Management of atrial fibrillation: role of population screening, biomarkers, and polygenic risk scores

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Sudden cardiac arrest (SCA) is a challenging situation, particularly when it happens out of hospital.1–4 This Focus Issue on arrhythmias contains the contribution entitled ‘Association between basic life support and survival in sports-related sudden cardiac arrest: a meta-analysis’ by Laurianne Michelland from Université Paris Cité in France, and colleagues.5 The authors evaluate the association of basic life support with survival after sports-related SCA (SR-SCA). In a systematic review and meta-analysis, a search of several databases from their inception to 31 July 2021 without language restrictions was conducted. Studies were considered eligible if they evaluated one of three scenarios in patients with SR-SCA: (i) bystander presence; (ii) bystander cardiopulmonary resuscitation (CPR); or (iii) bystander automated external defibrillator (AED) use, and provided information on survival. The primary outcome was survival at the longest follow-up. The meta-analysis was conducted using the random-effects model. The meta-analysis showed significant benefit on survival in all three groups: bystander presence [odds ratio (OR) 2.55], bystander CPR (OR 3.84), and bystander AED use (OR 5.25). Michelland and colleagues conclude that in patients with SR-SCA, bystander presence, bystander CPR, and bystander AED use are significantly associated with survival. These results highlight the importance of witness intervention and encourage countries to develop their first aid training policy and AED installation in sports settings. The contribution is accompanied by an Editorial by Domenico Corrado, Alessandro Zorzi, and Alberto Cipriani from the University of Padova in Italy.6 The three authors note that SR-SCA is characteristically witnessed, providing the opportunity for rapid CPR and prompt access to an on-site AED which results in excellent rates of survival, as shown by the study of Michelland et al. However, still today, athletes experiencing witnessed SCA may die or have severe cerebral damage because SCA is not promptly recognized, and defibrillation is too late. Since most SCAs during sports are shockable and early defibrillation critically influences the outcome, further improvement of survival is expected by immediate use of the AED in the case of a non-traumatic fall of an athlete, skipping traditional steps of the resuscitation protocol, such as time-consuming recognition of cardiac arrest, and letting the device do the job first. This working hypothesis needs to be tested by further studies. Implementation of emergency programmes for prevention of SCD in athletes is warranted, with widespread distribution of AEDs in sports arenas and training of coaches and staff to perform resuscitation intervention with early defibrillation. The best approach to the early detection of atrial fibrillation (AF) remains unsettled.7–11 In a Clinical Research article entitled ‘Cost-effectiveness of population screening for atrial fibrillation: the STROKESTOP study’, Johan Lyth from the Linköping University in Sweden, and colleagues note that the STROKESTOP study, which randomized 27 975 persons aged 75/76 years into a screening invitation group and a control group, has a median follow-up time of 6.9 years.12 The aim of this study was to estimate the cost-effectiveness of population-based screening for AF using clinical outcomes. The analysis is based on a Markov cohort model. The prevalence of AF, the use of oral anticoagulation, clinical event data, and all-cause mortality were taken from the STROKESTOP study. The cost for clinical events, age-specific utilities, utility decrement due to stroke, and stroke death was taken from the literature. Per 1000 individuals invited to the screening, there were 77 gained life years and 65 gained quality-adjusted life years. The incremental cost was €1.77 million lower in the screening invitation group. Gained quality-adjusted life years to a lower cost means that the screening strategy was dominant. The result from 10 000 Monte Carlo simulations showed that the AF screening strategy was cost-effective in 99.2% and cost-saving in 92.7% of the simulations (Figure 1). QALY, quality-adjusted life year.12 The authors conclude that based on the STROKESTOP study, this analysis shows that a broad AF screening strategy in an elderly population is cost-effective. Efforts should be made to increase screening participation. The contribution is accompanied by an Editorial contributed by Erica Spatz and Jeph Herrin from the Yale School of Medicine in New Haven, CT, USA.13 The authors note that globally, stroke remains the second leading cause of death and is associated with devastating morbidity. Potentially, a quarter of all strokes could be prevented with timely identification of AF and prophylactic treatment with anticoagulation; this is not only compelling but has been demonstrated to be feasible. Lyth et al.’s study on the cost-effectiveness of AF screening in an older