Long-term aspirin use in initially healthy older adults did not reduce major adverse cardiovascular events (HR 1.04) but significantly increased major hemorrhage (HR 1.24).
Absolute Event Rate: 0% vs 0%
For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Issue starts with an ESC Guidelines entitled ‘2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias’ by François Mach from Geneva University Hospital in Switzerland, and colleagues address.1 Since the publication of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias there have been several randomized controlled trials that might change patient management ahead of the next scheduled full dyslipidaemia Guidelines. This 2025 Focused Update addresses changes in recommendations for the treatment of dyslipidaemias based on new evidence published up until 31 March 2025. All major randomized controlled clinical trials and meta-analyses published after the publication of the 2019 ESC/EAS Guidelines were presented and discussed in detail before a consensus was reached about any possible classes of recommendations and levels of evidence to be assigned; these were then voted upon for inclusion by all Task Force members. Members with declared conflicts of interests in specific topics were asked to abstain from voting on those topics. The Issue continues with a focus on clinical trials starts. Chronic kidney disease (CKD) and cardiovascular disease are tightly interconnected, with common mechanisms that underlie the development and progression of both diseases, recently articulated into the framework of the cardiovascular-kidney-metabolic syndrome.2–4 In a State of the Art Review article entitled ‘Decline in glomerular filtration rate as an endpoint in heart failure clinical trials: challenges and solutions’ Lesley A. Inker from Tufts Medical Center in Boston, MA, USA, and colleagues describe the intersection of heart failure (HF) and CKD, how the glomerular filtration rate (GFR) and its change over time are assessed in both individual patients and in interventional trials, the evidence supporting the use of GFR changes as endpoints in CKD progression trials, and the challenges and possible solutions for the use of GFR as an endpoint in HF outcome trials and for the core of individual patients.5 CKD and HF commonly coexist in the same individual, with increasing evidence for common therapies in both disease states. It is valuable for patients, clinicians, and regulatory agencies to understand how to best assess CKD progression in patients with HF for evaluation of individual patients and as part of an endpoint for outcome trials. Given the relatively short duration of most HF outcome trials, early measures of CKD progression prior to the occurrence of clinical events of kidney replacement therapy would be desirable. Such surrogate measures include slowing of the decline in GFR either computed as annualized mean change in GFR (GFR slope) or time to substantial declines in GFR by specified threshold percentages (40% or 50% GFR decline). Regulatory agencies accept these endpoints for full drug approval which has enabled progress in the design and conduct of trials for CKD progression. Application of these endpoints in HF outcome trials has the potential for similar progress. However, an immediate reduction in GFR is common following initiation of several of the guideline-directed therapy for HF. Understanding how to best interpret an immediate GFR reduction vs long-term kidney benefit is critical to optimal assessment of endpoint in an outcome trial and in the use of these medications for the management of patients with HF. Here, the intersection of HF and CKD is described, how GFR and its change over time are assessed in both individual patients and in interventional trials, the evidence supporting use of GFR changes as endpoints in CKD progression trials, and the challenges and possible solutions for the use of GFR as endpoint in HF outcome trials and for care of individual patients, guided by case studies to inform the discussion. Invasive coronary function testing (CFT) identifies coronary vasomotor disorders in up to 90% of patients with angina with non-obstructive coronary arteries (ANOCA). In a Fast Track Clinical Research article entitled ‘Coronary function testing vs angiography alone to guide treatment of angina with non-obstructive coronary arteries: the ILIAS ANOCA trial’ by Coen K.M. Boerhout from Amsterdam University Medical Center in The Netherlands, and colleagues.6 After excluding patients with obstructive coronary artery disease (CAD) during clinically indicated invasive coronary angiography (ICA), eligible patients underwent CFT and were randomized to either the standard care group, where CFT results remained blinded, or the intervention group, where CFT results were disclosed along with a tailored medical therapy protocol. The primary outcome was the mean difference in the within-subject change in Seattle Angina Questionnaire Summary Score (SAQSS) between groups from baseline to a follow-up of 6 months. The trial is registered with the International Clinical Trials Registry Platform (NL-OMON20739). A total of 255 patients consented, of whom 153 patients (60%) without CAD underwent CFT and were randomized 1:1 to the standard care (n = 76) or intervention group (n = 77). All CFT procedures were successful without adverse events. A vasomotor disorder