time PCR, immunohistochemistry and Masson\'s trichrome staining.First, we demonstrate that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through induction of NOX2 and generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electrical remodeling in AF by upregulatingby a mechanism involving frequency-dependent activation of protein kinase C epsilon (PKC). The time to onset of non-sustained AF increased by more than 5-fold in NOX2 shRNA treated dogs. Furthermore, animals treated with NOX2 shRNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, at least in part due to attenuation of . Attenuated membrane translocation of PKC appeared to be a likely molecular mechanism underlying this beneficial electrophysiological remodeling.NOX2 oxidative injury: a) underlies onset as well as maintenance of electrical remodeling in AF, and b) can be successfully prevented with a novel, gene-based approach. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.



Circulation: 19 Jul 2020; epub ahead of print
Yoo S, Pfenniger A, Hoffman J, Zhang W, ... Aistrup GL, Arora R
Circulation: 19 Jul 2020; epub ahead of print | PMID: 32686471
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Abstract

Loss of SPEG Inhibitory Phosphorylation of RyR2 Promotes Atrial Fibrillation.

Campbell HM, Quick AP, Abu-Taha I, Chiang DY, ... Dobrev D, Wehrens XHT

Enhanced diastolic calcium (Ca) release via ryanodine receptor type-2 (RyR2) has been implicated in atrial fibrillation (AF) promotion. Diastolic sarcoplasmic reticulum (SR) Ca leak is caused by increased RyR2 phosphorylation by protein kinase A (PKA) or Ca/calmodulin-dependent kinase-II (CaMKII) phosphorylation, or less dephosphorylation by protein phosphatases. However, considerable controversy remains regarding the molecular mechanisms underlying altered RyR2 function in AF. We thus sought to determine the role of \'striated muscle preferentially expressed protein kinase\' (SPEG), a novel regulator of RyR2 phosphorylation, in AF pathogenesis.Western blotting was performed with right atrial biopsies from paroxysmal (p)AF patients. SPEG atrial knock-out (aKO) mice were generated using adeno-associated virus 9 (AAV9). In mice, AF inducibility was determined using intracardiac programmed electrical stimulation (PES), and diastolic Ca leak in atrial cardiomyocytes was assessed using confocal Ca imaging. Phospho-proteomics studies and western blotting were used to measure RyR2 phosphorylation. In order to test the effects of RyR2-S2367 phosphorylation, knock-in mice with an inactivated S2367 phosphorylation site (S2367A) and a constitutively activated S2367 residue (S2367D) were generated using CRISPR-Cas9.Western blotting revealed decreased SPEG protein levels in atrial biopsies from pAF patients in comparison to patients in sinus rhythm. SPEG aKO mice exhibited increased susceptibility to pacing-induced AF by PES and enhanced Ca spark frequency in atrial cardiomyocytes with Ca imaging, establishing a causal role for decreased SPEG in AF pathogenesis. Phospho-proteomics in hearts from SPEG cardiomyocyte knock-out mice identified RyR2-S2367 as a novel kinase substrate of SPEG. Additionally, western blotting demonstrated that RyR2-S2367 phosphorylation was also decreased in pAF patients. RyR2-S2367A mice exhibited an increased susceptibility to pacing-induced AF as well as aberrant atrial SR Ca leak. In contrast, RyR2-S2367D mice were resistant to pacing-induced AF.Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2-mediated SR Ca-release. Reduced SPEG levels and RyR2-S2367 phosphorylation typified patients with pAF. Studies in S2367 knock-in mouse models showed a causal relationship between reduced S2367 phosphorylation and AF susceptibility. Thus, modulating SPEG activity and phosphorylation levels of the novel S2367 site on RyR2 may represent a novel target for AF treatment.



Circulation: 19 Jul 2020; epub ahead of print
Campbell HM, Quick AP, Abu-Taha I, Chiang DY, ... Dobrev D, Wehrens XHT
Circulation: 19 Jul 2020; epub ahead of print | PMID: 32683896
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Abstract

Pulsed Field Ablation in Patients With Persistent Atrial Fibrillation.

Reddy VY, Anic A, Koruth J, Petru J, ... Kawamura I, Neuzil P
Background
Unlike for paroxysmal atrial fibrillation (AF), pulmonary vein isolation (PVI) alone is considered insufficient for many patients with persistent AF. Adjunctive ablation of the left atrial posterior wall (LAPW) may improve outcomes, but is limited by both the difficulty of achieving lesion durability and concerns of damage to the esophagus-situated behind the LAPW.
Objectives
This study sought to assess the safety and lesion durability of pulsed field ablation (PFA) for both PVI and LAPW ablation in persistent AF.
Methods
PersAFOne is a single-arm study evaluating biphasic, bipolar PFA using a multispline catheter for PVI and LAPW ablation under intracardiac echocardiographic guidance. A focal PFA catheter was used for cavotricuspid isthmus ablation. No esophageal protection strategy was used. Invasive remapping was mandated at 2 to 3 months to assess lesion durability.
Results
In 25 patients, acute PVI (96 of 96 pulmonary veins [PVs]; mean ablation time: 22 min; interquartile range [IQR]: 15 to 29 min) and LAPW ablation (24 of 24 patients; median ablation time: 10 min; IQR: 6 to 13 min) were 100% acutely successful with the multispline PFA catheter alone. Using the focal PFA catheter, acute cavotricuspid isthmus block was achieved in 13 of 13 patients (median: 9 min; IQR: 6 to 12 min). The median total procedure time was 125 min (IQR: 108 to 166 min) (including a median of 28 min [IQR: 25 to 33 min] for voltage mapping), with a median of 16 min (IQR: 12 to 23 min) fluoroscopy. Post-procedure esophagogastroduodenoscopy and repeat cardiac computed tomography revealed no mucosal lesions or PV narrowing, respectively. Invasive remapping demonstrated durable isolation (defined by entrance block) in 82 of 85 PVs (96%) and 21 of 21 LAPWs (100%) treated with the pentaspline catheter. In 3 patients, there was localized scar regression of the LAPW ablation, albeit without conduction breakthrough.
Conclusions
The unique safety profile of PFA potentiated efficient, safe, and durable PVI and LAPW ablation. This extends the potential role of PFA beyond paroxysmal to persistent forms of AF. (Pulsed Fields for Persistent Atrial Fibrillation [PersAFOne]; NCT04170621).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 31 Aug 2020; 76:1068-1080
Reddy VY, Anic A, Koruth J, Petru J, ... Kawamura I, Neuzil P
J Am Coll Cardiol: 31 Aug 2020; 76:1068-1080 | PMID: 32854842
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Abstract

Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.

Kirchhof P, Camm AJ, Goette A, Brandes A, ... Breithardt G,
Background
Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk.
Methods
In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation-related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated.
Results
In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P = 0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups.
Conclusions
Early rhythm-control therapy was associated with a lower risk of cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions. (Funded by the German Ministry of Education and Research and others; EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010-021258-20.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 Aug 2020; epub ahead of print
Kirchhof P, Camm AJ, Goette A, Brandes A, ... Breithardt G,
N Engl J Med: 28 Aug 2020; epub ahead of print | PMID: 32865375
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Abstract

Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

Okumura K, Akao M, Yoshida T, Kawata M, ... Yamashita T,
Background
Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding.
Methods
We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis.
Results
A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36).
Conclusions
In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Aug 2020; epub ahead of print
Okumura K, Akao M, Yoshida T, Kawata M, ... Yamashita T,
N Engl J Med: 29 Aug 2020; epub ahead of print | PMID: 32865374
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Abstract

Atrial Fibrillation and Dementia.

Bunch TJ

Atrial fibrillation is associated with multiple adverse comorbidities, including the development of dementia in patients with and without a history of stroke. Mechanistic models have been proposed to explain the association of AF and dementia. Alterations of brain perfusion from embolic events, bleeding, and rhythm-related hypoperfusion underlie many of these models. Multiple mediators such as oxidative injury, inflammatory and autoimmune mechanisms, and genetic predisposition also interplay in the disease association. There are potential therapeutic opportunities to reduce dementia risk, including early and effective use of anticoagulation and strategies to improve brain perfusion through rhythm and rate control approaches. Prospective trials are needed to evaluate these therapeutic opportunities that carefully measure cognitive function and dementia incidence.



Circulation: 17 Aug 2020; 142:618-620
Bunch TJ
Circulation: 17 Aug 2020; 142:618-620 | PMID: 32804567
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Abstract

Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study.

Fralick M, Colacci M, Schneeweiss S, Huybrechts KF, Lin KJ, Gagne JJ
Background
Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking.
Objective
To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation.
Design
New-user, active-comparator, retrospective cohort study.
Setting
A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019.
Patients
Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706).
Measurements
The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding.
Results
39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1).
Limitation
Unmeasured confounding, incomplete laboratory data.
Conclusion
In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban.
Primary funding source
Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women\'s Hospital.



Ann Intern Med: 09 Mar 2020; epub ahead of print
Fralick M, Colacci M, Schneeweiss S, Huybrechts KF, Lin KJ, Gagne JJ
Ann Intern Med: 09 Mar 2020; epub ahead of print | PMID: 32150751
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Abstract

Effect of Renal Denervation and Catheter Ablation vs Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension: The ERADICATE-AF Randomized Clinical Trial.

Steinberg JS, Shabanov V, Ponomarev D, Losik D, ... Pokushalov EA, Romanov AB
Importance
Renal denervation can reduce cardiac sympathetic activity that may result in an antiarrhythmic effect on atrial fibrillation.
Objective
To determine whether renal denervation when added to pulmonary vein isolation enhances long-term antiarrhythmic efficacy.
Design, setting, and participants
The Evaluate Renal Denervation in Addition to Catheter Ablation to Eliminate Atrial Fibrillation (ERADICATE-AF) trial was an investigator-initiated, multicenter, single-blind, randomized clinical trial conducted at 5 referral centers for catheter ablation of atrial fibrillation in the Russian Federation, Poland, and Germany. A total of 302 patients with hypertension despite taking at least 1 antihypertensive medication, paroxysmal atrial fibrillation, and plans for ablation were enrolled from April 2013 to March 2018. Follow-up concluded in March 2019.
Interventions
Patients were randomized to either pulmonary vein isolation alone (n = 148) or pulmonary vein isolation plus renal denervation (n = 154). Complete pulmonary vein isolation to v an end point of elimination of all pulmonary vein potentials; renal denervation using an irrigated-tip ablation catheter delivering radiofrequency energy to discrete sites in a spiral pattern from distal to proximal in both renal arteries.
Main outcomes and measures
The primary end point was freedom from atrial fibrillation, atrial flutter, or atrial tachycardia at 12 months. Secondary end points included procedural complications within 30 days and blood pressure control at 6 and 12 months.
Results
Of the 302 randomized patients (median age, 60 years [interquartile range, 55-65 years]; 182 men [60.3%]), 283 (93.7%) completed the trial. All successfully underwent their assigned procedures. Freedom from atrial fibrillation, flutter, or tachycardia at 12 months was observed in 84 of 148 (56.5%) of those undergoing pulmonary vein isolation alone and in 111 of 154 (72.1%) of those undergoing pulmonary vein isolation plus renal denervation (hazard ratio, 0.57; 95% CI, 0.38 to 0.85; P = .006). Of 5 prespecified secondary end points, 4 are reported and 3 differed between groups. Mean systolic blood pressure from baseline to 12 months decreased from 151 mm Hg to 147 mm Hg in the isolation-only group and from 150 mm Hg to 135 mm Hg in the renal denervation group (between-group difference, -13 mm Hg; 95% CI, -15 to -11 mm Hg; P < .001). Procedural complications occurred in 7 patients (4.7%) in the isolation-only group and 7 (4.5%) of the renal denervation group.
Conclusions and relevance
Among patients with paroxysmal atrial fibrillation and hypertension, renal denervation added to catheter ablation, compared with catheter ablation alone, significantly increased the likelihood of freedom from atrial fibrillation at 12 months. The lack of a formal sham-control renal denervation procedure should be considered in interpreting the results of this trial.
Trial registration
ClinicalTrials.gov Identifier: NCT01873352.



JAMA: 20 Jan 2020; 323:248-255
Steinberg JS, Shabanov V, Ponomarev D, Losik D, ... Pokushalov EA, Romanov AB
JAMA: 20 Jan 2020; 323:248-255 | PMID: 31961420
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Abstract

Mortality in Patients With Atrial Fibrillation Receiving Nonrecommended Doses of Direct Oral Anticoagulants.

Camm AJ, Cools F, Virdone S, Bassand JP, ... Kakkar AK,
Background
The recommended doses for direct oral anticoagulants (DOACs) to prevent stroke and systemic embolism (SE) in patients with atrial fibrillation (AF) are described in specific regulatory authority approvals.
Objectives
The impact of DOAC dosing, according to the recommended guidance on all-cause mortality, stroke/SE, and major bleeding, was assessed at 2-year follow-up in patients with newly diagnosed AF.
Methods
Of a total of 34,926 patients enrolled (2013 to 2016) in the prospective GARFIELD-AF (Global Anticoagulant Registry in the FIELD-AF), 10,426 patients received a DOAC.
Results
The majority of patients (72.9%) received recommended dosing, 23.2% were underdosed, and 3.8% were overdosed. Nonrecommended dosing (underdosage and overdosage combined) compared with recommended dosing was associated with a higher risk of all-cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.48); HR: 1.25 (95% CI: 1.04 to 1.50) for underdosing, and HR: 1.19 (95% CI: 0.83 to 1.71) for overdosing. The excess deaths were cardiovascular including heart failure and myocardial infarction. The risks of stroke/SE and major bleeding were not significantly different irrespective of the level of dosing, although underdosed patients had a significantly lower risk of bleeding. A nonsignificant trend to higher risks of stroke/SE (HR: 1.51; 95% CI: 0.79 to 2.91) and major bleeding (HR: 1.29; 95% CI: 0.59 to 2.78) was observed in patients with overdosing.
Conclusions
In GARFIELD-AF, most patients received the recommended DOAC doses according to country-specific guidelines. Prescription of nonrecommended doses was associated with an increased risk of death, mostly cardiovascular death, compared with patients on recommended doses, after adjusting for baseline factors. (Global Anticoagulant Registry in the Field-AF [GARFIELD-AF]; NCT01090362).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Sep 2020; 76:1425-1436
Camm AJ, Cools F, Virdone S, Bassand JP, ... Kakkar AK,
J Am Coll Cardiol: 21 Sep 2020; 76:1425-1436 | PMID: 32943160
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Abstract

Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation.

Wallentin L, Lindbäck J, Eriksson N, Hijazi Z, ... Oldgren J, Siegbahn A
Aims
The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability.
Methods and results
Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level.
Conclusions
Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 26 Sep 2020; epub ahead of print
Wallentin L, Lindbäck J, Eriksson N, Hijazi Z, ... Oldgren J, Siegbahn A
Eur Heart J: 26 Sep 2020; epub ahead of print | PMID: 32984892
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Abstract

Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study.

Kim D, Yang PS, Sung JH, Jang E, ... Lip GYH, Joung B
Aims
Accumulating evidence shows that atrial fibrillation (AF) is associated with an increased risk of dementia. Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving the quality of life. We investigated the association of catheter ablation for AF with the occurrence of dementia.
Methods and results
Using the Korean National Health Insurance Service database, among 194 928 adults with AF treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 January 2005 and 31 December 2015, we studied 9119 patients undergoing ablation and 17 978 patients managed with medical therapy. The time-at-risk was counted from the first medical therapy, and ablation was analysed as a time-varying exposure. Propensity score-matching was used to correct for differences between the groups. During a median follow-up of 52 months, compared with patients with medical therapy, ablated patients showed lower incidence and risk of overall dementia (8.1 and 5.6 per 1000 person-years, respectively; hazard ratio 0.73, 95% confidence interval 0.58-0.93). The associations between ablation and dementia risk were consistently observed after additionally censoring for incident stroke (hazard ratio 0.76, 95% confidence interval 0.61-0.95) and more pronounced in cases of ablation success whereas no significant differences observed in cases of ablation failure. Ablation was associated with lower risks of dementia subtypes including Alzheimer\'s disease and vascular dementia.
Conclusion
In this nationwide cohort of AF patients treated with catheter ablation or medical therapy, ablation was associated with decreased dementia risk. This relationship was evident after censoring for stroke and adjusting for clinical confounders.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 05 Oct 2020; epub ahead of print
Kim D, Yang PS, Sung JH, Jang E, ... Lip GYH, Joung B
Eur Heart J: 05 Oct 2020; epub ahead of print | PMID: 33022705
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Abstract

Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial.

