Challenges in antithrombotic treatment and in the management of valvular heart disease

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on thrombosis and antithrombotic treatment, and valvular heart disease contains a Special Article entitled ‘Antithrombotic drugs for acute coronary syndromes in women: sex-adjusted treatment and female representation in randomized clinical trials. A clinical consensus statement of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and the ESC Working Group on Thrombosis’ by Valeria Paradies from Maasstad Hospital in Rotterdam, the Netherlands, and colleagues which provides consensus-based guidance for optimizing antithrombotic treatment based on sex.1 Sex-related differences are increasingly recognized as relevant in the management of cardiovascular diseases.2–7 In particular, thrombotic and bleeding risks differ between sexes, partly in relation to distinct biology and hormonal status, but also due to differences in age, comorbidities, and body size at presentation. Women experience frequent fluctuations of prothrombotic and bleeding status related to the menstrual cycle, use of oral contraceptives, hormone replacement therapy, or menopause. Although clinical studies tend to under-represent women, available data consistently support sex-specific differences in the baseline thrombotic and haemorrhagic risks. Compared with men, women are susceptible to an increased risk of in-hospital bleeding related to invasive procedures, as well as long-term out-of-hospital bleeding events. In addition, the inappropriate dosing of antithrombotic drugs, which is not adapted to body weight or renal function, is more frequently associated with an increased risk of bleeding in women compared with men. While acute coronary syndrome (ACS) studies support similar antithrombotic drug efficacy, irrespective of sex, women may receive delayed treatment due to bias in their referral, diagnosis, and invasive treatment decisions. The current clinical consensus statement highlights the need for an increased awareness of sex-specific risks and biases in ACS management, with a focus on sex-specific bleeding mitigation strategies, antithrombotic management in special conditions (e.g. myocardial infarction with non-obstructive coronary arteries), and barriers to female representation in cardiovascular trials. This manuscript aims to provide expert opinion, based on the best available evidence, and consensus statements on optimizing antithrombotic therapy according to sex, which is critical to improve sex-based disparities in outcome. In a second Special Article entitled ‘Antithrombotic treatment following revascularization for chronic limb-threatening ischaemia: a scientific statement of the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy’, Oliver Schlager from the Medical University of Vienna, Austria, and colleagues provide a scientific statement that addresses peripheral arterial diseases.8 Chronic limb-threatening ischaemia (CLTI) is defined as ischaemic rest pain, or non-healing ulceration, requiring endovascular or surgical lower limb revascularization (LLR).9 Lower limb revascularization in CLTI entails a high risk of major adverse limb events (MALE) and major adverse cardiovascular events (MACE). This scientific statement addresses this risk based on a systematic review. A structured literature search was performed, and articles were independently evaluated by two investigators. In total, 1678 articles were identified, of which 34 were included in the final analysis. Only three randomized controlled trials (RCTs) addressed antithrombotic therapy in CLTI following LLR. None of these demonstrated superiority of any antithrombotic regimen over the other. Eight RCTs investigated antithrombotic therapy following LLR in populations with PAD including CLTI subgroups, and suggest a benefit of dual antiplatelet therapy on limb events. One large RCT demonstrated that dual pathway inhibition with aspirin and vascular-dose rivaroxaban reduced the risk of MALE, MACE, and unplanned target limb revascularization. Data from 22 observational studies suggest a benefit of dual antiplatelet therapy on overall survival and amputation-free survival after LLR as compared with single antiplatelet therapy. Intensified antithrombotic treatment should be proposed in patients with CLTI following LLR to reduce the risk of MALE and MACE. Randomized controlled trials on antithrombotic therapy in patients with CLTI following LLR are scarce. Dual pathway inhibition is the only regimen for which an RCT demonstrated a reduction of MALE and MACE following LLR. Dual antiplatelet therapy appears to be associated with a reduced risk of MALE in CLTI following LLR. Transcatheter aortic valve implantation (TAVI) has revolutionized the treatment of patients with severe aortic stenosis (AS).10–14 Originally developed for patients with tricuspid aortic valve (TAV) anatomy, the procedural success and expanding indications of TAVI have spurred interest in its application to more complex aortic valve anatomies, including the treatment of AS in bicuspid aortic valves (BAVs). In a State of the Art Review article entitled ‘Bicuspid aortic valve disease: advancements and challenges of transcatheter aortic valve implantation’, Marco Barbanti from Umberto I Hospital in Enna, Italy, and colleagues aim to provide a comprehensive overview of the current landscape of TAVI in BAV patients, including an analysis of anatomical considerations and procedural pitfalls, as well as improvements in outcomes with new device iterations (Figure 1).15 The growing interest in