Focus on trials: interventional cardiology, ischaemic heart disease, and long COVID

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. The Issue opens with a Viewpoint article ‘The Year in Cardiovascular Medicine 2024: the top 10 papers in interventional cardiology’, by Emanuele Barbato from Sapienza University of Rome, Italy, and colleagues.1 In this report, the authors provide a selection of the top 10 papers in interventional cardiology testifying to the tremendous progress witnessed in the interventional cardiology field. The year 2024 has confirmed the continuing efforts to refine percutaneous coronary intervention (PCI) success and outcomes especially in complex coronary interventions. Compelling evidence supports consideration of early interventional treatment of valve disease, in patients with asymptomatic severe aortic stenosis, and in heart failure patients with functional mitral or tricuspid regurgitation. Ongoing trials are awaited to further corroborate preliminary encouraging findings in the treatment of patients with cardiogenic shock or pulmonary embolism. The Issue continues with a focus on clinical trials. The treatment of ischaemic cardiomyopathy (ICM) remains controversial.2 In the STICHES trial, recruiting participants between 2002 and 2007, coronary artery bypass grafting (CABG) improved outcomes of patients with ischaemic left ventricular dysfunction receiving medical therapy, whereas in the REVIVED-BCIS2 trial, recruiting from 2013 to 2020, PCI did not. In a Fast Track Clinical Research article entitled ‘Medical therapy and outcomes in REVIVED-BCIS2 and STICHES: an individual patient data analysis’, Matthew Ryan from Kings College London, UK, and colleagues explore differences in outcomes of participants treated with medical therapy alone in STICHES vs. REVIVED-BCIS2 in this pooled analysis of individual participant data.3 All patients had left ventricular ejection fraction ≤35% and coronary artery disease, and received medical therapy. Participants were randomized 1:1 to CABG (STICHES) or PCI (REVIVED-BCIS2). The primary outcome was the composite of all-cause death and hospitalization for heart failure over all available follow-up. A total of 1912 participants (88% male, 76% white ethnicity) were included, with 98% completeness of follow-up for the primary outcome. The median follow-up was 118 months in STICHES and 41 months in REVIVED-BCIS2. Those receiving medical therapy alone in REVIVED-BCIS2 had fewer primary outcome events than those receiving medical therapy alone in STICHES (adjusted hazard ratio 0.60, P < .001). Patients receiving PCI in REVIVED-BCIS2 were less likely to experience a primary outcome event than those receiving CABG in STICHES. Adjusted outcomes of patients treated with CABG in STICHES were worse than those receiving medical therapy alone in REVIVED-BCIS2. The authors conclude that patients with ICM receiving medical therapy in REVIVED-BCIS2 have better outcomes than those in STICHES, with or without CABG surgery. The manuscript is accompanied by an Editorial by Kayla Chiew, Shayna Chotai, and Rasha Al-Lamee from the Imperial College London, UK.4 The authors note that the choice of PCI, CABG, or medication alone remains heterogenous and dependent on local opinions and expertise. To truly advance the treatment of patients with ICM, it must be recognized that the overall results of clinical trials may never be representative of the whole population. While it is admirable to hope for a mean effect that is expected in every patient, these patients are complex, with individual challenges that influence their response to treatment. They conclude that what we really need are trials that are designed to provide data on the individual predictors of response. Worldwide outcomes will only improve if we can target the right combination of treatment to the right patients. Remote ischaemic pre-conditioning (RIPC) delivered shortly prior to an angiographic procedure may reduce contrast-associated acute kidney injury (CA-AKI). Whether a longer interval between RIPC and contrast administration also reduces CA-AKI and post-procedural complications after coronary angiography (CAG) or PCI is unknown. In a Clinical Research article entitled ‘Remote ischaemic pre-conditioning, kidney injury, and outcomes after coronary angiography and intervention: a randomized trial’ by Ping Jia from Zhongshan Hospital, China, and colleagues.5 This was a multicentre, randomized trial of patients at risk of CA-AKI undergoing elective CAG or PCI comparing delayed RIPC (four cycles of 5 min inflations on one upper arm 24 h before the procedure) with sham RIPC. The primary endpoint was the incidence of AKI, defined according to the Kidney Disease Improving Global Outcomes criteria. Altogether, 501 patients (mean age 74 years) were randomly assigned to delayed (n = 250) or sham (n = 251) RIPC, of which 93% completed outcome assessments at day 90. The incidence of CA-AKI was 7.6% with sham and 3.2% with delayed RIPC (odds ratio 0.4; P = .03) (Figure 1). The authors conclude that among at-risk patients undergoing CAG or PCI, the incidence of CA-AKI is lower in patients receiving delayed compared with sham RIPC. The manuscript is accompanied by an Editorial by Gerd Heusch and Petra Kleinbongard from the University of Duisburg-Essen, Germany.6 The authors highlight that the present randomized trial adds to several recent experimental and clinical studies which suggest that ischaemic conditioning may not just be an experimental procedure in search of a clinical translation. Ischaemic conditioning is a systemic biological defence mechanism