Haldar S, Khan HR, Boyalla V, Kralj-Hans I, ... Wong T,
Aims
Long-standing persistent atrial fibrillation (LSPAF) is challenging to treat with suboptimal catheter ablation (CA) outcomes. Thoracoscopic surgical ablation (SA) has shown promising efficacy in atrial fibrillation (AF). This multicentre randomized controlled trial tested whether SA was superior to CA as the first interventional strategy in de novo LSPAF.
Methods and results
We randomized 120 LSPAF patients to SA or CA. All patients underwent predetermined lesion sets and implantable loop recorder insertion. Primary outcome was single procedure freedom from AF/atrial tachycardia (AT) ≥30 s without anti-arrhythmic drugs at 12 months. Secondary outcomes included clinical success (≥75% reduction in AF/AT burden); procedure-related serious adverse events; changes in patients\' symptoms and quality-of-life scores; and cost-effectiveness. At 12 months, freedom from AF/AT was recorded in 26% (14/54) of patients in SA vs. 28% (17/60) in the CA group [OR 1.128, 95% CI (0.46-2.83), P = 0.83]. Reduction in AF/AT burden ≥75% was recorded in 67% (36/54) vs. 77% (46/60) [OR 1.13, 95% CI (0.67-4.08), P = 0.3] in SA and CA groups, respectively. Procedure-related serious adverse events within 30 days of intervention were reported in 15% (8/55) of patients in SA vs. 10% (6/60) in CA, P = 0.46. One death was reported after SA. Improvements in AF symptoms were greater following CA. Over 12 months, SA was more expensive and provided fewer quality-adjusted life-years (QALYs) compared with CA (0.78 vs. 0.85, P = 0.02).
Conclusion
Single procedure thoracoscopic SA is not superior to CA in treating LSPAF. Catheter ablation provided greater improvements in symptoms and accrued significantly more QALYs during follow-up than SA.
Clinical trial registration
ISRCTN18250790 and ClinicalTrials.gov: NCT02755688.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 28 Aug 2020; epub ahead of print
Haldar S, Khan HR, Boyalla V, Kralj-Hans I, ... Wong T,
Eur Heart J: 28 Aug 2020; epub ahead of print | PMID: 32860414
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Abstract

Recurrence of Atrial Fibrillation After Catheter Ablation or Antiarrhythmic Drug Therapy in the CABANA Trial.

Poole JE, Bahnson TD, Monahan KH, Johnson G, ... Packer DL,
Background
The CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial randomized 2,204 patients with atrial fibrillation (AF) to catheter ablation or drug therapy. Analysis by intention-to-treat showed a nonsignificant 14% relative reduction in the primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest.
Objectives
The purpose of this study was to assess recurrence of AF in the CABANA trial.
Methods
The authors prospectively studied CABANA patients using a proprietary electrocardiogram recording monitor for symptom-activated and 24-h AF auto detection. The AF recurrence endpoint was any post-90-day blanking atrial tachyarrhythmias lasting 30 s or longer. Biannual 96-h Holter monitoring was used to assess AF burden. Patients who used the CABANA monitors and provided 90-day post-blanking recordings qualified for this analysis (n = 1,240; 56% of CABANA population). Treatment comparisons were performed using a modified intention-to-treat approach.
Results
Median age of the 1,240 patients was 68 years, 34.4% were women, and AF was paroxysmal in 43.0%. Over 60 months of follow-up, first recurrence of any symptomatic or asymptomatic AF (hazard ratio: 0.52; 95% confidence interval: 0.45 to 0.60; p < 0.001) or first symptomatic-only AF (hazard ratio: 0.49; 95% confidence interval: 0.39 to 0.61; p < 0.001) were both significantly reduced in the catheter ablation group. Baseline Holter AF burden in both treatment groups was 48%. At 12 months, AF burden in ablation patients averaged 6.3%, and in drug-therapy patients, 14.4%. AF burden was significantly less in catheter ablation compared with drug-therapy patients across the 5-year follow-up (p < 0.001). These findings were not sensitive to the baseline pattern of AF.
Conclusions
Catheter ablation was effective in reducing recurrence of any AF by 48% and symptomatic AF by 51% compared with drug therapy over 5 years of follow-up. Furthermore, AF burden was also significantly reduced in catheter ablation patients, regardless of their baseline AF type. (Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial [CABANA]; NCT00911508).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 29 Jun 2020; 75:3105-3118
Poole JE, Bahnson TD, Monahan KH, Johnson G, ... Packer DL,
J Am Coll Cardiol: 29 Jun 2020; 75:3105-3118 | PMID: 32586583
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Abstract

Left Atrial Appendage Closure Versus Direct Oral Anticoagulants in High-Risk Patients With Atrial Fibrillation.

Osmancik P, Herman D, Neuzil P, Hala P, ... Reddy VY,
Background
Percutaneous left atrial appendage closure (LAAC) is noninferior to vitamin K antagonists (VKAs) for preventing atrial fibrillation (AF)-related stroke. However, direct oral anticoagulants (DOACs) have an improved safety profile over VKAs, and their effect on cardiovascular and neurological outcomes relative to LAAC is unknown.
Objectives
This study sought to compare DOACs with LAAC in high-risk patients with AF.
Methods
Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation (PRAGUE-17) was a multicenter, randomized, noninferiority trial comparing LAAC with DOACs. Patients were eligible to be enrolled if they had nonvalvular AF; were indicated for oral anticoagulation (OAC); and had a history of bleeding requiring intervention or hospitalization, a history of a cardioembolic event while taking an OAC, and/or a CHADS-VASc of ≥3 and HAS-BLED of >2. Patients were randomized to receive LAAC or DOAC. The primary composite outcome was stroke, transient ischemic attack, systemic embolism, cardiovascular death, major or nonmajor clinically relevant bleeding, or procedure-/device-related complications. The primary analysis was by modified intention to treat.
Results
A high-risk patient cohort (CHADS-VASc: 4.7 ± 1.5) was randomized to receive LAAC (n = 201) or DOAC (n = 201). LAAC was successful in 181 of 201 (90.0%) patients. In the DOAC group, apixaban was most frequently used (192 of 201; 95.5%). At a median 19.9 months of follow-up, the annual rates of the primary outcome were 10.99% with LAAC and 13.42% with DOAC (subdistribution hazard ratio [sHR]: 0.84; 95% confidence interval [CI]: 0.53 to 1.31; p = 0.44; p = 0.004 for noninferiority). There were no differences between groups for the components of the composite endpoint: all-stroke/TIA (sHR: 1.00; 95% CI: 0.40 to 2.51), clinically significant bleeding (sHR: 0.81; 95% CI: 0.44 to 1.52), and cardiovascular death (sHR: 0.75; 95% CI: 0.34 to 1.62). Major LAAC-related complications occurred in 9 (4.5%) patients.
Conclusions
Among patients at high risk for stroke and increased risk of bleeding, LAAC was noninferior to DOAC in preventing major AF-related cardiovascular, neurological, and bleeding events. (Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation [PRAGUE-17]; NCT02426944).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 29 Jun 2020; 75:3122-3135
Osmancik P, Herman D, Neuzil P, Hala P, ... Reddy VY,
J Am Coll Cardiol: 29 Jun 2020; 75:3122-3135 | PMID: 32586585
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Abstract

New-onset atrial fibrillation: incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people.

Holt A, Gislason GH, Schou M, Zareini B, ... Torp-Pedersen C, Lamberts M
Aim
To determine the incidence, patient characteristics, and related events associated with new-onset atrial fibrillation (AF) during a national COVID-19 lockdown.
Methods and results
Using nationwide Danish registries, we included all patients, aged 18-90 years, receiving a new-onset AF diagnosis during the first 3 months of 2019 and 2020. The main comparison was between patients diagnosed during lockdown (12 March 12-1 April 2020) and patients diagnosed in the corresponding period 1 year previously. We found a lower incidence of new-onset AF during the 3 weeks of lockdown compared with the corresponding weeks in 2019 [incidence rate ratios with 95% confidence intervals (CIs) for the 3 weeks: 0.66 (0.56-0.78), 0.53 (0.45-0.64), and 0.41 (0.34-0.50)]. There was a 47% drop in total numbers (562 vs. 1053). Patients diagnosed during lockdown were younger and with a lower CHA2DS2-VASc score, while history of cancer, heart failure, and vascular disease were more prevalent. During lockdown, 30 (5.3%) patients with new-onset AF suffered an ischaemic stroke and 15 (2.7%) died, compared with 45 (4.3%) and 14 (1.3%) patients during the corresponding 2019 period, respectively. The adjusted odds ratio of a related event (ischaemic stroke or all-cause death) during lock-down compared with the corresponding weeks was 1.41 (95% CI 0.93-2.12).
Conclusions
Following a national lockdown in Denmark, a 47% drop in registered new-onset AF cases was observed. In the event of prolonged or subsequent lockdowns, the risk of undiagnosed AF patients developing complications could potentially translate into poorer outcomes in patients with AF during the COVID-19 pandemic.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 31 Dec 2019; 41:3072-3079
Holt A, Gislason GH, Schou M, Zareini B, ... Torp-Pedersen C, Lamberts M
Eur Heart J: 31 Dec 2019; 41:3072-3079 | PMID: 32578859
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Abstract

Early Initiation of Direct Oral Anticoagulants After Onset of Stroke and Short- and Long-Term Outcomes of Patients With Nonvalvular Atrial Fibrillation.

Mizoguchi T, Tanaka K, Toyoda K, Yoshimura S, ... Koga M,

Background and Purpose- We aimed to compare outcomes of ischemic stroke patients with nonvalvular atrial fibrillation between earlier and later initiation of direct oral anticoagulants (DOACs) after stroke onset. Methods- From data for 1192 nonvalvular atrial fibrillation patients with acute ischemic stroke or transient ischemic attack in a prospective, multicenter, observational study, patients who started DOACs during acute hospitalization were included and divided into 2 groups according to a median day of DOAC initiation after onset. Outcomes included stroke or systemic embolism, major bleeding, and death at 3 months, as well as those at 2 years. Results- DOACs were initiated during acute hospitalization in 499 patients in median 4 (interquartile range, 2-7) days after onset. Thus, 223 patients (median age, 74 [interquartile range, 68-81] years; 78 women) were assigned to the early group (≤3 days) and 276 patients (median age, 75 [interquartile range, 69-82] years; 101 women) to the late (≥4 days) group. The early group had lower baseline National Institutes of Health Stroke Scale score and smaller infarcts than the late group. The rate at which DOAC administration persisted at 2 years was 85.2% overall, excluding patients who died or were lost to follow-up. Multivariable Cox shared frailty models showed comparable hazards between the groups at 2 years for stroke or systemic embolism (hazard ratio, 0.86 [95% CI, 0.47-1.57]), major bleeding (hazard ratio, 1.39 [95% CI, 0.42-4.60]), and death (hazard ratio, 0.61 [95% CI, 0.28-1.33]). Outcome risks at 3 months also did not significantly differ between the groups. Conclusions- Risks for events including stroke or systemic embolism, major bleeding, and death were comparable whether DOACs were started within 3 days or from 4 days or more after the onset of nonvalvular atrial fibrillation-associated ischemic stroke or transient ischemic attack. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01581502.



Stroke: 21 Jan 2020:STROKEAHA119028118; epub ahead of print
Mizoguchi T, Tanaka K, Toyoda K, Yoshimura S, ... Koga M,
Stroke: 21 Jan 2020:STROKEAHA119028118; epub ahead of print | PMID: 31964290
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Abstract

Usefulness of Red Cells Distribution Width to Predict Worse Outcomes in Patients With Atrial Fibrillation.

Malavasi VL, Proietti M, Spagni S, Valenti AC, ... Lip GY, Boriani G

Red cells distribution width (RDW) is a measure of red cell size variability, but little is known about the relation between RDW and outcomes in atrial fibrillation (AF).The aims of our study were to evaluate the association between RDW values, AF patients\' profile and outcomes. Consecutive patients with ECG-confirmed AF were divided in 3 groups according to tertiles of RDW values (≤13.5%, 13.6% to 14.6%, >14.6%).We enrolled 457 patients, 61.9% males, median (interquartile range) age 74 (66 to 80). Both CHADS-VASc and HAS-BLED scores increased progressively according to RDW tertiles. During follow-up, there was an increased risk for all-cause death and the composite end point in the highest RDW tertile (p <0.001 for both outcomes). On multivariate Cox regression analysis, the highest RDW tertile was independently associated with all-cause death (hazard ratio [HR] 3.23, 95% confidence interval [CI] 1.04 to 10.00) and the composite end point (HR 2.04, 95% CI 1.12 to 3.70). RDW as a continuous variable was also independently associated with all cause death and the composite outcome (HR 1.16, 95% CI 1.02 to 1.31 and HR 1.16, 95% CI 1.05 to 1.27, respectively). In conclusion, in a real-life AF population, RDW is associated with clinical factors indicating a worse profile and is independently associated with increased risks of all-cause death and other clinical events.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Nov 2019; 124:1561-1567
Malavasi VL, Proietti M, Spagni S, Valenti AC, ... Lip GY, Boriani G
Am J Cardiol: 14 Nov 2019; 124:1561-1567 | PMID: 31521256
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Abstract

Ischemic Stroke and Bleeding: Clinical Benefit of Anticoagulation in Atrial Fibrillation After Intracerebral Hemorrhage.

Stanton RJ, Eckman MH, Woo D, Moomaw CJ, ... Flaherty ML, Kleindorfer DO

Background and Purpose- Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHADS-VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult. Methods- We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)-a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHADS-VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs. Results- Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs. Conclusions- Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH. Clinical trial registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00930280.



Stroke: 30 Jan 2020:STROKEAHA119027370; epub ahead of print
Stanton RJ, Eckman MH, Woo D, Moomaw CJ, ... Flaherty ML, Kleindorfer DO
Stroke: 30 Jan 2020:STROKEAHA119027370; epub ahead of print | PMID: 32000590
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Abstract

Atrial Fibrillation-Associated Ischemic Stroke Patients With Prior Anticoagulation Have Higher Risk for Recurrent Stroke.

Tanaka K, Koga M, Lee KJ, Kim BJ, ... Toyoda K,

Background and Purpose- Ischemic stroke associated with nonvalvular atrial fibrillation (NVAF) despite prior anticoagulation may indicate underlying problems that nullify the stroke-preventing effects of oral anticoagulants. We aimed to evaluate the risk for recurrent stroke in patients with NVAF with prior anticoagulation, compared with that in patients without prior anticoagulation. Methods- This study comprised pooled individual patient data on NVAF-associated acute ischemic stroke or transient ischemic attack from 2011 to 2014 arising from the Clinical Research Collaboration for Stroke in Korea (15 South Korean stroke centers) and the Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-NVAF registry (18 Japanese stroke centers). Data on 4841 eligible patients from the Clinical Research Collaboration for Stroke in Korea registry were pooled with data on all patients (n=1192) in the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NVAF registry. The primary outcome was recurrent ischemic stroke. The secondary outcomes were hemorrhagic stroke and all-cause death. Outcome events were captured up to 1 year after the index event. Results- Among the 6033 patients in the full cohort, 5645 patients were analyzed, of whom 1129 patients (20.0%) had received prior anticoagulation. Median age was 75 years (interquartile range, 69-81 years), and 2649 patients (46.9%) were women. Follow-up data of 4617 patient-years (median follow-up 365 days, interquartile range 335-365 days) were available. The cumulative incidence of recurrent ischemic stroke in patients with prior anticoagulation was 5.3% (60/1129), compared with the 2.9% (130/4516) incidence in patients without prior anticoagulation. The risk for recurrent ischemic stroke was higher in patients with prior anticoagulation than in those without (multivariable Cox shared-frailty model, hazard ratio 1.50 [95% CI, 1.02-2.21]). No significant differences in the risks for hemorrhagic stroke and mortality were seen between the 2 groups. Conclusions- The risk for recurrent ischemic stroke may be higher in NVAF-associated stroke patients with prior anticoagulation than in those without prior anticoagulation. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01581502.



