https://orcid.org/0000-0002-9482-411X
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This Focus Issue on trials and epidemiology, prevention, and healthcare policies contains the Fast Track Congress contribution ‘Acoustic-based rule-out of stable coronary artery disease: the FILTER-SCAD trial’ by Louise Hougesen Bjerking from the Copenhagen University Hospital—Bispebjerg and Frederiksberg in Denmark.1 The diagnostic workup of patients with suspected chronic coronary syndrome is complex and still controversial.2–9 The authors point out that overtesting of low-risk patients with suspect chronic coronary syndrome (CCS) is widespread. The acoustic-based coronary artery disease (CAD)-score has superior rule-out capabilities when added to pre-test probability (PTP). FILTER-SCAD tested whether providing a CAD-score and PTP to cardiologists was superior to PTP alone in limiting testing. At six Danish and Swedish outpatient clinics, patients with suspected new-onset CCS were randomized to either standard diagnostic examination (SDE) with PTP, or SDE plus CAD-score, and cardiologists were provided with corresponding recommended diagnostic flowcharts. The primary endpoint was the ncumulative number of diagnostic tests at 1 year and key safety endpoint major adverse cardiac events (MACE). In total, 2008 patients (46% male, median age 63 years) were randomized from October 2019 to September 2022. When randomized to CAD-score, it was successfully measured in 94%. Overall, 13% had PTP ≤5%, and 39% had CAD-score ≤20. Testing was deferred in 22%, with no differences in diagnostic tests between groups (P for superiority = .56). In the PTP ≤5% subgroup, the proportion with deferred testing increased from 28% to 52% (P < .001). Overall MACE was 2.4 per 100 person-years. Non-inferiority regarding safety was established (P for non-inferiority = .003). No differences were seen in angina-related health status or quality of life.
The authors conclude that the implementation strategy of providing cardiologists with a CAD-score alongside SDE does not reduce testing overall but indicates a possible role in patients with low CCS likelihood. The contribution is accompanied by an Editorial by Eugenio Picano from the University of Belgrade in Serbia.10 Picano notes that the problem of low value overtesting has become a modern pandemic, leading to unnecessary financial waste, health risks, and environmental impact. A convergence of factors—including vested interests and concerns about legal malpractice—drives overtesting, resulting in overdiagnosis and overtreatment. A key motivator for overtesting is patient reassurance. However, patients might be less reassured if they were informed transparently about the risks of excessive testing, as Bjerking clearly describes: ‘Excessive diagnostic testing also comes with some challenges and disadvantages including radiation, complications, incidental findings leading to more tests, economic costs, and patient anxiety. This in combination with a low diagnostic yield, a good prognosis, and the fact that angina pectoris often recedes without intervention, calls for a deferred testing strategy combined with optimal medical therapy and appropriate follow-up.’ To these drawbacks, we can add the significant environmental impact of medical imaging, which contributes to global carbon dioxide emissions, that affect climate change and global health.
There is growing interest in catheter ablation (CA) for atrial fibrillation (AF). Posterior wall isolation (PWI) is commonly incorporated into CA strategies for persistent AF in an attempt to improve outcomes.11–13 In a Fast Track Congress article entitled ‘Radiofrequency catheter ablation of persistent atrial fibrillation by pulmonary vein isolation with or without left atrial posterior wall isolation: long-term outcomes of the CAPLA trial’, Jeremy William from Monash University in Clayton, Australia, and colleagues remind us that in the CAPLA randomized study, adjunctive PWI did not improve freedom from atrial arrhythmia at 12 months compared with pulmonary vein isolation (PVI) alone.14 Whether additional PWI reduces arrhythmia recurrence over the longer term remains unknown. In this multicentre, international, randomized study, patients with persistent AF undergoing index CA using radiofrequency were randomized to PVI + PWI vs. PVI alone. Patients underwent regular follow-up including rhythm monitoring for a minimum of 3 years after CA. AF burden at 3 years after ablation was evaluated with either 28-day continuous ambulatory electrocardiogram (ECG) monitoring, twice-daily single-lead ECG, or from a cardiac implanted device. Evaluated endpoints included freedom from any documented atrial arrhythmia recurrence after a single procedure, AF burden, need for redo CA, rhythm at last clinical follow-up, healthcare utilization metrics, and AF-related quality of life. A total of 338 patients (mean age 64 years, 23% female) completed 3-year follow-up. At a median of 3.62 years after index ablation, freedom from recurrent atrial arrhythmia was achieved in 35% of patients randomized to PVI + PWI vs. 42% randomized to PVI alone (P = .55). Redo ablation was performed in 53% of patients in the PVI + PWI group vs. 30% (P = .68) in the PVI alone group. Sinus rhythm at final clinical follow-up was present in 85% of patients with PVI + PWI vs. 87% with PVI alone (P = .60). Mean quality-of-life score at 3 years after ablation was similar in the two groups (Figure 1).