against all sorts of irreversible tissue injury which can be recruited locally or more systemically at a distance. Protection can be recruited before (pre-), following (post-), and, in the case of remote ischaemic conditioning, also during (per-conditioning) ongoing injury. Protection involves the recruitment of acutely available signal mechanisms by release of auto-/paracrine substances, post-translational modification of proteins, and impact on mitochondrial function. However, ischaemic conditioning also acts in a more delayed form through transcriptional activation and increased expression of protective proteins. Of note, it acts not only locally, but also systemically, with a decisive involvement of the sensory and vagal nervous system and the spleen, thus utilizing a complex interaction of the autonomic nervous system, the immune system, and the circulation. Upon vagal activation by remote ischaemic conditioning, the spleen releases cardioprotective factors in pigs and humans which continue to circulate for several days; such continued circulation of protective factors may explain the protection of the kidneys in the present study when remote ischaemic conditioning was initiated 24 h before the coronary procedure. Of course, the contribution of each of these protective mechanisms and signals to the manifestation of protection under study can vary. Transcatheter aortic valve implantation vs. surgical aortic valve replacement in women with severe aortic stenosis. HR, hazard ratio; CI, confidence interval; TAVI, transcatheter aortic valve implantation20 The treatment of aortic stenosis (AS) keeps evolving.7–19 The RHEIA trial investigates the balance of benefits and risks of transcatheter aortic valve implantation (TAVI) vs. surgery in women. In a Clinical Research article entitled ‘Transcatheter vs. surgical aortic valve replacement in women: the RHEIA trial’, Didier Tchetche from Clinique Pasteur in Toulouse, France, and colleagues, focus on women randomized 1:1 to transfemoral TAVI with a balloon-expandable valve or surgery.20 The primary composite endpoint was death, stroke, or (valve-, procedure-, or heart failure-related) rehospitalization at 1 year. Non-inferiority testing with a pre-specified 6% margin and superiority testing were performed in the as-treated population. At 48 European centres, 443 women underwent randomization, and 420 were treated as randomized. Mean age was 73 years, and the mean estimated surgical risk of death was 2.1% (Society of Thoracic Surgeons risk score). Kaplan–Meier estimates of the primary endpoint event rates at 1 year were 8.9% in the TAVI and 15.6% in the surgery group. This difference of −6.8% with an upper 95% confidence limit of −1.5% demonstrated the non-inferiority of TAVI (P < .001). The two-sided 95% confidence interval of −13.0% to −0.5% further resulted in superiority (P = .034). The authors conclude that among women with severe AS, the incidence of the composite of death, stroke, or rehospitalization at 1 year is lower with TAVI than with surgery. The manuscript is accompanied by an Editorial by Kush Patel and Andreas Baumbach from St Bartholomew’s Hospital in London, UK.21 The authors note that there is awareness regarding the heterogeneity in clinical, pathological, and treatment outcomes between sexes. However, apart from using different computed tomography-based thresholds for defining severe calcific AS, our management does not differ between sexes. Transcatheter aortic valve implantation appears to be more favourable among women and, all things being equal, should be the preferred treatment. Such a significant paradigm change requires acceptance by the cardiology community, capacity in healthcare provision, and probably long-term evidence supporting favourable outcomes with TAVI. Women need to be considered with a different lens, appreciating their anatomical and physiological differences and consequently heading towards a more tailored treatment strategy. This differential assessment and treatment based on sex must be adopted by guidelines if the evidence continues to show dimorphic characteristics and outcomes. In acute coronary syndromes (ACS), vascular healing at the site of implantation of drug-eluting stents (DES) can be delayed. Titanium-nitride-oxide-coated stents (TiNOS) demonstrate faster strut coverage without the excessive intimal hyperplasia observed with bare metal stents. In a Clinical Research article entitled ‘Titanium-nitride-oxide-coated vs. drug-eluting stents in acute coronary syndromes: an individual patient data meta-analysis’, Thabo Mahendiran from OLV Clinic in Aalst, Belgium, and colleagues22 performed an individual participant data (IPD) meta-analysis of trials comparing TiNOS with DES for the treatment of ACS. The primary endpoint was major adverse cardiac events (MACE) at 5 years, a composite of cardiac death (CD), myocardial infarction (MI), and ischaemia-driven target lesion revascularization (TLR). Pre-specified secondary endpoints included CD, MI, TLR, and stent thrombosis. Patient-level data were obtained from three randomized controlled trials (TiNOS: n = 1620 vs. DES: n = 1123). After a median follow-up of 5 years, there was no significant difference in the primary endpoint between TiNOS and DES (12.6% vs. 16.2%, P = .051). However, TiNOS were associated with significantly lower rates of CD (1.5% vs. 3.7%; P = .007), MI (5.2% vs. 9.6%; P < .001), and stent thrombosis (1.1% vs. 3.8%; P < .001). The authors conclude that in ACS patients, TiNOS is associated with similar rates of MACE and TLR as compared with DES, but significantly lower rates of