Stroke: 25 Feb 2020:STROKEAHA119027275; epub ahead of print
Tanaka K, Koga M, Lee KJ, Kim BJ, ... Toyoda K,
Stroke: 25 Feb 2020:STROKEAHA119027275; epub ahead of print | PMID: 32098607
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Impact:
Abstract

Ibrutinib-Mediated Atrial Fibrillation Due to Inhibition of CSK.

Xiao L, Salem JE, Clauss S, Hanley A, ... Ellinor PT, Milan DJ

Ibrutinib is a Bruton\'s tyrosine kinase (BTK) inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF) which remains poorly understood.We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacologic experiments. The pharmacovigilance database, VigiBase was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.We demonstrate that treatment of mice with ibrutinib for four weeks results in inducible AF, left atrial enlargement, myocardial fibrosis and inflammation. This effect was reproduced in mice lacking BTK but not in mice treated with four-weeks of acalabrutinib, a more specific BTK inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving C-terminal src kinase (CSK) as the strongest candidate for ibrutinib induced AF. Cardiac specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in Vigibase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk vs non-Csk inhibitors, with a reporting odds-ratio of 8.0 [95% CI 7.3-8.7, p<0.0001].These data identify Csk inhibition as the mechanism by which ibrutinib leads to AF.URL: www.clinicaltrials.gov Unique Identifier: NCT03530215.



Circulation: 22 Oct 2020; epub ahead of print
Xiao L, Salem JE, Clauss S, Hanley A, ... Ellinor PT, Milan DJ
Circulation: 22 Oct 2020; epub ahead of print | PMID: 33092403
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Abstract

Heart Failure and Atrial Fibrillation Modify the Associations of Nocturnal Blood Pressure Dipping Pattern With Mortality in Hemodialysis Patients.

Mayer CC, Schmaderer C, Loutradis C, Matschkal J, ... Wassertheurer S, Sarafidis PA

Heart failure (HF), hypertension, and abnormal nocturnal blood pressure dipping are highly prevalent in hemodialysis patients. Atrial fibrillation (AF) and HF might be important mediators for the association of abnormal dipping patterns with worse prognosis. Thus, the aim of this study is to investigate the association of dipping with mortality in hemodialysis patients and to assess the influence of AF and HF. In total, 525 hemodialysis patients underwent 24-hour ambulatory blood pressure monitoring. All-cause and cardiovascular mortality served as end points. Patients were categorized according to their systolic dipping pattern (dipper, nondipper, and reverse dipper). Cox regression analysis was performed to determine the association between dipping pattern and study end points with dipping as reference. Subgroup analysis was performed for patients with and without AF or HF. In total, 185 patients with AF or HF and 340 patients without AF or HF were included. During a median follow-up of 37.8 months, 177 patients died; 81 from cardiovascular causes. Nondipping and reverse dipping were significantly associated with all-cause mortality in the whole cohort (nondipper: hazard ratio, 1.95 [1.22-3.14]; =0.006; reverse dipper: hazard ratio, 2.31 [1.42-3.76]; <0.001) and in patients without AF or HF (nondipper: hazard ratio, 2.78 [1.16-6.66]; =0.02; reverse dipper: hazard ratio, 4.48 [1.87-10.71]; <0.001) but not in patients with AF or HF. For cardiovascular mortality, associations were again significant in patients without AF or HF and in the whole cohort. The observed associations remained significant after adjustment for possible confounders. This study provides well-powered evidence for the association between abnormal dipping patterns and mortality in hemodialysis patients and suggests that HF or AF modifies this association.



Hypertension: 29 Sep 2020; 76:1231-1239
Mayer CC, Schmaderer C, Loutradis C, Matschkal J, ... Wassertheurer S, Sarafidis PA
Hypertension: 29 Sep 2020; 76:1231-1239 | PMID: 32862707
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Abstract

Genetics of height and risk of atrial fibrillation: A Mendelian randomization study.

Levin MG, Judy R, Gill D, Vujkovic M, ... Voight BF, Damrauer SM
Background
Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.
Methods and findings
In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.
Conclusions
In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.



PLoS Med: 29 Sep 2020; 17:e1003288
Levin MG, Judy R, Gill D, Vujkovic M, ... Voight BF, Damrauer SM
PLoS Med: 29 Sep 2020; 17:e1003288 | PMID: 33031386
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Abstract

Association Between the European Society of Cardiology/European Society of Hypertension Heart Rate Thresholds for Cardiovascular Risk and Neuroadrenergic Markers.

Grassi G, Quarti-Trevano F, Seravalle G, Dell\'Oro R, Facchetti R, Mancia G

The recent European Society of Cardiology/European Society of Hypertension hypertension guidelines identify resting heart rate (HR) values >80 bpm as predictors of cardiovascular risk, with the unproven assumption that this might reflect the presence of a sympathetic overdrive. In the present study, we tested this hypothesis throughout the use of direct and indirect sympathetic markers. In 193 untreated moderate essential hypertensives aged 50.4±0.6 years (mean±SEM), we measured clinic and ambulatory blood pressure and corresponding HR, venous plasma norepinephrine (high performance liquid chromatography), and muscle sympathetic nerve traffic (microneurography). We then subdivided the study population into 2 groups according to HR < or >80 bpm. Eighty-four patients displayed resting HR >80 bpm, which was this cutoff value in the remaining 109 patients, the 2 groups showing superimposable age, and sex distribution. Clinic and ambulatory blood pressure were similar in the 2 groups, whereas left ventricular mass index was significantly greater in the group with HR >80 bpm. Muscle sympathetic nerve traffic values were also significantly greater in this latter group (72.77±0.9 versus vs 36.83±1.3 bursts/min, <0.0001); this being the case also for norepinephrine (293.0±8.7 versus 254.1±8.9 pg/mL, <0.002). In the whole population, there was a significant direct relationship between muscle sympathetic nerve traffic, norepinephrine, left ventricular mass index, and HR values. Similar results were obtained when 24-hour HR values were analyzed. Thus patients with hypertension displaying HR >80 bpm are characterized by a marked sympathetic overdrive, particularly when direct adrenergic markers are used. This finding suggests that cardiac and peripheral sympathetic activation are involved in the increased cardiovascular risk detected in this group of patients.



Hypertension: 30 Jul 2020; 76:577-582
Grassi G, Quarti-Trevano F, Seravalle G, Dell'Oro R, Facchetti R, Mancia G
Hypertension: 30 Jul 2020; 76:577-582 | PMID: 32594806
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Abstract

Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice.

Zhang YL, Cao HJ, Han X, Teng F, ... Guo SB, Li HH

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2 immune cells markedly increased in Ang II-infused atria in a time-dependent manner. Moreover, Ang II-infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2 monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.



Hypertension: 30 Jul 2020; 76:381-392
Zhang YL, Cao HJ, Han X, Teng F, ... Guo SB, Li HH
Hypertension: 30 Jul 2020; 76:381-392 | PMID: 32639881
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Abstract

Trends in excess mortality associated with atrial fibrillation over 45 years (Framingham Heart Study): community based cohort study.

Vinter N, Huang Q, Fenger-Grøn M, Frost L, Benjamin EJ, Trinquart L
Objective
To assess temporal trends in the association between newly diagnosed atrial fibrillation and death.
Design
Community based cohort study.
Setting
Framingham Heart Study cohort, in 1972-85, 1986-2000, and 2001-15 (periods 1-3, respectively), in Framingham, MA, USA.
Participants
Participants with no atrial fibrillation, aged 45-95 in each time period, and identified with newly diagnosed atrial fibrillation (or atrial flutter) during each time period.
Main outcome measures
The main outcome was all cause mortality. Hazard ratios for the association between time varying atrial fibrillation and all cause mortality were calculated with adjustment for time varying confounding factors. The difference in restricted mean survival times, adjusted for confounders, between participants with atrial fibrillation and matched referents at 10 years after a diagnosis of atrial fibrillation was estimated. Meta-regression was used to test for linear trends in hazard ratios and restricted mean survival times over the different time periods.
Results
5671 participants were selected in time period 1, 6177 in period 2, and 6174 in period 3. Adjusted hazard ratios for all cause mortality between participants with and without atrial fibrillation were 1.9 (95% confidence interval 1.7 to 2.2) in time period 1, 1.4 (1.3 to 1.6) in period 2, and 1.7 (1.5 to 2.0) in period 3 (P=0.70). Ten years after diagnosis of atrial fibrillation, the adjusted difference in restricted mean survival times between participants with atrial fibrillation and matched referents decreased by 31%, from -2.9 years (95% confidence interval -3.2 to -2.5) in period 1, to -2.1 years (-2.4 to -1.8) in period 2, to -2.0 years (-2.3 to -1.7) in period 3 (P=0.03).
Conclusions
No evidence of a temporal trend in hazard ratios for the association between atrial fibrillation and all cause mortality was found. The mean number of life years lost to atrial fibrillation at 10 years had improved significantly, but a two year gap compared with individuals without atrial fibrillation still remained.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 10 Jan 2020; 370:m2724
Vinter N, Huang Q, Fenger-Grøn M, Frost L, Benjamin EJ, Trinquart L
BMJ: 10 Jan 2020; 370:m2724 | PMID: 32784208
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Abstract

Opportunistic screening for atrial fibrillation by clinical pharmacists in UK general practice during the influenza vaccination season: A cross-sectional feasibility study.

Savickas V, Stewart AJ, Rees-Roberts M, Short V, ... Mathie A, Veale EL
Background
Growing prevalence of atrial fibrillation (AF) in the ageing population and its associated life-changing health and resource implications have led to a need to improve its early detection. Primary care is an ideal place to screen for AF; however, this is limited by shortages in general practitioner (GP) resources. Recent increases in the number of clinical pharmacists within primary care makes them ideally placed to conduct AF screening. This study aimed to determine the feasibility of GP practice-based clinical pharmacists to screen the over-65s for AF, using digital technology and pulse palpation during the influenza vaccination season.
Methods and findings
Screening was conducted over two influenza vaccination seasons, 2017-2018 and 2018-2019, in four GP practices in Kent, United Kingdom. Pharmacists were trained by a cardiologist to pulse palpate, record, and interpret a single-lead ECG (SLECG). Eligible persons aged ≥65 years (y) attending an influenza vaccination clinic were offered a free heart rhythm check. Six hundred four participants were screened (median age 73 y, 42.7% male). Total prevalence of AF was 4.3%. All participants with AF qualified for anticoagulation and were more likely to be male (57.7%); be older; have an increased body mass index (BMI); and have a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, previous Stroke, Vascular disease, Age 65-74 years, Sex category) score ≥ 3. The sensitivity and specificity of clinical pharmacists diagnosing AF using pulse palpation was 76.9% (95% confidence interval [CI] 56.4-91.0) and 92.2% (95% CI 89.7-94.3), respectively. This rose to 88.5% (95% CI 69.9-97.6) and 97.2% (95% CI 95.5-98.4) with an SLECG. At follow-up, four participants (0.7%) were diagnosed with new AF and three (0.5%) were initiated on anticoagulation. Screening with SLECG also helped identify new non-AF cardiovascular diagnoses, such as left ventricular hypertrophy, in 28 participants (4.6%). The screening strategy was cost-effective in 71.8% and 64.3% of the estimates for SLECG or pulse palpation, respectively. Feedback from participants (422/604) was generally positive. Key limitations of the study were that the intervention did not reach individuals who did not attend the practice for an influenza vaccination and there was a limited representation of UK ethnic minority groups in the study cohort.
Conclusions
This study demonstrates that AF screening performed by GP practice-based pharmacists was feasible, economically viable, and positively endorsed by participants. Furthermore, diagnosis of AF by the clinical pharmacist using an SLECG was more sensitive and more specific than the use of pulse palpation alone. Future research should explore the key barriers preventing the adoption of national screening programmes.



PLoS Med: 30 Dec 2019; 17:e1003197
Savickas V, Stewart AJ, Rees-Roberts M, Short V, ... Mathie A, Veale EL
PLoS Med: 30 Dec 2019; 17:e1003197 | PMID: 32678820
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Abstract

Detection rate and treatment gap for atrial fibrillation identified through screening in community health centers in China (AF-CATCH): A prospective multicenter study.

Chen Y, Huang QF, Sheng CS, Zhang W, ... Freedman B, Wang JG
Background
Atrial fibrillation (AF) is underdiagnosed and especially undertreated in China. We aimed to investigate the prevalence of unknown and untreated AF in community residents (≥65 years old) and to determine whether an education intervention could improve oral anticoagulant (OAC) prescription.
Methods and findings
We performed a single-time point screening for AF with a handheld single-lead electrocardiography (ECG) in Chinese residents (≥65 years old) in 5 community health centers in Shanghai from April to September 2017. Disease education and advice on referral to specialist clinics for OAC treatment were provided to all patients with actionable AF (newly detected or undertreated known AF) at the time of screening, and education was reinforced at 1 month. Follow-up occurred at 12 months. In total, 4,531 participants were screened (response rate 94.7%, mean age 71.6 ± 6.3 years, 44% male). Overall AF prevalence was 4.0% (known AF 3.5% [n = 161], new AF 0.5% [n = 22]). The 183 patients with AF were older (p < 0.001), taller (p = 0.02), and more likely to be male (p = 0.01), and they had a higher prevalence of cardiovascular disease than those without AF (p < 0.001). In total, 85% (155/183) of patients were recommended for OAC treatment by the established guidelines (CHA2DS2-VASc ≥ 2 for men; ≥ 3 for women). OAC prescription rate for known AF was 20% (28/138), and actionable AF constituted 2.8% of all those screened. At the 12-month follow-up in 103 patients (81% complete), despite disease education and advice on specialist referral, only 17 attended specialist clinics, and 4 were prescribed OAC. Of those not attending specialist clinics, 71 chose instead to attend community health centers or secondary hospital clinics, with none prescribed OAC, and 15 had no review. Of the 17 patients with new AF and a class 1 recommendation for OAC, only 3 attended a specialist clinic, and none were prescribed OAC. Of the 28 AF patients taking OAC at baseline, OAC was no longer taken in 4. Ischemic stroke (n = 2) or death (n = 3) occurred in 5/126 (4%), with none receiving OAC. As screening was performed at a single time point, some paroxysmal AF cases may have been missed; thus, the rate of new AF may be underestimated.
Conclusions
We demonstrated a noticeable gap in AF detection and treatment in community-based elderly Chinese: actionable AF constituted a high proportion of those screened. Disease education and advice on specialist referral are insufficient to close the gap. Before more frequent or intensive screening for unknown AF could be recommended in China, greater efforts must be made to increase appropriate OAC therapy in known AF to prevent AF-related stroke.



PLoS Med: 30 Dec 2019; 17:e1003146
Chen Y, Huang QF, Sheng CS, Zhang W, ... Freedman B, Wang JG
PLoS Med: 30 Dec 2019; 17:e1003146 | PMID: 32673305
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Abstract

Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation: A Population-Based Cohort Study.