Structured Graphical Abstract14
The authors conclude that in patients with persistent AF, the addition of PWI to PVI alone at index radiofrequency CA does not significantly improve freedom from atrial arrhythmia recurrence at long-term follow-up. The contribution is accompanied by an Editorial by Jayanthi Koneru and Kenneth Ellenbogen from the Virginia Commonwealth University School of Medicine in Richmond, VA, USA.15 The authors highlight that the guidelines for AF ablation have so far not focused on re-do procedures and there is no ablation strategy that has been advocated by the Heart Rhythm societies. There is an urgent need to fill this scientific and therapy gap, and future AF ablation guidelines should try to address these deficiencies. Importantly, the absence of data on additional ablation beyond PVI in re-do procedures should be stressed. It is encouraging to witness this trend of publishing ‘negative’ trials, because acts of omission are equally important as acts of commission in the realm of persistent AF ablation.
Conceptual framework and key results from a study of cardiovascular events following COVID-19 vaccination, based on a nationwide cohort of 8 million Swedish adults followed from December 2020 to December 202216
While the rationale for coronavirus disease 2019 (COVID-19) vaccination is to reduce complications and overall mortality, some cardiovascular complications from the vaccine itself have been demonstrated. Myocarditis and pericarditis are recognized as rare acute adverse events after mRNA vaccines in young males, while evidence regarding other cardiovascular events remains limited and inconsistent. In a Clinical Research article entitled ‘Cardiovascular events following coronavirus disease 2019 vaccination in adults: a nationwide Swedish study’, Yiyi Xu from the University of Gothenburg in Sweden, and colleagues assessed the risks of several cardiovascular and cerebrovascular events in a Swedish nationwide register-based cohort.16 Post-vaccination risk of myocarditis/pericarditis, dysrhythmias, heart failure, myocardial infarction, and cerebrovascular events (transient ischaemic attack and stroke) in several risk windows after each vaccine dose were assessed among all Swedish adults (n = 8 070 674). Hazard ratios (HRs) with 95% confidence intervals compared with unvaccinated individuals were estimated from Cox regression models adjusted for potential confounders. For most studied outcomes, decreased risks of cardiovascular events post-vaccination were observed, especially after dose three (HRs for dose three ranging from 0.69 to 0.81), while replicating the increased risk of myocarditis and pericarditis 1–2 weeks after COVID-19 mRNA vaccination. Slightly increased risks, similar across vaccines, were observed for extrasystoles (HR 1.17 for dose one and HR 1.22 for dose two, stronger in the elderly and males) but not for arrhythmias, and for transient ischaemic attack (HR 1.13) but not for stroke (Figure 2).
Xu et al. conclude that risk of myopericarditis (mRNA vaccines only), extrasystoles, and transient ischaemic attack is transiently increased after COVID-19 vaccination, but full vaccination substantially reduces the risk of several more severe COVID-19-associated cardiovascular outcomes, underscoring the protective benefits of complete vaccination. The contribution is accompanied by an Editorial by C. Raina MacIntyre from the UNSW Kirby Institute in Sydney, Australia.17 MacIntyre concludes by noting that long COVID is emerging as an important population health problem, and a significant component of it is related to cardiovascular diseases. The present study confirms that COVID-19 vaccines are safe, and it is important to ensure wider access to and uptake of boosters to all working adults, and especially those with cardiovascular risk factors.
In a Clinical Research article entitled ‘Urinary tartaric acid as a biomarker of wine consumption and cardiovascular risk: the PREDIMED trial’, Ramon Estruch from the Hospital Clinic de Barcelona in Spain and colleagues evaluate the association between urinary tartaric acid, an objective biomarker of wine consumption, and the rate of a composite clinical cardiovascular disease (CVD) event.18 A case–cohort nested study was designed within the PREDIMED trial with 1310 participants, comprising 685 incident cases of CVD and a random subcohort of 625 participants. Wine consumption was registered using validated food frequency questionnaires. Liquid chromatography–tandem mass spectrometry was used to measure urinary tartaric acid at baseline and after 1 year of intervention. Weighted Cox regression models were used to estimate the HR of CVD. Tartaric acid was correlated with self-reported wine consumption at baseline. Five categories of post-hoc urinary tartaric acid excretion were used for better representation of risk patterns. Concentrations of 3–12 and 12–35 μg/mL, which reflect ∼3–12 and 12–35 glasses/month of wine, were associated with lower CVD risk (HR = 0.62, P-value = .050 and HR = 0.50, P-value = .035, respectively). Less significant associations between self-reported wine consumption and CVD risk were observed.