was identified in 120 patients (78%). At 6 month follow-up, the SAQSS improved significantly in the intervention group compared with the control group, with an intervention effect of 9.4 units (P = .001). There were no major adverse cardiac events at the 6 month follow-up (Figure 1). Graphical summary of the study flow, safety outcomes, CFT diagnoses, and primary outcome of Seattle Angina Questionnaire Summary Score change from baseline to a follow-up of 6 months. ANOCA, angina with non-obstructive coronary arteries; CFT, coronary function testing; CI, confidence interval; CMD, coronary microvascular dysfunction; SAQ, Seattle Angina Questionnaire6 The authors conclude that routine CFT during the initial ICA is feasible, safe, and has high diagnostic yield. Implementing a pragmatic CFT protocol combined with a disease-specific treatment protocol significantly improves disease-related quality of life in patients with ANOCA compared with standard care. The manuscript is accompanied by an Editorial by Rocco A. Montone, Antonio Maria Leone, and Filippo Crea from Agostino Gemelli University Hospital Foundation IRCCS in Rome, Italy, and Catholic University of the Sacred Heart in Rome, Italy. 7 The authors note that ANOCA progressed from the initial scepticism of the scientific community regarding its existence to the demonstration of its clinical relevance and the need for a standardized diagnostic algorithm (as recommended in current ESC Guidelines), which leads to the identification of successful antianginal treatments for patients who frequently present invalidating symptoms. Thus, although unfinished, this is a success story. The utilization of aspirin in primary prevention and its role in dual antithrombotic treatment remains debated.8,9 In a Clinical Research article entitled ‘Aspirin, cardiovascular events, and major bleeding in older adults: extended follow-up of the ASPREE trial’ by Rory Wolfe from Monash University in Melbourne, Australia, and colleagues aim to estimate long-term and post-trial effects of aspirin on major adverse cardiovascular events (MACE) and major haemorrhage using extended follow-up of participants from the ASPREE trial. 10 In-trial (2010–17) and post-trial (2017–22) data were analysed. At enrolment, participants were aged ≥70 years (≥65 years for US minorities) without prior cardiovascular events, dementia, or independence-limiting physical disability. Randomization was to daily low-dose aspirin or matching placebo for the 4.7 years of the trial. Of the 19 114 participants randomized, 15 668 without in-trial MACE consented to post-trial follow-up. No long-term benefit of randomization to aspirin was observed for MACE for the entire in-trial and post-trial period hazard ratio (HR) 1.04. However, during the post-trial period (median 4.3 years), there was a significantly higher rate of MACE (HR 1.17) in those randomized to aspirin compared with placebo. Over the entire period, a significantly higher rate of major haemorrhage was observed in the randomized aspirin group compared with placebo (HR 1.24) (Figure 2). Effects of aspirin on cardiovascular events and major haemorrhage in ASPREE extended follow-up. CVD, cardiovascular disease; MACE, major adverse cardiovascular events; ASPREE, ASPirin in Reducing Events in the Elderly10 The authors conclude that the present study provides novel evidence concerning long-term MACE and bleeding following aspirin use in initially healthy older adults. The manuscript is accompanied by an Editorial by Colin Baigent, Alistair Roddick, and Carlo Patrono from the University of Oxford, in the UK, and Catholic University School of Medicine in Rome, Italy. 11 The authors underscore that the chief uncertainty about aspirin for healthy people remains whether, leaving aside the debate about its value for the primary prevention of cardiovascular disease, the benefits of long-term aspirin might be supplemented by a protective effect on certain cancers. In ASPREE, there was no significant effect of aspirin on all incident cancers, but there was an apparent excess of cancers that had metastasized, a finding at odds with an earlier report of a protective effect of aspirin on risk of cancer metastasis during five primary prevention trials with a mean follow-up of 6.5 years. The reasons for this excess in ASPREE are unclear and need to be better understood before aspirin can be contemplated for large-scale use for the prevention of cancer. Catheter ablation plays a key role for atrial fibrillation (AF).12–21 Various energy sources are employed for catheter ablation for AF, including radiofrequency, cryoballoon, laser balloon, hot balloon, and pulsed-field. There are limited prospective data on the efficacy, safety, and impact on reverse remodelling of cryoballoon, as compared with radiofrequency ablation for persistent AF. In a Clinical Research article entitled ‘Cryoballoon vs radiofrequency ablation in persistent atrial fibrillation: the CRRD-PeAF trial’ Koji Miyamoto from the National Cerebral and Cardiovascular Center in Osaka, Japan, and colleagues aim to compare the efficacy and safety of cryoballoon vs radiofrequency ablation in a large cohort of patients with persistent AF. Additionally, the authors compare the impact of these technologies on the extent of reverse remodelling post-ablation. 