Lau WCY, Cheung CL, Man KKC, Chan EW, ... Lee ACH, Wong ICK
Background
It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF).
Objective
To compare the risk for osteoporotic fracture between anticoagulants.
Design
Population-based cohort study.
Setting
Territory-wide electronic health record database of the Hong Kong Hospital Authority.
Participants
Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018.
Measurements
Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs).
Results
There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]).
Limitation
Residual confounding is possible.
Conclusion
Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants.
Primary funding source
The University of Hong Kong and University College London Strategic Partnership Fund.



Ann Intern Med: 06 Jul 2020; 173:1-9
Lau WCY, Cheung CL, Man KKC, Chan EW, ... Lee ACH, Wong ICK
Ann Intern Med: 06 Jul 2020; 173:1-9 | PMID: 32423351
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Abstract

Effect of Intensive Blood Pressure Lowering on the Risk of Atrial Fibrillation.

Soliman EZ, Rahman AF, Zhang ZM, Rodriguez CJ, ... Ambrosius WT, Lewis CE

It remains uncertain whether intensive control of blood pressure (BP) results in a lower risk of atrial fibrillation (AF) in patients with hypertension. Using data from SPRINT (Systolic Blood Pressure Intervention Trial), which enrolled participants with hypertension at increased risk of cardiovascular disease, we examined whether intensive BP lowering (target systolic BP [SBP] <120 mm Hg), compared with standard BP lowering (target SBP<140 mm Hg), results in a lower risk of AF. This analysis included 8022 participants (4003 randomized to the intensive arm and 4019 to standard BP arm) who were free of AF at the time of enrollment and with available baseline and follow-up electrocardiographic data. AF was ascertained from standard 12-lead electrocardiograms recorded at biannual study examinations and an exit visit. During up to 5.2 years of follow-up and a total of 28 322 person-years, 206 incident AF cases occurred; 88 in the intensive BP-lowering arm and 118 in the standard BP-lowering arm. Intensive BP lowering was associated with a 26% lower risk of developing new AF (hazard ratio, 0.74 [95% CI, 0.56-0.98]; =0.037). This effect was consistent among prespecified subgroups of SPRINT participants stratified by age, sex, race, SBP tertiles, prior cardiovascular disease, and prior chronic kidney disease when interactions between treatment effect and these subgroups were assessed using Hommel adjustedvalues. In conclusion, intensive treatment to a target of SBP <120 mm Hg in patients with hypertension at high risk of cardiovascular disease has the potential to reduce the risk of AF. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.



Hypertension: 30 May 2020; 75:1491-1496
Soliman EZ, Rahman AF, Zhang ZM, Rodriguez CJ, ... Ambrosius WT, Lewis CE
Hypertension: 30 May 2020; 75:1491-1496 | PMID: 32362229
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Abstract

Incidence and Implications of Atrial Fibrillation/Flutter in Hypertension: Insights From the SPRINT Trial.

Parcha V, Patel N, Kalra R, Kim J, ... Arora G, Arora P

We evaluated the impact of intensive blood pressure control on the incidence of new-onset atrial fibrillation/flutter (AF) and the prognostic implications of preexisting and new-onset AF in SPRINT (Systolic Blood Pressure Intervention Trial) participants. New-onset AF was defined as occurrence of AF in 12-lead electrocardiograms after randomization in participants free of AF at baseline. Poisson regression modeling was used to calculate incident rates of new-onset AF. Multivariable-adjusted Cox proportional hazard models were used to evaluate the risk of adverse cardiovascular events (composite of myocardial infarction, non-myocardial infarction acute coronary syndrome, stroke, heart failure, or cardiovascular death). In 9327 participants, 8.45% had preexisting AF, and 1.65% had new-onset AF. The incidence of new-onset AF was 4.53 per 1000-person years, with similar rates in the standard and intensive treatment arms (4.95 versus 4.11 per 1000-person years; adjusted =0.14). Participants with preexisting AF (adjusted hazard ratio, 1.83 [95% CI, 1.46-2.31]; <0.001) and new-onset AF (adjusted hazard ratio, 2.45 [95% CI, 1.58-3.80]; <0.001) had a greater risk for development of adverse cardiovascular events compared with those with no AF. Participants with preexisting AF who achieved blood pressure <120/80 mm Hg at 3 months continued have a poor prognosis (adjusted hazard ratio, 1.88 [95% CI, 1.32-2.70]; =0.001) compared with those with no AF. Intensive blood pressure control does not diminish the incidence of new-onset AF in an older, high-risk, nondiabetic population. Both preexisting and new-onset AF have adverse prognostic implications. In participants with preexisting AF, residual cardiovascular risk is evident even with on-treatment blood pressure <120/80 mm Hg. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.



Hypertension: 30 May 2020; 75:1483-1490
Parcha V, Patel N, Kalra R, Kim J, ... Arora G, Arora P
Hypertension: 30 May 2020; 75:1483-1490 | PMID: 32362231
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Abstract

Validity of daily self-pulse palpation for atrial fibrillation screening in patients 65 years and older: A cross-sectional study.

Ghazal F, Theobald H, Rosenqvist M, Al-Khalili F
Background
The European Society of Cardiology guidelines recommend (Class IA) single-time-point screening for atrial fibrillation (AF) using pulse palpation. The role of pulse palpation for AF detection has not been validated against electrocardiogram (ECG) recordings. We aimed to study the validity of AF screening using self-pulse palpation compared with an ECG recording conducted at the same time using a handheld ECG 3 times a day for 2 weeks.
Methods and findings
In this cross-sectional screening study, patients 65 years of age and older attending 4 primary care centers (PCCs) outside Stockholm County were invited to take part in AF screening from July 2017 to December 2018. Patients were included irrespective of their reason for visiting the PCC. Handheld intermittent ECGs 3 times per day were offered to patients without AF for a period of 2 weeks, and patients were instructed in how to take their own pulse at the same time. A total of 1,010 patients (mean age 73 years, 61% female, with an average CHA2DS2-VASc score 2.9) participated in the study, and 27 (2.7%, 95% CI 1.8%-3.9%) new cases of AF were detected. Anticoagulants (ACs) could be initiated in 26 (96%, 95% CI 81%-100%) of these cases. A total of 53,782 simultaneous ECG recordings and pulse measurements were registered. AF was verified in 311 ECG recordings, of which the pulse was palpated as irregular in 77 recordings (25%, 95% CI 20%-30% sensitivity per measurement occasion). Of the 27 AF cases, 15 cases felt an irregular pulse on at least one occasion (56%, 95% CI 35%-75% sensitivity per individual). 187 individuals without AF felt an irregular pulse on at least one occasion. The specificity per measurement occasion and per individual was (98%, 95% CI 98%-98%) and (81%, 95% CI 78%-83%), respectively.
Conclusions
AF screening using self-pulse palpation 3 times daily for 2 weeks has lower sensitivity compared with simultaneous intermittent ECG. Thus, it may be better to screen for AF using intermittent ECG without stepwise screening using pulse palpation. A limitation of this model could be the reduced availability of handheld ECG recorders in primary care centers.



PLoS Med: 30 Dec 2019; 17:e1003063
Ghazal F, Theobald H, Rosenqvist M, Al-Khalili F
PLoS Med: 30 Dec 2019; 17:e1003063 | PMID: 32231369
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Abstract

Blood Pressure Control and Dementia Risk in Midlife Patients With Atrial Fibrillation.

Kim D, Yang PS, Jang E, Tae Yu H, ... Lip GYH, Joung B

Atrial fibrillation (AF) is associated with increased risk of cognitive impairment and dementia, even with no overt stroke. Hypertension has been a potentially modifiable risk factor for dementia, especially in midlife (<70 years) individuals. We aimed to investigate the associations of blood pressure (BP) and hypertension burden with dementia risk among midlife AF patients. From the Korean National Health Insurance Service database, we enrolled 171 228 incident AF patients aged 50 to 69 years with no prior dementia from 2005 to 2016. During a mean of 6.6 years of follow-up, 9909 patients received a first-time diagnosis of dementia. U-shaped relationships were noted between systolic or diastolic BP and dementia risk: A 10 mm Hg increase or decrease in systolic BP starting from 120 mm Hg was associated with 4.4% (95% CI, 2.7%-6.0%) and 4.6% (95% CI, 0.1%-8.2%) higher dementia risk, respectively. An increase or decrease in diastolic BP starting from 80 mm Hg also increased dementia risk. In subtype analyses, Alzheimer disease increases with BP decrease whereas vascular dementia increases according to BP increase. When BP changes over time were accounted for in time-updated models, BP of 120 to 129/80 to 84 mm Hg was associated with the lowest dementia risk. Increasing hypertension burden (the proportion of days with increased BP during follow-up) was associated with higher dementia risk (hazard ratio, 1.10 per 10% increase [95% CI, 1.08-1.12]). Among midlife AF patients, there were a U-shaped association of BP and a log-linear association of hypertension burden with dementia risk. Minimizing the burden of hypertension in AF patients might help to prevent dementia.



Hypertension: 29 Apr 2020; 75:1296-1304
Kim D, Yang PS, Jang E, Tae Yu H, ... Lip GYH, Joung B
Hypertension: 29 Apr 2020; 75:1296-1304 | PMID: 32172620
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Abstract

Opportunistic screening versus usual care for detection of atrial fibrillation in primary care: cluster randomised controlled trial.

Uittenbogaart SB, Verbiest-van Gurp N, Lucassen WAM, Winkens B, ... van Weert HCPM, Stoffers HEJH
Objective
To investigate whether opportunistic screening in primary care increases the detection of atrial fibrillation compared with usual care.
Design
Cluster randomised controlled trial.
Setting
47 intention-to-screen and 49 usual care primary care practices in the Netherlands, not blinded for allocation; the study was carried out from September 2015 to August 2018.
Participants
In each practice, a fixed sample of 200 eligible patients, aged 65 or older, with no known history of atrial fibrillation in the electronic medical record system, were randomly selected. In the intention-to-screen group, 9218 patients eligible for screening were included, 55.0% women, mean age 75.2 years. In the usual care group, 9526 patients were eligible for screening, 54.3% women, mean age 75.0 years.
Interventions
Opportunistic screening (that is, screening in patients visiting their general practice) consisted of three index tests: pulse palpation, electronic blood pressure measurement with an atrial fibrillation algorithm, and electrocardiography (ECG) with a handheld single lead electrocardiographic device. The reference standard was 12 lead ECG, performed in patients with at least one positive index test and in a sample of patients (10%) with three negative tests. If 12 lead ECG showed no atrial fibrillation, patients were invited for more screening by continuous monitoring with a Holter electrocardiograph for two weeks.
Main outcome measures
Difference in the detection rate of newly diagnosed atrial fibrillation over one year in intention-to-screen versus usual care practices.
Results
Follow-up was complete for 8874 patients in the intention-to-screen practices and for 9102 patients in the usual care practices. 144 (1.62%) new diagnoses of atrial fibrillation in the intention-to-screen group versus 139 (1.53%) in the usual care group were found (adjusted odds ratio 1.06 (95% confidence interval 0.84 to 1.35)). Of 9218 eligible patients in the intention-to-screen group, 4106 (44.5%) participated in the screening protocol. In these patients, 12 lead ECG detected newly diagnosed atrial fibrillation in 26 patients (0.63%). In the 266 patients who continued with Holter monitoring, four more diagnoses of atrial fibrillation were found.
Conclusions
Opportunistic screening for atrial fibrillation in primary care patients, aged 65 and over, did not increase the detection rate of atrial fibrillation, which implies that opportunistic screening for atrial fibrillation is not useful in this setting.
Trial registration
Netherlands Trial Register No NL4776 (old NTR4914).

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 15 Jan 2020; 370:m3208
Uittenbogaart SB, Verbiest-van Gurp N, Lucassen WAM, Winkens B, ... van Weert HCPM, Stoffers HEJH
BMJ: 15 Jan 2020; 370:m3208 | PMID: 32938633
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Abstract

Blood Pressure Variability and Incidence of New-Onset Atrial Fibrillation: A Nationwide Population-Based Study.

Lee SR, Choi YJ, Choi EK, Han KD, ... Oh S, Lip GYH

Blood pressure variability is a well-known risk factor for cardiovascular disease, but its association with atrial fibrillation (AF) is uncertain. We aimed to evaluate the association between visit-to-visit blood pressure variability and incident AF. This population-based cohort study used database from the Health Screening Cohort, which contained a complete set of medical claims and a biannual health checkup information of the Koran population. A total of 8 063 922 individuals who had at least 3 health checkups with blood pressure measurement between 2004 and 2010 were collected after excluding subjects with preexisting AF. Blood pressure variability was defined as variability independence of the mean and was divided into 4 quartiles. During a mean follow-up of 6.8 years, 140 086 subjects were newly diagnosed with AF. The highest blood pressure variability (fourth quartile) was associated with an increased risk of AF (hazard ratio, 95% CI; systolic blood pressure: 1.06, 1.05-1.08; diastolic blood pressure: 1.07, 1.05-1.08) compared with the lowest (first quartile). Among subjects in the fourth quartile in both systolic and diastolic blood pressure variability, the risk of AF was 7.6% higher than those in the first quartile. Moreover, this result was consistent in both patients with or without prevalent hypertension. In subgroup analysis, the impact of high blood pressure variability on AF development was stronger in high-risk subjects, who were older (≥65 years), with diabetes mellitus or chronic kidney disease. Our findings demonstrated that higher blood pressure variability was associated with a modestly increased risk of AF.



Hypertension: 30 Jan 2020; 75:309-315
Lee SR, Choi YJ, Choi EK, Han KD, ... Oh S, Lip GYH
Hypertension: 30 Jan 2020; 75:309-315 | PMID: 31838903
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Abstract

Meta-Analysis Comparing Double Versus Triple Antithrombotic Therapy in Patients With Atrial Fibrillation and Coronary Artery Disease.

Ravi V, Pulipati P, Vij A, Kodumuri V

Atrial fibrillation (AF) and concomitant coronary artery disease (CAD) create a therapeutic dilemma as the risk of bleeding with triple antithrombotic therapy (TATT) must be balanced against the risk of ischemic events with double antithrombotic therapy (DATT). The aim of this meta-analysis is to compare the efficacy and safety of DATT versus TATT in AF and CAD. MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched for relevant articles published from inception to May 1, 2019. Studies comparing the safety and efficacy of DATT versus TATT in patients with AF and CAD were included. Among 9 studies, where 6,104 patients received DATT and 7,333 patients received TATT, there was no statistically significant difference in the outcomes of mortality, nonfatal myocardial infarction, stent thrombosis, and stroke. There was a lower rate of major bleeding in DATT (risk ratio [RR] 0.64 [95% confidence interval [CI] 0.54 to 0.75]; p <0.001). There was no significant difference in stent thrombosis (RR 1.52 [95% CI 0.97 to 2.38]; p = 0.07). However, subgroup analysis of trials with direct oral anticoagulant use demonstrated a borderline higher rate of stent thrombosis in DATT (RR 1.66 [95% CI 1.01 to 2.73]; p = 0.05). In conclusion, DATT showed no difference in the outcomes of mortality, stroke, nonfatal myocardial infarction, and stent thrombosis compared with TATT. DATT demonstrated a lower rate of major bleeding. DATT demonstrated a borderline higher rate of stent thrombosis in the subgroup analysis of trials with direct oral anticoagulant which needs to be evaluated in further studies.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Dec 2019; 125:19-28
Ravi V, Pulipati P, Vij A, Kodumuri V
Am J Cardiol: 31 Dec 2019; 125:19-28 | PMID: 31837732
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Abstract

Pathophysiology of Atrial Fibrillation and Chronic Kidney Disease.