Estruch et al. conclude that light-to-moderate wine consumption, measured through an objective biomarker (tartaric acid), is prospectively associated with a lower CVD rate in a Mediterranean population at high cardiovascular risk. This manuscript is accompanied by an Editorial by Giovanni de Gaetano, Simona Costanzo, and Augusto Di Castelnuovo from IRCCS Neuromed in Pozzilli, Italy.19 The authors note that this study represents an important step forward in our understanding of the complex relationship between wine consumption and cardiovascular health. By leveraging urinary tartaric acid as an objective biomarker, the authors provide robust evidence that light wine consumption is associated with lower CVD risk in a Mediterranean population at high cardiovascular risk. This work not only highlights the value of objective biomarkers in nutritional epidemiology but also supports the notion that light-to-moderate wine consumption may be part of a heart-healthy diet. However, the findings also remind us of the risks associated with higher levels of consumption, underscoring the importance of moderation. Future research should continue to explore the potential of biomarkers in unravelling the intricate links between dietary habits, lifestyle, and health outcomes.
Although extreme cardiac adaptions mirroring phenotypes of cardiomyopathy have been observed in endurance athletes, adaptions to high levels of physical activity within the wider population are underexplored. In a Clinical Research article entitled ‘Device-measured physical activity and cardiac structure by magnetic resonance’, Thomas Yates from the University of Leicester in the UK, and colleagues investigated associations between device-measured physical activity and clinically relevant cardiac magnetic resonance volumetric indices.20 Individuals without known cardiovascular disease or hypertension were included from the UK Biobank. Cardiac magnetic resonance data were collected between 2015 and 2019, and measures of end-diastolic chamber volume, left ventricular (LV) wall thickness, and LV ejection fraction were extracted. Moderate-to-vigorous-intensity physical activity (MVPA), vigorous-intensity physical activity (VPA), and total physical activity were assessed via wrist-worn accelerometers. A total of 5977 women (median age 62 years) and 4134 men (64 years) were included. Each additional 10 min/day of MVPA was associated with a 0.70 mL/m2 higher indexed LV end-diastolic volume (LVEDVi) in women and a 1.08 mL/m2 higher LVEDVi in men. However, even within the top decile of MVPA, LVEDVi values remained within the normal ranges. Associations with MVPA were also observed for the right ventricle and the left/right atria, with an inverse association observed for LV ejection fraction. Associations of MVPA with maximum or average LV wall thickness were not clinically meaningful. Results for total physical activity and VPA mirrored those for MVPA.
Yates and colleagues conclude that high levels of device-measured physical activity are associated with cardiac remodelling within normal ranges. The contribution is accompanied by an Editorial by Viviana Maestrini, Maria Rosaria Squeo, and Sara Monosilio from the Sapienza University of Rome in Italy.21 The authors conclude that Yates and colleagues presented a valuable study providing information on cardiac remodelling in response to physical activity in the general population, suggesting a possible future approach based on activity quantification by wearable devices. The new generation of accelerometers may add a new dimension to the evaluation. Furthermore, the authors demonstrated the need to increase our knowledge on adaptation to the broad spectrum of possible physical activity practised by the general population, extending the analysis to different ethnicities and ages, and including different exercise regimens. This will contribute to improving our diagnostic accuracy in interpretation of cardiovascular imaging tests.
Standardized definitions for outcome measures in randomized clinical trials and observational studies are essential for robust and valid evaluation of medical products, interventions, care, and outcomes. In a Clinical Research article entitled ‘Definitions of clinical study outcome measures for cardiovascular diseases: the European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart)’, Chris Wilkinson from the University of York in the UK, and colleagues point out that the European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) project of the European Society of Cardiology aimed to create international data standards for cardiovascular clinical study outcome measures.22 The EuroHeart methods for data standard development were used. From a Global Cardiovascular Outcomes Consortium of 82 experts, five Working Groups were formed to identify and define key outcome measures for: cardiovascular disease (generic outcomes), acute coronary syndrome and percutaneous coronary intervention, atrial fibrillation, heart failure, and transcatheter aortic valve implantation. A systematic review of the literature informed a modified Delphi method to reach consensus on a final set of variables. For each variable, the Working Group provided a definition and categorized the variable as mandatory (Level 1) or optional (Level 2) based on its clinical importance and feasibility. Across the five domains, 24 Level 1 and 48 Level 2 outcome measures were identified.
The authors conclude that internationally derived and endorsed definitions for outcome measures for a range of common cardiovascular diseases and interventions are presented. These may be used for data alignment to enable high-quality observational and randomized clinical research, audit, and quality improvement for patient benefit. The manuscript is accompanied by an Editorial by Adam Timmis from the Queen Mary University of London in the UK.23 Timmis highlights that the next steps are to further expand the collaboration with new participating countries, to start up datasets in additional disease domains, and to utilize the common registry infrastructure to initiate registry-based randomized trials and safety surveillance of novel drugs and devices. This ambition is not unrealistic, and with support from national cardiac societies the EuroHeart project has the potential to become a world leader in cardiovascular data collection and analysis, making an important contribution to the ESC’s mission to reduce the burden of cardiovascular disease. This will take time, however, and meanwhile the ESC’s Atlas project is available for the provision of cardiovascular management and outcome data for all ESC member countries.
The editors hope that this issue of the European Heart Journal will be of interest to its readers.
Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, enarini outside the submitted work.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