22 In this prospective, multicentre, randomized, non-inferiority clinical trial, 500 patients with persistent AF were randomized across 12 centres. The primary endpoint was the occurrence of atrial tachyarrhythmias at 1 year with a 90 day blanking period after ablation. The final analysis included 499 patients, with a median age of 69 years. In the intention-to-treat analysis, the primary endpoint was observed in 22% of patients in the cryoballoon group and in 23.2% in the radiofrequency group, and the cryoballoon group demonstrated non-inferiority compared with the radiofrequency group for the primary endpoint (P = .96). The radiofrequency group showed a greater reduction in left atrial size (left atrial volume index) at 1 year than the cryoballoon group (P < .001). The authors conclude that in this randomized trial, cryoballoon ablation is non-inferior to radiofrequency ablation for the occurrence of atrial tachyarrhythmias at 1 year in patients with persistent AF. The manuscript is accompanied by an Editorial by Jason G. Andrade and Laurent Macle from the University of Montreal in Canada. 23 The authors highlight that adverse electrical and structural atrial remodelling is thought to play a central role in the onset and maintenance of AF. Several studies have observed significant reductions in the left atrial dimension and volume following catheter ablation. This observation is presumed secondary to beneficial reverse structural remodelling following sustained sinus rhythm maintenance. However, the relationship between left atrial structural change and clinical outcomes (e.g. freedom from AF and reduced AF burden) has been inconsistent. The application of radiofrequency energy results in diffuse cellular destruction and denaturation of the extracellular tissue matrix, and induces a marked inflammatory reaction with subsequent neointimal proliferation and fibrotic transformation, resulting in endovascular contraction. In contrast, cryothermal ablation lesions are associated with preserved ultrastructural integrity, an observation attributed to the resilience of fibroblasts and collagen fibres. It is possible that the observed differences in left atrial diameter and left atrial volume observed in the current study were secondary to a more extensive adjunctive left atrial radiofrequency ablation combined with the histopathological difference in lesion maturation. At the end of the day, while interesting, the finding of differential left atrial dimensions remains hypothesis generating given the lack of difference observed in arrhythmia outcomes. Acetazolamide is effective in reducing blood pressure in people with obstructive sleep apnoea (OSA) living at low altitudes and in those ascending to high altitudes. However, its impact on 24 h blood pressure in people living at high altitude has not been studied. In a Rapid Communications article entitled ‘Acetazolamide effect on ambulatory blood pressure in patients with obstructive sleep apnoea living at high altitude: a randomized trial’ by Lu Tan from Sichuan University in China, and colleagues evaluate the efficacy of acetazolamide on 24 h mean arterial blood pressure (MAP) and breathing variables in people with OSA living at high altitude.24 In this randomized, placebo-controlled, double-blind crossover trial, 41 patients with moderate to severe OSA living in Lhasa (3650 m) were randomly assigned to receive either 500 mg/day acetazolamide or placebo for 2 weeks each, separated by a 1 week washout period. At the end of each treatment period, 24 h ambulatory blood pressure and polysomnography were carried out. The primary outcome was the difference in 24 h mean blood pressure (MAP) between the 2 week acetazolamide and placebo treatment. Of the 41 included in the intention-to-treat analysis, median age was 35 years, median body mass index was 25.6 kg/m2, and 85% were men. With placebo, the median 24 h MAP was 88 mmHg. Acetazolamide significantly decreased 24 h MAP by a mean of 3 mmHg, 24 h heart rate by 4 beats/min and apnoea-hypopnoea index (AHI) by 15.7 events/h and increased nocturnal oxygen saturation by 2.8%. Mild to moderate paraesthesia in the limbs was the most common side effect. The authors conclude that acetazolamide reduces MAP and heart rate and improves AHI in people with OSA living at high altitude, suggesting it might be a useful treatment for preventing or treating hypertension in similar populations. The issue is also complemented by a Discussion Forum contribution. In a commentary entitled ‘Can the effects of vagus nerve stimulation on improving motor function and inflammation be applied to the general healthy population?’ Jing-Yi Lin and Yu-Lei Xie from the Affiliated Hospital of North Sichuan Medical College in China, comment on the recently published paper entitled ‘Non-invasive vagus nerve stimulation and exercise capacity in healthy volunteers: a randomized trial’, by Gareth L. Ackland et al., from the University of London, in the UK.25,26 The Editors hope that this issue of the European Heart Journal will find the interest of its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Lindsay Washington, Johanna Huggler, Amelia Meier-Batschelet, and Martin Meyer for help with compilation of this article.
Filippo Crea (Fri,) reported a other. Long-term aspirin use in initially healthy older adults did not reduce major adverse cardiovascular events (HR 1.04) but significantly increased major hemorrhage (HR 1.24).