Ding WY, Gupta D, Wong CF, Lip GYH

Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related conditions with shared risk factors. The growing prevalence of both AF and CKD indicates that more patients will suffer from concurrent conditions. There are various complex interlinking mechanisms with important implications for the management of these patients. Furthermore, there is uncertainty regarding the use of oral anticoagulation in AF and CKD that is reflected by a lack of consensus between international guidelines. Therefore, the importance of understanding the implications of co-existing AF and CKD should not be underestimated. In this review, we discuss the pathophysiology and association between AF and CKD, including the underlying mechanisms, risk of thromboembolic and bleeding complications, influence on stroke management, and evidence surrounding the use of oral anticoagulation for stroke prevention.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 31 Aug 2020; epub ahead of print
Ding WY, Gupta D, Wong CF, Lip GYH
Cardiovasc Res: 31 Aug 2020; epub ahead of print | PMID: 32871005
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Abstract

Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation.

Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Aims
The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.
Methods/results
We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.
Conclusion
Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Sep 2020; epub ahead of print
Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Heart: 15 Sep 2020; epub ahead of print | PMID: 32938772
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Abstract

Atrial fibrillation and the prothrombotic state: revisiting Virchow\'s triad in 2020.

Ding WY, Gupta D, Lip GYH

Atrial fibrillation (AF) is characterised by an increased risk of pathological thrombus formation due to a disruption of physiological haemostatic mechanisms that are better understood by reference to Virchow\'s triad of \'abnormal blood constituents\', \'vessel wall abnormalities\' and \'abnormal blood flow\'. First, there is increased activation of the coagulation cascade, platelet reactivity and impaired fibrinolysis as a result of AF per se, and these processes are amplified with pre-existing comorbidities. Several prothrombotic biomarkers including platelet factor 4, von Willebrand factor, fibrinogen, β-thromboglobulin and D-dimer have been implicated in this process. Second, structural changes such as atrial fibrosis and endothelial dysfunction are linked to the development of AF which promote further atrial remodelling, thereby providing a suitable platform for clot formation and subsequent embolisation. Third, these factors are compounded by the presence of reduced blood flow secondary to dilatation of cardiac chambers and loss of atrial systole which have been confirmed using various imaging techniques. Overall, an improved understanding of the various factors involved in thrombus formation will allow better clinical risk stratification and targeted therapies in AF.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Sep 2020; 106:1463-1468
Ding WY, Gupta D, Lip GYH
Heart: 29 Sep 2020; 106:1463-1468 | PMID: 32675218
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Abstract

Association of household income and adverse outcomes in patients with atrial fibrillation.

LaRosa AR, Claxton J, O\'Neal WT, Lutsey PL, ... Alonso A, Magnani JW
Background
Social determinants of health are relevant to cardiovascular outcomes but have had limited examination in atrial fibrillation (AF).
Objectives
The purpose of this study was to examine the association of annual household income and cardiovascular outcomes in individuals with AF.
Methods
We analysed administrative claims for individuals with AF from 2009 to 2015 captured by a health claims database. We categorised estimates of annual household income as <$40 000; $40-$59 999; $60-$74 999; $75-$99 999; and ≥$100 000. Covariates included demographics, education, cardiovascular disease risk factors, comorbid conditions and anticoagulation. We examined event rates by income category and in multivariable-adjusted models in reference to the highest income category (≥$100 000).
Results
Our analysis included 336 736 individuals (age 72.7±11.9 years; 44.5% women; 82.6% white, 8.4% black, 7.0% Hispanic and 2.1% Asian) with AF followed for median (25th and 75th percentile) of 1.5 (95% CI 0.6 to 3.0) years. We observed an inverse association between income and heart failure and myocardial infarction (MI) with evidence of progressive risk across decreased income categories. Individuals with household income <$40 000 had the greatest risk for heart failure (HR 1.17; 95% CI 1.05 to 1.30) and MI (HR 1.18; 95% CI 0.98 to 1.41) compared with those with income ≥$100 000.
Conclusions
We identified an association between lower household income and adverse outcomes in a large cohort of individuals with AF. Our findings support consideration of income in the evaluation of cardiovascular risk in individuals with AF.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2020; 106:1679-1685
LaRosa AR, Claxton J, O'Neal WT, Lutsey PL, ... Alonso A, Magnani JW
Heart: 30 Oct 2020; 106:1679-1685 | PMID: 32144188
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Abstract

Risk of Ischemic Stroke in Patients With Atrial Fibrillation After Extracranial Hemorrhage.

Zhou E, Lord A, Boehme A, Henninger N, ... Elkind MSV, Yaghi S
Background and purpose
Anticoagulation therapy not only reduces the risk of ischemic stroke in atrial fibrillation (AF) but also predisposes patients to hemorrhagic complications. There is limited knowledge on the risk of first-ever ischemic stroke in patients with AF after extracranial hemorrhage (ECH).
Methods
We conducted a retrospective study using the California State Inpatient Database including all nonfederal hospital admissions in California from 2005 to 2011. The exposure variable was hospitalization with a diagnosis of ECH with a previous diagnosis of AF. The outcome variable was a subsequent hospitalization with acute ischemic stroke. We excluded patients with stroke before or at the time of ECH diagnosis. We calculated adjusted hazard ratios for ischemic stroke during follow-up and at 6-month intervals using Cox regression models adjusted for pertinent demographics and comorbidities. In subgroup analyses, subjects were stratified by primary ECH diagnosis, severity/type of ECH, age, CHADS-VASc score, or the presence/absence of a gastrointestinal or genitourinary cancer.
Results
We identified 764 257 patients with AF (mean age 75 years, 49% women) without a documented history of stroke. Of these, 98 647 (13%) had an ECH-associated hospitalization, and 22 748 patients (3%) developed an ischemic stroke during the study period. Compared to patients without ECH, subjects with ECH had ≈15% higher rate of ischemic stroke (overall adjusted hazard ratio, 1.15 [95% CI, 1.11-1.19]). The risk appeared to remain elevated for at least 18 months after the index ECH. In subgroup analyses, the risk was highest in subjects with a primary admission diagnosis of ECH, severe ECH, gastrointestinal-type ECH, with gastrointestinal or genitourinary cancer, and age ≥60 years.
Conclusions
Patients with AF hospitalized with ECH may have a slightly elevated risk for future ischemic stroke. Particular consideration should be given to the optimal balance between the benefits and risks of anticoagulation therapy and the use of nonanticoagulant alternatives, such as left atrial appendage closure in this vulnerable population.



Stroke: 07 Oct 2020:STROKEAHA120029959; epub ahead of print
Zhou E, Lord A, Boehme A, Henninger N, ... Elkind MSV, Yaghi S
Stroke: 07 Oct 2020:STROKEAHA120029959; epub ahead of print | PMID: 33028172
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Abstract

Cessation of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

Middeldorp ME, Gupta A, Elliott A, Kadhim K, ... Lau D, Sanders P
Objective
To characterise the rate, causes and predictors of cessation of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF).
Patients and methods
Consecutive patients with AF with a long-term anticoagulation indication treated with NOACs (dabigatran, apixaban and rivaroxaban) in our centre from September 2010 through December 2016 were included. Prospectively collected data with baseline characteristics, causes of cessation, mean duration-to-cessation and predictors of cessation were analysed.
Results
The study comprised 1415 consecutive patients with AF, of whom 439 had a CHADS-VASc≥1 and were on a NOAC. Mean age was 71.9±8.7 years and 37% were females. Over a median follow-up of 3.6 years (IQR=2.7-5.3), 147 (33.5%) patients ceased their index-NOAC (113 switched to a different form of OAC), at a rate of 8.8 per 100 patient-years. Serious adverse events warranting NOAC cessation occurred in 28 patients (6.4%) at a rate of 1.6 events per 100 patient-years. The mean duration-to-cessation was 4.9 years (95% CI 4.6 to 5.1) and apixaban had the longest duration-to-cessation with (5.1, 95% CI 4.8 to 5.4) years, compared with dabigatran (4.6, 95% CI 4.2 to 4.9) and rivaroxaban (4.5, 95% CI 3.9 to 5.1), pairwise log-rank p=0.002 and 0.025, respectively. In multivariable analyses, age was an independent predictor of index-NOAC cessation (HR 1.03, 95% CI 1.01 to 1.05; p=0.006). Female gender (HR 2.2, 95% CI 1.04 to 4.64; p=0.04) independently predicted serious adverse events.
Conclusion
In this \'real world\' cohort, NOAC use is safe and well-tolerated when prescribed in an integrated care clinic. Whether apixaban is better tolerated compared with other NOACs warrants further study.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Oct 2020; epub ahead of print
Middeldorp ME, Gupta A, Elliott A, Kadhim K, ... Lau D, Sanders P
Heart: 15 Oct 2020; epub ahead of print | PMID: 33067328
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Abstract

Changes in quality of life, cognition and functional status following catheter ablation of atrial fibrillation.

Piccini JP, Todd DM, Massaro T, Lougee A, ... Di Biase L, Kirchhof P
Objective
To investigate changes in quality of life (QoL), cognition and functional status according to arrhythmia recurrence after atrial fibrillation (AF) ablation.
Methods
We compared QoL, cognition and functional status in patients with recurrent atrial tachycardia (AT)/AF versus those without recurrent AT/AF in the AXAFA-AFNET 5 clinical trial. We also sought to identify factors associated with improvement in QoL and functional status following AF ablation by overall change scores with and without analysis of covariance (ANCOVA).
Results
Among 518 patients who underwent AF ablation, 154 (29.7%) experienced recurrent AT/AF at 3 months. Patients with recurrent AT/AF had higher mean CHADS-VASc scores (2.8 vs 2.3, p<0.001) and more persistent forms of AF (51 vs 39%, p=0.012). Median changes in the SF-12 physical (3 (25th, 75th: -1, 8) vs 1 (-5, 8), p=0.026) and mental scores (2 (-3, 9) vs 0 (-4, 5), p=0.004), EQ-5D (0 (0,2) vs 0 (-0.1, 0.1), p=0.027) and Karnofsky functional status scores (10 (0, 10) vs 0 (0, 10), p=0.001) were more favourable in patients without recurrent AT/AF. In the overall cohort, the proportion with at least mild cognitive impairment (Montreal Cognitive Assessment <26) declined from 30.3% (n=157) at baseline to 21.8% (n=113) at follow-up. ANCOVA identified greater improvement in Karnofsky functional status (p<0.001) but not SF-12 physical (p=0.238) or mental scores (p=0.065) in those without recurrent AT/AF compared with patients with recurrent AT/AF.
Conclusions
Patients without recurrent AT/AF appear to experience greater improvement in functional status but similar QoL as those with recurrent AT/AF after AF ablation.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Heart: 11 Oct 2020; epub ahead of print
Piccini JP, Todd DM, Massaro T, Lougee A, ... Di Biase L, Kirchhof P
Heart: 11 Oct 2020; epub ahead of print | PMID: 33046527
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Abstract

Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation.

Heijman J, Muna AP, Veleva T, Molina CE, ... Wehrens XHT, Dobrev D
Rationale
Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.
Objective
To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.
Methods and results
Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca]-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca-release events and L-type Ca-current alternans occurred more frequently. CaMKII (Ca/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca-content was unchanged in POAF despite greater SR Ca-leak, with a trend towards increased SR Ca-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca-uptake are sufficient to reproduce the Ca-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β.
Conclusions
Preexisting Ca-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.



Circ Res: 24 Sep 2020; 127:1036-1055
Heijman J, Muna AP, Veleva T, Molina CE, ... Wehrens XHT, Dobrev D
Circ Res: 24 Sep 2020; 127:1036-1055 | PMID: 32762493
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Abstract

Global variations in the prevalence, treatment, and impact of atrial fibrillation in a multi-national cohort of 153,152 middle-aged individuals.

Joseph PG, Healey JS, Raina P, Connolly SJ, ... Rangarajan S, Yusuf S
Aims
To compare the prevalence of electrocardiogram (ECG)-documented atrial fibrillation (or flutter) (AF) across eight regions of the world, and to examine anti-thrombotic use and clinical outcomes.
Methods and results
Baseline ECGs were collected in 153,152 middle-aged participants (ages 35 to 70 years) to document AF in two community-based studies, spanning 20 countries. Medication use and clinical outcome data (mean follow up of 7.4 years) were available in one cohort. Cross sectional analyses were performed to document the prevalence of AF and medication use, and associations between AF and clinical events were examined prospectively. Mean age of participants was 52.1 years, and 57.7% were female. Age and sex-standardized prevalence of AF varied 12-fold between regions; with the highest in North America, Europe, China and Southeast Asia (270-360 cases per 100,000 persons); and lowest in the Middle East, Africa, and South Asia (30-60 cases per 100,000 persons)(p < 0.001). Compared with low-income countries (LICs), AF prevalence was 7-fold higher in middle-income countries (MICs) and 11-fold higher in high-income countries (HICs)(p < 0.001). Differences in AF prevalence remained significant after adjusting for traditional AF risk factors. In LICs/MICs, 24% of participants with AF and a CHADS2 score ≥1 received anti-thrombotic therapy, compared with 85% in HICs. AF was associated with an increased risk of stroke (hazard ratio [HR: 2.29; 95% confidence interval [CI] 1.49-3.52) and death (HR: 2.97; 95% CI 2.25-3.93); with similar rates in different country income levels.
Conclusions
Large variations in AF prevalence occur in different regions and country income settings, but this is only partially explained by traditional AF risk factors. Anti-thrombotic therapy is infrequently used in poorer countries despite the high risk of stroke associated with AF.
Translational perspective
We examined atrial fibrillation (AF) prevalence in 153,152 middle-aged participants spanning 20 countries. Age and sex-standardized prevalence of AF varied by as much as 12-fold between regions; highest in North America, Europe, China and Southeast Asia (270-360 cases per 100,000 persons); and lowest in the Middle East, Africa, and South Asia (30-60 cases per 100,000 persons)(p < 0.001); and by as much as 11-fold between groups of countries at different income levels (p < 0.001). Global variations were poorly explained by traditional AF risk factors. Future studies are needed to understand the predominant determinants driving the variation in AF burden across different regions of the world.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 09 Aug 2020; epub ahead of print
Joseph PG, Healey JS, Raina P, Connolly SJ, ... Rangarajan S, Yusuf S
Cardiovasc Res: 09 Aug 2020; epub ahead of print | PMID: 32777820
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Abstract

Prevalence and Outcome of Potential Candidates for Left Atrial Appendage Closure After Stroke With Atrial Fibrillation: WATCH-AF Registry.

Ong E, Meseguer E, Guidoux C, Lavallée PC, ... Nighoghossian N, Amarenco P
Background and purpose
As a result of contraindications (eg, frailty, cognitive impairment, comorbidities) or patient refusal, many patients with stroke and atrial fibrillation cannot be discharged on oral anticoagulant. Among them, the proportion of potential candidates for left atrial appendage closure (LAAC) and their 12-month outcome is not well known.
Methods
The prospective WATCH-AF registry (Warfarin Aspirin Ten-A Inhibitors and Cerebral Infarction and Hemorrhage and Atrial Fibrillation) enrolled consecutive patients admitted within 72 hours of an acute stroke associated with atrial fibrillation in 2 stroke centers. Scales to evaluate stroke severity, disability, functional independence, risk of fall, cognition, ischemic and hemorrhagic risk-stratification, and comorbidities were systematically collected at admission, discharge, 3, 12 months poststroke. The 2 main end points were death or dependency (modified Rankin Scale score >3) and recurrent stroke (brain infarction and brain hemorrhage).
Results
Among 400 enrolled patients (370 with brain infarction, 30 with brain hemorrhage), 31 died before discharge and 57 (14.3%) were possible European Heart Rhythm Association/European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Rhythm Society candidates for LAAC. At 12 months, the rate of death or dependency was 17.9%, and the rate of stroke recurrence was 9.8% in the 274/400 (68.5%) patients discharged on a long-term oral anticoagulant strategy, as compared with 17.5% and 24.7%, respectively, in 57 patients candidate for LAAC. As compared with patients on a long-term oral anticoagulant strategy, there was a 2-fold increase in the risk of stroke recurrence in the group with an indication for LAAC (adjusted hazard ratio, 2.58 [95% CI, 1.40-4.76]; P=0.002).
Conclusions
Fourteen percent of patients with stroke associated with atrial fibrillation were potential candidates for LAAC. The 12-month stroke risk of these candidates was 3-fold the risk of anticoagulated patients.