this specific subset of patients with AS is driven by the recent extension of TAVI indications to younger individuals, who exhibit a notably higher incidence of bicuspid anatomy compared with older populations. Bicuspid aortic valves present distinct anatomical and pathological complexities that pose significant challenges to the conventional TAVI approach. These include asymmetric calcification, aortic root dilation, and variations in cusp fusion patterns, which can affect valve deployment, transcatheter heart valve sealing, and long-term durability. Despite these challenges, advancements in imaging techniques, valve design, and procedural strategies have led to increased adoption of TAVI in BAV patients. However, surgical aortic valve replacement still retains a more prominent role in this group compared with patients with tricuspid valves. This preference is partly due to the exclusion of BAV patients from almost all previous RCTs, which limits the available evidence supporting the use of TAVI in this unique cohort. This state-of-the-art review provides a comprehensive overview of the current landscape of TAVI in BAV patients, including an analysis of anatomical considerations and procedural pitfalls, as well as improvements in outcomes with new device iterations. It also explores clinical data, tackling the risks, benefits, and the evolving role of TAVI in this unique patient cohort. Graphical Abstract15 In a Viewpoint article entitled ‘The year in cardiovascular medicine 2024: the top 10 papers in diabetes and metabolic disorders’, Francesco Cosentino from Karolinska University Hospital in Stockholm, Sweden, and colleagues have selected papers published in 2024 that capture the major advances and trends in diabetes and metabolic disorders disease.16 This is a new stimulating addition to this successful series. Classification and risk stratification in aortic (AR), mitral (MR), and tricuspid regurgitation (TR) remains a significant clinical challenge. In a Fast Track Clinical Research article entitled ‘Deep learning for echocardiographic assessment and risk stratification of aortic, mitral, and tricuspid regurgitation: the DELINEATE-regurgitation study’, Aaron Long from Columbia University Irving Medical Center in New York, NY, USA, and colleagues aim to develop an artificial intelligence (AI) system to assess valvular regurgitation and stratify MR progression risk.17 Using transthoracic echocardiograms (TTEs) at two sites (internal development/test and external test), the DELINEATE-Regurgitation study was developed to classify AR, MR, and TR severity using colour Doppler videos. Methods of summating video-level classifications into study-level predictions were tested, comparing single-view with multiview approaches integrating predictions across multiple videos. Model agreement with cardiologists was assessed by weighted kappa. A separate AI system (DELINEATE-MR-Progression) analysing colour Doppler videos was developed to predict which patients with mild, mild to moderate, and moderate MR were most likely to progress to moderate to severe or severe MR with analysis by Kaplan–Meier and Cox proportional hazards models. A total of 71 660 TTEs with 1 203 980 colour Doppler videos were included. The weighted kappa in internal/external test sets for regurgitation classification was 0.81/0.76 for AR, 0.76/0.72 for MR, and 0.73/0.64 for TR using a multiview approach taking all colour Doppler videos in a study, demonstrating substantial agreement with cardiologist interpretation, with superiority of multiview over single-view approaches. In the progression analysis, the AI score stratified MR progression risk even when controlled for clinical factors known to be associated with MR progression [internal test set hazard ratio 4.1. The authors conclude that an AI system can accurately classify AR, MR, and TR, and predict MR progression beyond currently known risk factors. The manuscript is accompanied by an Editorial by Neal Yuan from the University of California, CA, USA.18 The author notes that the study by Long et al. is the product of tremendous work and effort in building the infrastructure and datasets to train and test the described AI models. In addition to having important clinical implications, there are also broader themes here for the field of AI applied to TTE. Long et al. have iterated upon their prior models: progressing from a single-task convolutional neural network to a transformer-based architecture that can take in multiple videos. Transformers, the key deep learning architecture behind all modern large language models (e.g. ChatGPT, Gemini, and Claude), enable models to process and find relationships in large data inputs such as the multiple videos of a TTE study. The authors’ progression in this study parallels an evolution within the field of AI-TTE as we move from single-task one-off models now to early forms of more general, transformer-based, TTE models that can perform multiple tasks from whole studies. Such general models may incorporate and build upon the innovations and datasets used in studies such as that of Long et al. to produce full end-to-end automated TTE interpretation and multimodal disease prediction for a wide spectrum of conditions, perhaps the true holy grail of the field’s efforts. Mitral valve prolapse (MVP) is associated with progressive MR requiring surgical correction. A subset of patients with MVP exhibit mitral annular disjunction (MAD) which has been associated with ventricular arrhythmias (VAs). In a Clinical Research article entitled ‘Mitral annular disjunction and mitral valve prolapse: long-term risk of ventricular arrhythmias after surgery’, Klara Lodin from Karolinska Institute in Solna, Sweden, and colleagues assess the long-term risk of VAs in patients with MAD and MVP undergoing mitral valve surgery for MR.19 Patients with MVP with moderate or severe degenerative MR undergoing mitral valve surgery (repair or replacement) in 2010–22 at Karolinska University Hospital were included. Mitral annular disjunction was measured at end-systole on pre- and post-operative TTE. The primary outcome consisted of VA including hospitalizations, outpatient visits, or ablation for confirmed sustained or non-sustained ventricular tachycardia, or high burden of premature ventricular complexes, and was assessed from medical records. Of 599 patients undergoing mitral valve surgery, 96 (16%) had pre-operative MAD. The median MAD length was 8.0 mm. Compared with patients without MAD, patients with MAD were younger (55 vs. 63 years), were more often women (31% vs. 17%), and had more Barlow’s disease (70% vs. 27%). Mitral annular disjunction was surgically corrected in all patients. During a median follow-up time of 5.4 years, patients with pre-operative MAD had a higher risk of VAs (hazard ratio adjusted for age and sex 3.33) regardless of repair/replacement (Pinteraction = .18) (Figure 2). CI, confidence interval; HR, hazard ratio; MAD, mitral annular disjunction19 The authors conclude that MAD in patients with MVP and MR is associated with a three-fold increased long-term risk of VAs post-mitral valve surgery, despite anatomical correction of MAD. The manuscript is accompanied by an Editorial by Antonia van Kampen, Robert A. Levine, and Michael A. Borger from the University Clinic of Cardiac Surgery in Leipzig, Germany, and Harvard Medical School in Boston, MA, USA.20 The authors highlight that the study by Lodin et al. has demonstrated that mitral valve surgery eliminates MAD in MVP patients, and that post-operative VAs are associated with pre-operative MAD. Ongoing trials will further enhance our understanding of this disease process by more precisely defining the role of echocardiographic- and cardiac magnetic resonance-derived risk factors, contributing mechanistic insights into the disease process, and evaluating the timing and effectiveness of current mitral valve repair options. We are currently entering an era of rapid knowledge gain into arrhythmogenic MVP, a very serious entity within the MVP spectrum. Pulmonary embolism (PE) is a challenging disease.21–25 Epidemiology of PE may have shifted since the coronavirus disease (COVID-19) pandemic. In a Clinical Research article entitled ‘Incidence, risk factors, and mortality of pulmonary embolism in the Netherlands (2015–22): sex differences and shifts during the coronavirus disease 2019 pandemic’, Qingui Chen from Leiden University Medical Center in the Netherlands, and colleagues describe temporal trends in PE epidemiology in the Netherlands since 2015.26 Using nationwide data from Statistics Netherlands, all Dutch inhabitants (>16 million) without a history of PE were dynamically identified on January 1st of each year to assemble eight cohorts of PE-free Dutch inhabitants in 2015–22. They were individually followed until the end of that respective year to determine 1 year risk of PE (identified by hospital diagnoses/primary cause of death) and establish relevant risk factors. The PE cases were subsequently studied to determine 1 year all-cause mortality following PE. Multivariable logistic regression with cluster-robust standard errors and robust Poisson regression were respectively employed to evaluate relative differences in PE incidence and mortality between years. PE incidence in the Dutch population decreased from 2015 to 2019 but markedly increased by 23, 52, and 7% in 2020, 2021, and 2022 (vs. 2019), respectively. Most traditional PE risk factors remained associated with PE in 2020–22 but generally with a weaker association. Pulmonary embolism mortality was stable until 2019 but then increased by 10% in 2020 and by 9% in 2021, while the increase (2%) was insignificant in 2022. The above-mentioned changes since 2020 were generally greater in males than in females. The authors conclude that the seemingly favourable pre-pandemic temporal trends in PE epidemiology in the Netherlands reversed during the COVID-19 pandemic but appear to revert to pre-pandemic levels after 2022. The manuscript is accompanied by an Editorial by Florian Langer from the University Medical Center Hamburg-Eppendorf in Germany.27 The author concludes that ∼5 years after the outbreak of SARS-CoV-2 in Wuhan, China, in December 2019, nationwide individual-level data from the complete Dutch population of >16 million inhabitants show the full burden of COVID-19-associated PE during the first 2 years of the pandemic. Thus, the study by Chen et al. not only confirms the findings of initial cohort studies from the same country, but it will also serve as the most recent benchmark for future investigations on PE epidemiology. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Glycoprotein VI inhibitors: glenzocimab and EMA601 two inhibitory Fabs’, Pierre H. Mangin and Martine Jandrot-Perrus, from the University of Strasbourg in France and Paris Cité University in France, commented on the discussion piece ‘EMA601 and glenzocimab: two glycoprotein VI inhibitory Fabs with different potency’, by Bernard Nieswandt, David Stegner, and Stefano Navarro from the University of Würzburg in Germany.28,29 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, 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.