CD, MI, and stent thrombosis. This manuscript is accompanied by an Editorial by Margaret B. McEntegart, Anja Oksnes, and Martin Leon from Columbia University Medical Center in New York, NY, USA and the Haukeland University Hospital in Bergen, Norway.23 The authors note that the notion that TiNOS is an effective and safer alternative to DES in the specific context of ACS should be considered hypothesis-generating. The differences observed in the study were for unpowered secondary endpoints. The authors themselves discuss several large-scale IPD and network meta-analyses supporting the efficacy and safety of DES in both chronic and acute coronary syndrome, and it is within that context that these data should be interpreted. A modern era physiology- and intravascular imaging-guided randomized trial in ACS patients, with contemporary DES and dual antiplatelet therapy, powered to detect differences in safety endpoints (target vessel MI, stent thrombosis, and CD), is required to confirm or refute the findings. Structured Graphical Abstract24 Preventing new cardiovascular events in patients with established cardiovascular disease (CVD) is a daunting task for clinicians. Intestinal microbiota may help identify patients at risk, thus improving the strategies of secondary prevention. In a Clinical Research article entitled ‘A microbiota pattern associated with cardiovascular events in secondary prevention: the CORDIOPREV study’, Javier Arenas-Montes from the Hospital Universitario Reina Sofía in Cordoba, Spain, and colleagues,24 evaluated the baseline differences between the gut microbiota from coronary heart disease (CHD) patients suffering new MACE in the following 7 years, compared with CHD patients who did not have any new MACE in this period, to build a score associated with the risk of suffering new MACE. Within the framework of the CORDIOPREV study, a clinical trial that involved 1002 patients with CHD, the intestinal microbiota was examined in patients with available faecal samples (n = 679, 132 MACE), through 16S metagenomics on the Illumina MiSeq and Quiime2 software. Random survival forest identified 10 bacterial taxa with a higher predictive power for MACE incidence. Receiver operating characteristic curves yielded an area under the curve of 65% in the training set and 69% in the validation set. The intestinal microbiota risk score was significantly associated with a MACE incidence hazard ratio of 2.01 (Figure 2). The authors conclude that these results reinforce the relationship between intestinal microbiota and CVD, and suggest that a specific microbiota profile is associated with MACE in CHD patients. This manuscript is accompanied by an Editorial by Barbara Verhaar, Max Nieuwdorp, and Bert-Jan van den Born from the University of Amsterdam, The Netherlands, and the Icahn School of Medicine at Mount Sinai in New York, NY, USA.25 The authors conclude that this study represents a significant step forward in associating gut microbiota composition with long-term cardiovascular outcomes through the development of a microbiota-based risk score for MACE. By addressing methodological challenges inherent to the gut microbiome field, future research can refine these tools and explore their potential for clinical application. As research in this area progresses, the gut microbiome holds the promise of becoming a valuable component of cardiovascular risk stratification and targeted interventions. Long COVID is a novel condition for which Guidelines recommend supervised exercise, but evidence guiding safe and effective interventions is limited. In a Rapid Communications article entitled ‘Exercise training in long COVID: the EXER-COVID trial’, Robinson Ramírez-Vélez from the Universidad Pública de Navarra in Pamplona, Spain, and colleagues, performed a crossover study that included 100 participants with long COVID (mean age 48 years; 68% women) at a single centre in Spain from 1 March 2021 to 30 September 2022.26 Participants were randomized 1:1 to 6 weeks of exercise training followed by 6 weeks of standard of care or 6 weeks of standard of care followed by 6 weeks of exercise training. Cardiorespiratory fitness, muscle strength, long COVID symptoms, cognitive performance, quality of life, depression, and psychological distress were assessed. The exercise training intervention significantly improved the peak VO2 by 2.10 mL/kg/min (P < .001). Post-intervention, muscle strength (1RM) improvements were observed in the pectoral press, bilateral leg press, knee extension, and back press (P < .001 each). Significant reductions in psychological distress scores (P < .001), alongside enhancements in quality of life (P = .041), cognitive capabilities (P = .014), and cognitive performance (P = .036) were also documented. The authors conclude that a supervised 6 week exercise training programme improves cardiorespiratory fitness, strength, and mental health in participants with long COVID. Further mechanistic studies are needed to confirm these findings. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Cholinergic control of cardiac electrical conduction and ventricular arrhythmia: endogenous or exogenous?’, Dongze Zhang from the University of Texas Health Science Center at Houston, Texas, USA,27 comments on the recent publication ‘The endogenous cholinergic system overwhelmingly predominates over the exogenous system in regulating ventricular bioelectrical homeostasis’ by Duanyang Xie, Yi Liu, and Yi-Han Chen, from Tongji University in Shanghai, China.28 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, and Martin Meyer for help with compilation of this article.