Stroke: 30 Jul 2020; 51:2355-2363
Ong E, Meseguer E, Guidoux C, Lavallée PC, ... Nighoghossian N, Amarenco P
Stroke: 30 Jul 2020; 51:2355-2363 | PMID: 32640939
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Abstract

Tailoring anticoagulant treatment of patients with atrial fibrillation using a novel bleeding risk score.

Chu G, Valerio L, van der Wall SJ, Barco S, ... Huisman MV, Klok FA
Objectives
Current international guidelines advocate the application of bleeding risk scores only to identify modifiable risk factors, but not to withhold treatment in patients at high risk of bleeding. VTE-BLEED (ActiVe cancer, male with uncontrolled hyperTension, anaEmia, history of BLeeding, agE and rEnal Dysfunction) is a simple bleeding risk score that predicts major bleeding (MB) in patients with venous thromboembolism, but has never been evaluated in patients with atrial fibrillation (AF). We sought to evaluate VTE-BLEED in patients with AF included in the Randomised Evaluation of Long-term anticoagulant therapY (RE-LY) trial, to assess whether score classes (high vs low bleeding risk) interact with the tested dabigatran doses (150 vs 110 mg twice daily), and to investigate whether dose reductions based on this interaction might help to lower the incidence of the composite outcome MB, stroke/systemic embolism or death.
Methods
The score was calculated in the safety population of RE-LY (n=18 040) and recalibrated for AF (AF-adapted VTE-BLEED or AF-BLEED). HRs were calculated to evaluate the score\'s predictive accuracy for MB. The risk ratios (RRs) for the composite outcome comparing dabigatran 150 and 110 mg twice daily were calculated for the high-risk group.
Results
AF-BLEED classified 3534 patients (19.6%) at high bleeding risk, characterised by a 2.9-fold to 3.4-fold higher risk of bleeding than low bleeding risk patients, across the treatment arms. High bleeding risk patients randomised to 110 mg twice daily had a lower incidence of the composite outcome than those randomised to 150 mg twice daily, for an RR of 0.52 (95% CI 0.35 to 0.78). Compared with the label criteria for dose reduction, AF-BLEED identified an additional 11% of patients who might have benefited from dose reduction.
Conclusions
AF-BLEED identified patients with AF at high risk of bleeding. Our findings raise the hypothesis that dabigatran 110 mg twice daily might be considered in patients classified as high risk according to the AF-BLEED score. This study provides a basis for future studies to explore safe dose reductions of direct oral anticoagulants in selected patient groups based on bleeding scores.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 08 Sep 2020; epub ahead of print
Chu G, Valerio L, van der Wall SJ, Barco S, ... Huisman MV, Klok FA
Heart: 08 Sep 2020; epub ahead of print | PMID: 32907824
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Impact:
Abstract

Residual risks of ischaemic stroke and systemic embolism among atrial fibrillation patients with anticoagulation: large-scale real-world data (F-CREATE project).

Maeda T, Nishi T, Funakoshi S, Tada K, ... Yoshimura C, Arima H
Objective
Among patients with atrial fibrillation, the risks of ischaemic stroke and systemic embolism (IS/SE) are high even with effective anticoagulation. Using large-scale, real-world data from Japan, this study aims to clarify residual risks of IS/SE attributable to modifiable risk factors among patients with atrial fibrillation who are taking oral anticoagulants.
Methods
The study design we employed was a retrospective cohort. Health check-ups and insurance claims data of Japanese health insurance companies were accumulated from January 2005 to June 2017. We identified 11 848 participants with atrial fibrillation who were on oral anticoagulants during the study period. We set the modifiable risk factors as hypertension, diabetes and dyslipidaemia. A Cox proportional hazards model was used to obtain the effects of the risk factors for IS/SE.
Results
During an average of 3 years\' follow-up, 200 cases of IS/SE occurred (incidence rate 0.57 per 100 person-years). In multivariable analyses, older age (65-74 vs <65 years; adjusted HR 2.02 (95% CI 1.49 to 2.73)), hypertension (adjusted HR 1.41 (1.04 to 1.92)) and dyslipidaemia (adjusted HR 1.46 (1.07 to 1.98)) were significantly associated with increased risk of IS/SE. Percentage of IS/SE risk attributable to modifiable risk factors (hypertension, diabetes and dyslipidaemia) was 30.0% (16.1% to 41.6%).
Conclusion
Among patients with atrial fibrillation on anticoagulant therapy, approximately one-third of the residual risks were estimated to be attributable to modifiable risk factors such as hypertension, diabetes and dyslipidaemia.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 13 Aug 2020; epub ahead of print
Maeda T, Nishi T, Funakoshi S, Tada K, ... Yoshimura C, Arima H
Heart: 13 Aug 2020; epub ahead of print | PMID: 32817313
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Impact:
Abstract

Prevalence and incidence rates of atrial fibrillation in Norway 2004-2014.

Kjerpeseth LJ, Igland J, Selmer R, Ellekjær H, ... Tell GS, Ariansen I
Objective
To study time trends in incidence of atrial fibrillation (AF) in the entire Norwegian population from 2004 to 2014, by age and sex, and to estimate the prevalence of AF at the end of the study period.
Methods
A national cohort of patients with AF (≥18 years) was identified from inpatient admissions with AF and deaths with AF as underlying cause (1994-2014), and AF outpatient visits (2008-2014) in the Cardiovascular Disease in Norway (CVDNOR) project. AF admissions or out-of-hospital death from AF, with no AF admission the previous 10 years defined incident AF. Age-standardised incidence rates (IR) and incidence rate ratios (IRR) were calculated. All AF cases identified through inpatient admissions and outpatient visits and alive as of 31 December 2014 defined AF prevalence.
Results
We identified 175 979 incident AF cases (30% primary diagnosis, 69% secondary diagnosis, 0.6% out-of-hospital deaths). AF IRs (95% confidence intervals) per 100 000 person years were stable from 2004 (433 (426-440)) to 2014 (440 (433-447)). IRs were stable or declining across strata of sex and age with the exception of an average yearly increase of 2.4% in 18-44 year-olds: IRR 1.024 (1.014-1.034). In 2014, the prevalence of AF in the adult population was 3.4%.
Conclusions
We found overall stable IRs of AF for the adult Norwegian population from 2004 to 2014. The prevalence of AF was 3.4% at the end of 2014, which is higher than reported in previous studies. Signs of an increasing incidence of early-onset AF (<45 years) are worrying and need further investigation.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 19 Aug 2020; epub ahead of print
Kjerpeseth LJ, Igland J, Selmer R, Ellekjær H, ... Tell GS, Ariansen I
Heart: 19 Aug 2020; epub ahead of print | PMID: 32820014
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Impact:
Abstract

Impact of different anticoagulation management strategies on outcomes in atrial fibrillation: Dutch and Belgian results from the GARFIELD-AF registry.

Seelig J, Hemels MEW, Xhaët O, Bongaerts MCM, ... Ten Cate H,
Background
The uptake rate of non-vitamin K oral anticoagulants (NOAC) for the treatment of non-valvular atrial fibrillation (AF) was far lower in the Netherlands (NL) compared to Belgium (BE). Also, patients on VKA in NL were treated with a higher target international normalized ratio (INR) range of 2.5 to 3.5.
Objectives
To explore the effect of these differences on thromboembolism (TE) and bleeding.
Methods
Data from the GARFIELD-AF registry was used. Patients with new-onset AF and ≥1 investigator-determined risk factor for stroke were included between 2010 and 2016. Event rates from 2 years of follow-up were used.
Results
In NL and BE, 1186 and 1705 patients were included, respectively. Female sex (42.3% vs 42.2%), mean age (70.7 vs 71.3 years), CHA DS -VASc (3.1 vs 3.1), and HAS-BLED score (1.4 vs 1.5) were comparable between NL and BE. At diagnosis in NL vs BE, 72.1% vs 14.6% received vitamin K antagonists (VKA) and 17.8% vs 65.5% NOACs, varying greatly across cohorts. Mean INR was 2.9 (±1.0) and 2.4 (±1.0) in NL and BE, respectively. Event rates per 100 patient-years in NL and BE, respectively, of all-cause mortality (3.38 vs 3.90; hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.65-1.15), ischemic stroke/TE (0.82 vs 0.72; HR 1.14, 95% CI 0.62-2.11), and major bleeding (2.06 vs 1.54; HR 1.33, 95% CI 0.89-1.99) did not differ significantly.
Conclusions
In GARFIELD-AF, despite similar characteristics, patients on anticoagulants were treated differently in NL and BE. Although the rate of major bleeding was 33% higher in NL, variations in bleeding, mortality, and TE rates were not statistically significant.

© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 03 Sep 2020; epub ahead of print
Seelig J, Hemels MEW, Xhaët O, Bongaerts MCM, ... Ten Cate H,
J Thromb Haemost: 03 Sep 2020; epub ahead of print | PMID: 32886853
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Impact:
Abstract

Initial Stroke Severity in Patients With Atrial Fibrillation According to Antithrombotic Therapy Before Ischemic Stroke.

Jung YH, Kim YD, Kim J, Han SW, ... Lee JS, Lee KY
Background and purpose
Atrial fibrillation (AF) is the leading cause of ischemic stroke. Preventive antithrombotic use, especially for anticoagulation, reduces the incidence of ischemic stroke in patients with AF. Using data from the nationwide multicenter stroke registry, we investigated the trends of preceding antithrombotic medication use in patients with acute ischemic stroke (AIS) with AF and its association with initial stroke severity and in-hospital outcomes.
Methods
This study included 6786 patients with AIS with known AF before stroke admission across 39 hospitals between June 2008 and December 2018. We collected the data on antithrombotic medication use (no antithrombotic/antiplatelet/anticoagulant) preceding AIS. Initial stroke severity was measured using the National Institutes of Health Stroke Scale, and in-hospital outcome was determined by modified Rankin Scale score at discharge.
Results
During the study period, anticoagulant use continued to increase. However, nearly one-third of patients with AIS with known AF did not receive antithrombotics before stroke. Initial National Institutes of Health Stroke Scale scores varied according to preceding antithrombotic therapy (<0.001). It was higher in patients who did not receive antithrombotics than in those who received antiplatelets or anticoagulants (median National Institutes of Health Stroke Scale score: 8 versus 7 and 8 versus 6, respectively). Favorable outcome at discharge (modified Rankin Scale score, 0-2) was more prevalent in patients who received antiplatelets or anticoagulants (<0.001). Use of antiplatelets (odds ratio, 1.23 [95% CI, 1.09-1.38]) and anticoagulants (odds ratio, 1.31 [95% CI, 1.15-1.50]) was associated with a mild initial neurological deficit (National Institutes of Health Stroke Scale score ≤5) in patients with AIS with AF.
Conclusions
Throughout the study period, the proportion of patients taking anticoagulants increased among patients with AIS with known AF. However, a large portion of AF patients still did not receive antithrombotics before AIS. Furthermore, prehospitalization use of anticoagulants was associated with a significantly higher likelihood of a mild initial neurological deficit and favorable outcome at discharge.



Stroke: 30 Aug 2020; 51:2733-2741
Jung YH, Kim YD, Kim J, Han SW, ... Lee JS, Lee KY
Stroke: 30 Aug 2020; 51:2733-2741 | PMID: 32811392
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Impact:
Abstract

Safety of Anticoagulation in Patients Treated With Urgent Reperfusion for Ischemic Stroke Related to Atrial Fibrillation.

Giustozzi M, Acciarresi M, Agnelli G, Caso V, ... Paciaroni M, Masotti L
Background and purpose
The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention.
Methods
We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features.
Results
A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50-1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53-2.02]).
Conclusions
Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation-related acute ischemic stroke, who started on oral anticoagulant.



Stroke: 30 Jul 2020; 51:2347-2354
Giustozzi M, Acciarresi M, Agnelli G, Caso V, ... Paciaroni M, Masotti L
Stroke: 30 Jul 2020; 51:2347-2354 | PMID: 32646335
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Impact:
Abstract

Direct-Acting Oral Anticoagulants Versus Warfarin in Medicare Patients With Chronic Kidney Disease and Atrial Fibrillation.

Wetmore JB, Roetker NS, Yan H, Reyes JL, Herzog CA
Background and purpose
The comparative effectiveness of direct-acting oral anticoagulants, compared with warfarin, for risks of stroke/systemic embolism, major bleeding, or death have not been studied in Medicare beneficiaries with atrial fibrillation and nondialysis-dependent chronic kidney disease.
Methods
Medicare data from 2011 to 2017 were used to identify patients with stages 3, 4, or 5 chronic kidney disease and new atrial fibrillation who received a new prescription for warfarin, apixaban, rivaroxaban, or dabigatran. We estimated marginal hazard ratios with 95% CIs for the association of each direct-acting oral anticoagulant, compared with warfarin, for the outcomes of interest using inverse-probability-of-treatment weighted Cox proportional hazards models in as-treated and intention-to-treat analyses.
Results
A total of 22 739 individuals met criteria (46.3% warfarin, 29.6% apixaban, 17.2% rivaroxaban, 6.9% dabigatran). Across the groups of anticoagulant users, mean age was 78.4 to 79.0 years; 50.3% to 51.4% were women, and 80.3% to 82.8% had stage 3 chronic kidney disease. In the as-treated analysis, for stroke/systemic embolism, hazard ratios, all compared with warfarin, were 0.70 (0.51-0.96) for apixaban, 0.80 (0.54-1.17) for rivaroxaban, and 1.15 (0.69-1.94) for dabigatran. For major bleeding, analogous hazard ratios were 0.47 (0.37-0.59) for apixaban, 1.05 (0.85-1.30) for rivaroxaban, and 0.95 (0.70-1.31) for dabigatran. There was no difference in the risk of all-cause mortality between the direct-acting oral anticoagulants and warfarin. Results of the intention-to-treat analysis were similar.
Conclusions
Apixaban, compared with warfarin, was associated with decreased risk of stroke/systemic embolism and major bleeding; risks for both outcomes with rivaroxaban and dabigatran did not differ from risks with warfarin.



Stroke: 30 Jul 2020; 51:2364-2373
Wetmore JB, Roetker NS, Yan H, Reyes JL, Herzog CA
Stroke: 30 Jul 2020; 51:2364-2373 | PMID: 32640949
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Impact:
Abstract

Diagnostic accuracy of handheld electrocardiogram devices in detecting atrial fibrillation in adults in community versus hospital settings: a systematic review and meta-analysis.

Wong KC, Klimis H, Lowres N, von Huben A, Marschner S, Chow CK

With increasing use of handheld ECG devices for atrial fibrillation (AF) screening, it is important to understand their accuracy in community and hospital settings and how it differs among settings and other factors. A systematic review of eligible studies from community or hospital settings reporting the diagnostic accuracy of handheld ECG devices (ie, devices producing a rhythm strip) in detecting AF in adults, compared with a gold standard 12-lead ECG or Holter monitor, was performed. Bivariate hierarchical random-effects meta-analysis and meta-regression were performed using R V.3.6.0. The search identified 858 articles, of which 14 were included. Six studies recruited from community (n=6064 ECGs) and eight studies from hospital (n=2116 ECGs) settings. The pooled sensitivity was 89% (95% CI 81% to 94%) in the community and 92% (95% CI 83% to 97%) in the hospital. The pooled specificity was 99% (95% CI 98% to 99%) in the community and 95% (95% CI 90% to 98%) in the hospital. Accuracy of ECG devices varied: sensitivity ranged from 54.5% to 100% and specificity ranged from 61.9% to 100%. Meta-regression showed that setting (p=0.032) and ECG device type (p=0.022) significantly contributed to variations in sensitivity and specificity. The pooled sensitivity and specificity of single-lead handheld ECG devices were high. Setting and handheld ECG device type were significant factors of variation in sensitivity and specificity. These findings suggest that the setting including user training and handheld ECG device type should be carefully reviewed.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Jul 2020; 106:1211-1217
Wong KC, Klimis H, Lowres N, von Huben A, Marschner S, Chow CK
Heart: 30 Jul 2020; 106:1211-1217 | PMID: 32393588
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Impact:
Abstract

Impact of atrial fibrillation in patients with heart failure and reduced, mid-range or preserved ejection fraction.