population adds to this justification, with the potential for cost savings driven by stroke reduction. Future studies in different countries and contextual environments and with different healthcare utilization and cost considerations from those assumed in this study will need to be conducted to determine whether these findings apply to other settings. In the meantime, this study sheds light on the costs and benefits of a large-scale population-based screening programme for AF in Sweden, that could be a blueprint for stopping preventable strokes. While biomarkers are widely used in the management of myocardial infarction and heart failure, their utilization in the setting of AF is limited.14–16 Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. In a Clinical Research article entitled ‘Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation’, Ziad Hijazi from Uppsala University in Sweden, and colleagues evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with or without oral anticoagulation (OAC).17 BMP10 was measured in plasma samples collected at randomization in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). Associations with outcomes were evaluated by Cox regression models adjusted for clinical characteristics, kidney function, and N-terminal probrain natriuretic peptide (NT-proBNP). Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death. Hijazi et al. conclude that the novel atrial biomarker BMP10 is independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke. The contribution is accompanied by an Editorial by Moritz Sinner and Aenne von Falkenhausen from LMU Munich in Germany.18 Sinner and von Falkenhausen conclude that the new insights into AF and stroke pathophysiology presented by Hijazi et al. are highly valuable. The improved characterization of BMP10 as an easily measurable biomarker of high atrial specificity might improve clinical applicability soon. However, the causal role of BMP10 in the pathophysiology of AF or atrial cardiomyopathy will require further elaboration. Polygenic risk scores are emerging in several fields of cardiovascular medicine.19,20 In a Clinical Research article entitled ‘A polygenic risk score predicts atrial fibrillation in cardiovascular disease’, Nicholas Marston from Brigham and Women’s Hospital in Boston, MA, USA and colleagues indicate that interest in targeted screening programmes for AF has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear.21 A total of 36 662 subjects without prior AF were analysed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan–Meier event rates, adjusted hazard ratios (HRs), C-indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and NT-proBNP. Over 2.3 years, 1018 new AF cases developed. The AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1 SD increase in PRS (HR 1.40, P < 0.001). Those with a high AF PRS (top 20%) were more than two-fold more likely to develop AF (HR 2.45, P < 0.001) compared with those with a low PRS (bottom 20%). Furthermore, the PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C-index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP and increased further to 0.70 (P < 0.001) with the addition of the PRS (Figure 2). Classification of the study population by genetic, clinical, and biomarker risk for atrial fibrillation (AF). PRS, polygenic risk score; CHARGE-AF, Cohorts for Heart and Aging Research in Genomic Epidemiology for Atrial Fibrillation (risk score including age, height, weight, systolic blood pressure, diastolic blood pressure, current tobacco use, antihypertensive medication use, diabetes, heart failure, and prior myocardial infarction). Rates of incident AF by genetic, clinical, and biomarker risk categories are shown.21 Marston et al. conclude that in patients with cardiovascular conditions, the AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP. This manuscript is accompanied by an Editorial by Paulus Kirchhof from University Medical Center Hamburg–Eppendorf in Germany, and colleagues.22 The authors conclude that further work is needed to demonstrate that integrating this type of information can be used to guide AF management. Harnessing this information can help to prevent the complications of AF earlier, e.g. by initiating early rhythm control therapy and OAC. Future concepts of AF therapy tailored to PRS genotypes or biomolecule patterns will require clinical testing, but are imaginable in the future. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Are there other factors that influence the assessment of bleeding risk comparing potent P2Y12 inhibitors with clopidogrel?’, Cheng Xie, Yuzhen Zhang, and Jia Lin from the The First Affiliated Hospital of Soochow University in China comment on the recent publication ‘Comparative effects of guided vs. potent P2Y12 inhibitor therapy in acute coronary syndrome: a network meta-analysis of 61 898 patients from 15 randomized trials’ by Mattia Galli from the University of Florida College of Medicine in Jacksonville, FL, USA.23,24 Galli et al. respond in a separate comment.25 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.