Son MK, Park JJ, Lim NK, Kim WH, Choi DJ
Objective
To determine the prognostic value of atrial fibrillation (AF) in patients with heart failure (HF) and preserved, mid-range or reduced ejection fraction (EF).
Methods
Patients hospitalised for acute HF were enrolled in the Korean Acute Heart Failure registry, a prospective, observational, multicentre cohort study, between March 2011 and February 2014. HF types were defined as reduced EF (HFrEF, LVEF <40%), mid-range EF (HFmrEF, LVEF 40%-49%) or preserved EF (HFpEF, LVEF ≥50%).
Results
Of 5414 patients enrolled, HFrEF, HFmrEF and HFpEF were seen in 3182 (58.8%), 875 (16.2%) and 1357 (25.1%) patients, respectively. The prevalence of AF significantly increased with increasing EF (HFrEF 28.9%, HFmrEF 39.8%, HFpEF 45.2%; p for trend <0.001). During follow-up (median, 4.03 years; IQR, 1.39-5.58 years), 2806 (51.8%) patients died. The adjusted HR of AF for all-cause death was 1.06 (0.93-1.21) in the HFrEF, 1.10 (0.87-1.39) in the HFmrEF and 1.22 (1.02-1.46) in the HFpEF groups. The HR for the composite of all-cause death or readmission was 0.97 (0.87-1.07), 1.14 (0.93-1.38) and 1.03 (0.88-1.19) in the HFrEF, HFmrEF and HFpEF groups, respectively, and the HR for stroke was 1.53 (1.03-2.29), 1.04 (0.57-1.91) and 1.90 (1.13-3.20), respectively. Similar results were observed after propensity score matching analysis.
Conclusions
AF was more common with increasing EF. AF was seen to be associated with increased mortality only in patients with HFpEF and was associated with an increased risk of stroke in patients with HFrEF or HFpEF.
Trial registration number
NCT01389843.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Jul 2020; 106:1160-1168
Son MK, Park JJ, Lim NK, Kim WH, Choi DJ
Heart: 30 Jul 2020; 106:1160-1168 | PMID: 32341140
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Impact:
Abstract

Atrial fibrillation detection with a portable device during cardiovascular screening in primary care.

Diamantino AC, Nascimento BR, Beaton AZ, Nunes MCP, ... Sable C, Brant LCC
Introduction
A novel handheld dual-electrode stick is a portable atrial fibrillation (AF) screening device (AFSD). We evaluated AFSD performance in primary care patients referred for echocardiogram (echo).
Methods
The AFSD has a light indication of irregular rhythm and single-lead ECG recording. Patients were instructed to hold the device for 1 min, and AF indication was recorded. A 12-lead ECG was performed for all AFSD-positive patients and 250 patients with negative AFSD screen. Echos were performed based on a clinical risk score: all high-risk patients and a sampling of low-risk patients underwent complete echo. Intermediate risk patients first had a screening echocardiogram, with a follow-up complete study if abnormality was suspected.
Results
In 5 days, 1518 patients underwent clinical evaluation and cardiovascular risk stratification: mean age 58±16 years, 66% women. The AFSD was positive in 6.4%: 12.6% high risk, 6.1% intermediate risk and 2.2% low risk. Older age was a risk factor (9.3% vs 4.8% in those more than and less than 65 years, p=0.001). AFSD positive was independently associated with heart disease in echo (OR=3.9, 95% CI 2.1 to 7.2, p<0.001). Compared with 12-lead ECG, the AFSD had sensitivity of 90.2% (95% CI 77.0% to 97.3%) and specificity of 84.0% (95% CI 79.3% to 88.0%) for AF detection.
Conclusion
AFSD demonstrated high sensitivity for AF detection in primary care patients referred for echo. AF prevalence was substantial and independently associated with structural or functional heart disease, suggesting that AFSD screening could be a useful primary care tool to stratify risk and prioritise echo.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Jul 2020; 106:1261-1266
Diamantino AC, Nascimento BR, Beaton AZ, Nunes MCP, ... Sable C, Brant LCC
Heart: 30 Jul 2020; 106:1261-1266 | PMID: 32019822
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Impact:
Abstract

Stroke and thromboembolism prevention in atrial fibrillation.

Jame S, Barnes G

Prevention of stroke and systemic thromboembolism remains the cornerstone for management of atrial fibrillation (AF) and flutter. Multiple risk assessment models for stroke and systemic thromboembolism are currently available. The score, with its known limitations, remains as the recommended risk stratification tool in most major guidelines. Once at-risk patients are identified, vitamin K antagonists (VKAs) and, more recently, direct oral anticoagulants (DOACs) are the primary medical therapy for stroke prevention. In those with contraindication for long-term anticoagulation, left atrial appendage occluding devices are developing as a possible alternative therapy. Some controversy exists regarding anticoagulation management for cardioversion of acute AF (<48 hours); however, systemic anticoagulation precardioversion and postcardioversion is recommended for those with longer duration of AF. Anticoagulation management peri-AF ablation is also evolving. Uninterrupted VKA and DOAC therapy has been shown to reduce perioperative thromboembolic risk with no significant escalation in major bleeding. Currently, under investigation is a minimally interrupted approach to anticoagulation with DOACs periablation. Questions remain, especially regarding the delivery of anticoagulation care and integration of wearable rhythm monitors in AF management.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Dec 2019; 106:10-17
Jame S, Barnes G
Heart: 30 Dec 2019; 106:10-17 | PMID: 31533990
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Impact:
Abstract

The association of ischaemic stroke in patients with heart failure without atrial flutter/fibrillation.

Chou YL, Liou JT, Cheng CC, Tsai MC, ... Lin CS, Kao CH
Purpose
This study evaluated the association between ischaemic stroke (IS) and heart failure (HF) in the absence of atrial fibrillation (AF) or atrial flutter (AFL) using a population-based nation-wide cohort database.
Method
Newly diagnosed patients with HF without previous stroke and acute myocardial infarction (AMI) were enrolled. Based on the propensity scores matching age, sex and all comorbidities, our studies comprised 12 179 patients with HF and 12 179 patients without HF. Cox proportion hazard regression models and competing-risk regression models were used to evaluate the risk of IS among patients with HF without AF or AFL.
Results
In the multivariable analysis, older age (adjusted HR (95% CI)=1.05 (1.04 to 1.05)), male sex (adjusted HR (95% CI)=1.36 (1.24 to 1.50)), diabetes (adjusted HR (95% CI)=2.22 (1.97 to 2.49)) and hypertension (adjusted HR (95% CI)=1.60 (1.41 to 1.82)) were markedly associated with IS in patients with HF. The HF group had a markedly higher risk of IS than did the non-HF group (subdistribution HR (SHR)=1.51, 95% CI: 1.37 to 1.66) and AMI (SHR=3.40, 95% CI: 2.71 to 4.28). Additionally, according to the Kaplan-Meier analysis, patients with HF were at a significantly higher risk of cumulative incidence of IS and AMI than did patients with non-HF (p value of log-rank test <0.001).
Conclusion
This study indicated that HF is a strong independent risk factor for IS, even in the absence of AF or AFL. Clinical physicians should investigate IS through routine screening and careful monitoring of patients with HF.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2020; 106:616-623
Chou YL, Liou JT, Cheng CC, Tsai MC, ... Lin CS, Kao CH
Heart: 30 Mar 2020; 106:616-623 | PMID: 31582568
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Impact:
Abstract

Female sex as a risk factor for ischaemic stroke varies with age in patients with atrial fibrillation.

Wu VC, Wu M, Aboyans V, Chang SH, ... Chu PH, Lin YS
Objectives
Female sex is an inconsistent ischaemic stroke risk factor in patients with atrial fibrillation (AF). We hypothesised that the ischaemic stroke risk varies with age among women compared with men.
Methods
We retrieved the patients with newly diagnosed AF during 2001-2013 from Taiwan\'s National Health Insurance Research Database. Patients with missing information, age <20 years, history of valvular heart disease and surgery, rheumatic heart disease, hyperthyroidism or anticoagulation and/or antiplatelet use were excluded. Propensity score matching (PSM) included patient comorbidities, medications and index date stratified by age and sex groups. Primary outcome was defined as ischaemic stroke at follow-up.
Results
After exclusion criteria, 87 369 men and 71 853 women remained for analysis (aged 73.1±14.4 years). After 1:1 PSM, we included 59 583 men (aged 73.5±13.7 years) and 59 583 women (aged 73.4±13.8 years) for analysis. We also stratified patients by age. The ischaemic stroke risk varied with age in women compared with men: lower in the ≤55 years (subdistribution HR (SHR)=0.75, 95% CI 0.62 to 0.90) and 56-65 years (SHR=0.87, 95% CI 0.78 to 0.98) groups, neutral in the 66-75 years group (SHR=1.01, 95% CI 0.94 to 1.08) and adverse in the >75 years group (SHR=1.14, 95% CI 1.09 to 1.19).
Conclusions
The female/male ischaemic stroke risk ratio varied with age. Only women aged >75 years had a higher risk, whereas women aged <65 years had a lower risk compared with men. These findings challenge the \'sex category\' component of the CHADS-VASc score, used to make decision regarding anticoagulation treatment in AF patients.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2020; 106:534-540
Wu VC, Wu M, Aboyans V, Chang SH, ... Chu PH, Lin YS
Heart: 30 Mar 2020; 106:534-540 | PMID: 31558571
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Impact:
Abstract

D-dimer blood concentrations to exclude left atrial thrombus in patients with atrial fibrillation.

Almorad A, Ohanyan A, Pintea Bentea G, Wielandts JY, ... Knecht S, Castro Rodriguez J
Objective
Left atrial (LA) thrombus is routinely excluded by transoesophageal echocardiography (TOE) before cardioversion for non-valvular atrial fibrillation (AF). In the D-dimer blood concentrations to exclude LA thrombus in patients with AF study, two D-dimer cut-offs were compared to exclude LA thrombus prior to cardioversion. One was fixed to 500 ng/mL (DD500), based on clinical practice where such values are commonly accepted to exclude a thrombus. The other cut-off was adjusted to 10 times the patient\'s age (DDAge), based on the cut-off used to exclude pulmonary embolism.
Methods
142 consecutive patients with non-valvular AF aged 69.7±11.4 years (52% with paroxysmal AF) referred for precardioversion TOE to exclude LA thrombus were prospectively enrolled. D-dimers were measured at the time of TOE by an ELISA test.
Results
LA thrombus was excluded with TOE in 129 (91%) and confirmed in 13 (9%) patients. D-dimers were significantly lower in patients without LA thrombus (729±611 vs 2376±1081 ng/L; p<0.05). DDAge indicated absence of LA thrombus with higher specificity than DD500 (66.4% vs 50.4%; p<0.05). Both cut-offs were able to identify all 13 patients with LA thrombus (false negative 0%). Patients with D-dimers Conclusions
This study demonstrates the efficacy of D-dimer cut-offs to exclude LA thrombus in patients with AF. Age adjustment greatly increases the proportion of patients in whom LA thrombus can be safely excluded and consequently avoid precardioversion TOE.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 20 Oct 2020; epub ahead of print
Almorad A, Ohanyan A, Pintea Bentea G, Wielandts JY, ... Knecht S, Castro Rodriguez J
Heart: 20 Oct 2020; epub ahead of print | PMID: 33087410
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Impact:
Abstract

Association Between Atrial Fibrillation and Sudden Cardiac Death: Pathophysiological and Epidemiological Insights.

Waldmann V, Jouven X, Narayanan K, Piot O, ... Albert CM, Marijon E

Emerging evidence suggests that atrial fibrillation (AF) may be associated with an increased risk of sudden cardiac death (SCD). However, AF shares risk factors with numerous cardiac conditions, including coronary heart disease and heart failure-the 2 most common substrates for SCD-making the AF-SCD relationship particularly challenging to address. A careful consideration of confounding factors is essential, since interventions for AF will be effective in reducing SCD only if there is a causal association between these 2 conditions. In this translational review, we detail the plausible underlying pathophysiological mechanisms through which AF may promote or lead to SCD, as well as the existing epidemiological evidence supporting an association between AF and SCD. While the role of AF in predicting SCD in the general population appears limited and not established, AF might be integrated to improve risk stratification in some specific phenotypes. Optimal AF management, including that of its associated conditions, appears to be of interest to prevent AF-related SCD, especially because the AF-SCD relationship is in part driven by heart failure.



Circ Res: 02 Jul 2020; 127:301-309
Waldmann V, Jouven X, Narayanan K, Piot O, ... Albert CM, Marijon E
Circ Res: 02 Jul 2020; 127:301-309 | PMID: 32833581
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Impact:
Abstract

Epidemiology of Atrial Fibrillation in the 21st Century: Novel Methods and New Insights.

Kornej J, Börschel CS, Benjamin EJ, Schnabel RB

Accompanying the aging of populations worldwide, and increased survival with chronic diseases, the incidence and prevalence of atrial fibrillation (AF) are rising, justifying the term global epidemic. This multifactorial arrhythmia is intertwined with common concomitant cardiovascular diseases, which share classical cardiovascular risk factors. Targeted prevention programs are largely missing. Prevention needs to start at an early age with primordial interventions at the population level. The public health dimension of AF motivates research in modifiable AF risk factors and improved precision in AF prediction and management. In this review, we summarize current knowledge in an attempt to untangle these multifaceted associations from an epidemiological perspective. We discuss disease trends, preventive opportunities offered by underlying risk factors and concomitant disorders, current developments in diagnosis and risk prediction, and prognostic implications of AF and its complications. Finally, we review current technological (eg, eHealth) and methodological (artificial intelligence) advances and their relevance for future prevention and disease management.



Circ Res: 18 Jan 2020; 127:4-20
Kornej J, Börschel CS, Benjamin EJ, Schnabel RB
Circ Res: 18 Jan 2020; 127:4-20 | PMID: 32716709
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Impact:
Abstract

Vitamin K versus warfarin interruption alone in patients without bleeding and an international normalized ratio > 10.

Farrow GS, Delate T, McNeil K, Jones AE, ... Crowther MA, Clark NP
Background
Reversal of an international normalized ratio (INR) > 10 with vitamin K is recommended in patients experiencing bleeding; however, information on outcomes with reversal using vitamin K in non-bleeding patients is lacking.
Objective
To compare clinical and safety outcomes between non-bleeding patients receiving warfarin with an INR > 10 who did and did not receive a prescription for vitamin K.
Patients/methods
This was a retrospective cohort study conducted in an integrated health-care delivery system. Adult patients receiving warfarin therapy who experienced an INR > 10 without bleeding between 01/01/2006 and 06/30/2018 were included. Patients were assessed for an outpatient dispensing or in-office administration of vitamin K on the day of or the day after an INR > 10 and then clinically relevant bleeding, thromboembolism, all-cause mortality, and time to INR < 4 within the next 30 days.
Results
A total of 809 patients was included with 332 and 477 who were and were not dispensed vitamin K, respectively. Overall, mean patient age was 71.7 years, 60.1% were female and the mean INR was 10.4 at presentation. There were no differences between groups in 30-day rates of bleeding or thromboembolism (both P > .05). Patients dispensed vitamin K had a higher likelihood of mortality (15.1% versus 10.1%, P = .032, adjusted odds ratio = 1.63, 95% confidence interval 1.03 to 2.57). Overall, time to an INR < 4 was similar between groups.
Conclusion
Vitamin K administration was not associated with improved clinical outcomes in asymptomatic patients with an INR > 10.

© 2020 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 30 Dec 2019; 18:1133-1140
Farrow GS, Delate T, McNeil K, Jones AE, ... Crowther MA, Clark NP
J Thromb Haemost: 30 Dec 2019; 18:1133-1140 | PMID: 32073738
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Impact:
Abstract

Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages.

Barra ME, Das AS, Hayes BD, Rosenthal ES, ... Goldstein JN, Roberts RJ
Background/objective
Before approval of andexanet alfa, off-label treatment with 4-factor prothrombin complex concentrate (4F-PCC) was often utilized for the management of life-threatening hemorrhages associated with oral factor Xa inhibitors. We evaluated the operational processes and outcomes of patients with oral factor Xa inhibitor-associated intracranial hemorrhages (ICH) treated with andexanet alfa or 4F-PCC.
Methods
We performed a retrospective, single-center case series of rivaroxaban or apixaban-associated ICH between 2016-2019 treated with andexanet alfa or 4F-PCC. Good or excellent hemostatic effectiveness, good functional outcome (Glasgow Outcome Score [GOS]> 3) at hospital discharge, and incidence of thrombosis within 30 days were reported.
Results
Eighteen patients were included in the andexanet alfa cohort and 11 in the 4F-PCC cohort. Excellent or good hemostasis occurred in 88.9% of andexanet alfa-treated patients and 60% of 4F-PCC-treated patients. Good functional outcome on discharge occurred in 55.6% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Thrombotic complications occurred in 16.7% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Median order-to-administration time was 1.1 hours [0.8-1.4] versus 0.5 hours [0.1-0.8] in the andexanet alfa and 4F-PCC group, respectively. The median cost of therapy was $29970/patient versus $6925/patient in the andexanet alfa and 4F-PCC group, respectively.
Conclusions
We observed higher rates of occurrence of good or excellent hemostasis and GOS > 3 on hospital discharge and increased incidence of thrombosis in patients who received andexanet alfa compared to 4F-PCC for oral factor Xa inhibitor reversal. However, patients receiving 4F-PCC had lower pre-reversal Glasgow Coma Scale (GCS)score and larger pre-reversal ICH volume.

© 2020 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 29 Jun 2020; 18:1637-1647
Barra ME, Das AS, Hayes BD, Rosenthal ES, ... Goldstein JN, Roberts RJ
J Thromb Haemost: 29 Jun 2020; 18:1637-1647 | PMID: 32291874
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Abstract

Association of New-Onset Atrial Fibrillation After Noncardiac Surgery With Subsequent Stroke and Transient Ischemic Attack.

Siontis KC, Gersh BJ, Weston SA, Jiang R, ... Noseworthy PA, Chamberlain AM
Importance
Outcomes of postoperative atrial fibrillation (AF) after noncardiac surgery are not well defined.
Objective
To determine the association of new-onset postoperative AF vs no AF after noncardiac surgery with risk of nonfatal and fatal outcomes.
Design, setting, and participants
Retrospective cohort study in Olmsted County, Minnesota, involving 550 patients who had their first-ever documented AF within 30 days after undergoing a noncardiac surgery (postoperative AF) between 2000 and 2013. Of these patients, 452 were matched 1:1 on age, sex, year of surgery, and type of surgery to patients with noncardiac surgery who were not diagnosed with AF within 30 days following the surgery (no AF). The last date of follow-up was December 31, 2018.
Exposures
Postoperative AF vs no AF after noncardiac surgery.
Main outcomes and measures
The primary outcome was ischemic stroke or transient ischemic attack (TIA). Secondary outcomes included subsequent documented AF, all-cause mortality, and cardiovascular mortality.
Results
The median age of the 452 matched patients was 75 years (IQR, 67-82 years) and 51.8% of patients were men. Patients with postoperative AF had significantly higher CHA2DS2-VASc scores than those in the no AF group (median, 4 [IQR, 2-5] vs 3 [IQR, 2-5]; P < .001). Over a median follow-up of 5.4 years (IQR, 1.4-9.2 years), there were 71 ischemic strokes or TIAs, 266 subsequent documented AF episodes, and 571 deaths, of which 172 were cardiovascular related. Patients with postoperative AF exhibited a statistically significantly higher risk of ischemic stroke or TIA (incidence rate, 18.9 vs 10.0 per 1000 person-years; absolute risk difference [RD] at 5 years, 4.7%; 95% CI, 1.0%-8.4%; HR, 2.69; 95% CI, 1.35-5.37) compared with those with no AF. Patients with postoperative AF had statistically significantly higher risks of subsequent documented AF (incidence rate 136.4 vs 21.6 per 1000 person-years; absolute RD at 5 years, 39.3%; 95% CI, 33.6%-45.0%; HR, 7.94; 95% CI, 4.85-12.98), and all-cause death (incidence rate, 133.2 vs 86.8 per 1000 person-years; absolute RD at 5 years, 9.4%; 95% CI, 4.9%-13.7%; HR, 1.66; 95% CI, 1.32-2.09). No significant difference in the risk of cardiovascular death was observed for patients with and without postoperative AF (incidence rate, 42.5 vs 25.0 per 1000 person-years; absolute RD at 5 years, 6.2%; 95% CI, 2.2%-10.4%; HR, 1.51; 95% CI, 0.97-2.34).
Conclusions and relevance
Among patients undergoing noncardiac surgery, new-onset postoperative AF compared with no AF was associated with a significant increased risk of stroke or TIA. However, the implications of these findings for the management of postoperative AF, such as the need for anticoagulation therapy, require investigation in randomized trials.



JAMA: 31 Dec 2019; 324:871-878
Siontis KC, Gersh BJ, Weston SA, Jiang R, ... Noseworthy PA, Chamberlain AM
JAMA: 31 Dec 2019; 324:871-878 | PMID: 32870297
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Abstract

How Will Machine Learning Inform the Clinical Care of Atrial Fibrillation?

Siontis KC, Yao X, Pirruccello JP, Philippakis AA, Noseworthy PA

Machine learning applications in cardiology have rapidly evolved in the past decade. With the availability of machine learning tools coupled with vast data sources, the management of atrial fibrillation (AF), a common chronic disease with significant associated morbidity and socioeconomic impact, is undergoing a knowledge and practice transformation in the increasingly complex healthcare environment. Among other advances, deep-learning machine learning methods, including convolutional neural networks, have enabled the development of AF screening pathways using the ubiquitous 12-lead ECG to detect asymptomatic paroxysmal AF in at-risk populations (such as those with cryptogenic stroke), the refinement of AF and stroke prediction schemes through comprehensive digital phenotyping using structured and unstructured data abstraction from the electronic health record or wearable monitoring technologies, and the optimization of treatment strategies, ranging from stroke prophylaxis to monitoring of antiarrhythmic drug (AAD) therapy. Although the clinical and population-wide impact of these tools continues to be elucidated, such transformative progress does not come without challenges, such as the concerns about adopting black box technologies, assessing input data quality for training such models, and the risk of perpetuating rather than alleviating health disparities. This review critically appraises the advances of machine learning related to the care of AF thus far, their potential future directions, and its potential limitations and challenges.



Circ Res: 18 Jan 2020; 127:155-169
Siontis KC, Yao X, Pirruccello JP, Philippakis AA, Noseworthy PA
Circ Res: 18 Jan 2020; 127:155-169 | PMID: 32833571
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Abstract

Emerging Technologies for Identifying Atrial Fibrillation.

Ding EY, Marcus GM, McManus DD

Atrial fibrillation (AF) is a major cause of morbidity and mortality globally, and much of this is driven by challenges in its timely diagnosis and treatment. Existing and emerging mobile technologies have been used to successfully identify AF in a variety of clinical and community settings, and while these technologies offer great promise for revolutionizing AF detection and screening, several major barriers may impede their effectiveness. The unclear clinical significance of device-detected AF, potential challenges in integrating patient-generated data into existing healthcare systems and clinical workflows, harm resulting from potential false positives, and identifying the appropriate scope of population-based screening efforts are all potential concerns that warrant further investigation. It is crucial for stakeholders such as healthcare providers, researchers, funding agencies, insurers, and engineers to actively work together in fulfilling the tremendous potential of mobile technologies to improve AF identification and management on a population level.



Circ Res: 18 Jan 2020; 127:128-142
Ding EY, Marcus GM, McManus DD
Circ Res: 18 Jan 2020; 127:128-142 | PMID: 32716695
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Abstract

How Will Genetics Inform the Clinical Care of Atrial Fibrillation?

Shoemaker MB, Shah RL, Roden DM, Perez MV

Susceptibility to atrial fibrillation (AF) is determined by well-recognized risk factors such as diabetes mellitus or hypertension, emerging risk factors such as sleep apnea or inflammation, and increasingly well-defined genetic variants. As discussed in detail in a companion article in this series, studies in families and in large populations have identified multiple genetic loci, specific genes, and specific variants increasing susceptibility to AF. Since it is becoming increasingly inexpensive to obtain genotype data and indeed whole genome sequence data, the question then becomes to define whether using emerging new genetics knowledge can improve care for patients both before and after development of AF. Examples of improvements in care could include identifying patients at increased risk for AF (and thus deploying increased surveillance or even low-risk preventive therapies should these be available), identifying patient subsets in whom specific therapies are likely to be effective or ineffective or in whom the driving biology could motivate the development of new mechanism-based therapies or identifying an underlying susceptibility to comorbid cardiovascular disease. While current guidelines for the care of patients with AF do not recommend routine genetic testing, this rapidly increasing knowledge base suggests that testing may now or soon have a place in the management of select patients. The opportunity is to generate, validate, and deploy clinical predictors (including family history) of AF risk, to assess the utility of incorporating genomic variants into those predictors, and to identify and validate interventions such as wearable or implantable device-based monitoring ultimately to intervene in patients with AF before they present with catastrophic complications like heart failure or stroke.



Circ Res: 18 Jan 2020; 127:111-127
Shoemaker MB, Shah RL, Roden DM, Perez MV
Circ Res: 18 Jan 2020; 127:111-127 | PMID: 32716712
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Abstract

Population-Based Screening for Atrial Fibrillation.

Khurshid S, Healey JS, McIntyre WF, Lubitz SA

Atrial fibrillation (AF) is a common and morbid arrhythmia. Stroke is a major hazard of AF and may be preventable with oral anticoagulation. Yet since AF is often asymptomatic, many individuals with AF may be unaware and do not receive treatment that could prevent a stroke. Screening for AF has gained substantial attention in recent years as several studies have demonstrated that screening is feasible. Advances in technology have enabled a variety of approaches to facilitate screening for AF using both medical-prescribed devices as well as consumer electronic devices capable of detecting AF. Yet controversy about the utility of AF screening remains owing to concerns about potential harms resulting from screening in the absence of randomized data demonstrating effectiveness of screening on outcomes such as stroke and bleeding. In this review, we summarize current literature, present technology, population-based screening considerations, and consensus guidelines addressing the role of AF screening in practice.



Circ Res: 18 Jan 2020; 127:143-154
Khurshid S, Healey JS, McIntyre WF, Lubitz SA
Circ Res: 18 Jan 2020; 127:143-154 | PMID: 32716713
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Abstract

Genetics of Atrial Fibrillation in 2020: GWAS, Genome Sequencing, Polygenic Risk, and Beyond.

Roselli C, Rienstra M, Ellinor PT

Atrial fibrillation is a common heart rhythm disorder that leads to an increased risk for stroke and heart failure. Atrial fibrillation is a complex disease with both environmental and genetic risk factors that contribute to the arrhythmia. Over the last decade, rapid progress has been made in identifying the genetic basis for this common condition. In this review, we provide an overview of the primary types of genetic analyses performed for atrial fibrillation, including linkage studies, genome-wide association studies, and studies of rare coding variation. With these results in mind, we aim to highlighting the existing knowledge gaps and future directions for atrial fibrillation genetics research.



Circ Res: 18 Jan 2020; 127:21-33
Roselli C, Rienstra M, Ellinor PT
Circ Res: 18 Jan 2020; 127:21-33 | PMID: 32716721
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Abstract

Animal Models of Atrial Fibrillation.

Schüttler D, Bapat A, Kääb S, Lee K, ... Clauss S, Hucker WJ

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although \"natural\" AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a \"perfect\" animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.



Circ Res: 18 Jan 2020; 127:91-110
Schüttler D, Bapat A, Kääb S, Lee K, ... Clauss S, Hucker WJ
Circ Res: 18 Jan 2020; 127:91-110 | PMID: 32716814
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Abstract

Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation.

van Ouwerkerk AF, Hall AW, Kadow ZA, Lazarevic S, ... Moskowitz IP, Christoffels VM

Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. In this review, we discuss a transcriptional regulatory network model for AF defined by effector genes in Genome-wide association studies loci. We describe the current state of the field regarding the identification and function of AF-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. We illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact AF risk. Last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.



Circ Res: 18 Jan 2020; 127:34-50
van Ouwerkerk AF, Hall AW, Kadow ZA, Lazarevic S, ... Moskowitz IP, Christoffels VM
Circ Res: 18 Jan 2020; 127:34-50 | PMID: 32717170
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Abstract

Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective.

Nattel S, Heijman J, Zhou L, Dobrev D

Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality. There have been significant management advances over the past 2 decades, but the burden of the disease continues to increase and there is certainly plenty of room for improvement in treatment options. A potential key to therapeutic innovation is a better understanding of underlying fundamental mechanisms. This article reviews recent advances in understanding the molecular basis for AF, with a particular emphasis on relating these new insights to opportunities for clinical translation. We first review the evidence relating basic electrophysiological mechanisms to the characteristics of clinical AF. We then discuss the molecular control of factors leading to some of the principal determinants, including abnormalities in impulse conduction (such as tissue fibrosis and other extra-cardiomyocyte alterations, connexin dysregulation and Na-channel dysfunction), electrical refractoriness, and impulse generation. We then consider the molecular drivers of AF progression, including a range of Ca-dependent intracellular processes, microRNA changes, and inflammatory signaling. The concept of key interactome-related nodal points is then evaluated, dealing with systems like those associated with CaMKII (Ca/calmodulin-dependent protein kinase-II), NLRP3 (NACHT, LRR, and PYD domains-containing protein-3), and transcription-factors like TBX5 and PitX2c. We conclude with a critical discussion of therapeutic implications, knowledge gaps and future directions, dealing with such aspects as drug repurposing, biologicals, multispecific drugs, the targeting of cardiomyocyte inflammatory signaling and potential considerations in intervening at the level of interactomes and gene-regulation. The area of molecular intervention for AF management presents exciting new opportunities, along with substantial challenges.



Circ Res: 18 Jan 2020; 127:51-72
Nattel S, Heijman J, Zhou L, Dobrev D
Circ Res: 18 Jan 2020; 127:51-72 | PMID: 32717172
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Abstract

A New Therapeutic Framework for Atrial Fibrillation Drug Development.

Ang YS, Rajamani S, Haldar SM, Hüser J

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia and cause of significant morbidity and mortality. Its increasing prevalence in aging societies constitutes a growing challenge to global healthcare systems. Despite substantial unmet needs in AF prevention and treatment, drug developments hitherto have been challenging, and the current pharmaceutical pipeline is nearly empty. In this review, we argue that current drugs for AF are inadequate because of an oversimplified system for patient classification and the development of drugs that do not interdict underlying disease mechanisms. We posit that an improved understanding of AF molecular pathophysiology related to the continuous identification of novel disease-modifying drug targets and an increased appreciation of patient heterogeneity provide a new framework to personalize AF drug development. Together with recent innovations in diagnostics, remote rhythm monitoring, and big data capabilities, we anticipate that adoption of a new framework for patient subsegmentation based on pathophysiological, genetic, and molecular subsets will improve success rates of clinical trials and advance drugs that reduce the individual patient and public health burden of AF.



Circ Res: 18 Jan 2020; 127:184-201
Ang YS, Rajamani S, Haldar SM, Hüser J
Circ Res: 18 Jan 2020; 127:184-201 | PMID: 32717173
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