Advances in Clinical Cardiology 2025: A Summary of Key Clinical Trials

Abstract

Introduction

Over the course of 2025, numerous key clinical trials in the field of cardiology were published or presented at major international conferences. This review seeks to collate and summarise these trials and reflect on their clinical context. With the rapid advancements in the management of cardiovascular diseases, it is critical to evaluate the emerging evidence that may influence clinical practice and impact the development of future guidelines.

Methods

The authors evaluated all clinical trials presented at major cardiology conferences during 2025, with a focus on those likely to influence or change current clinical practice. We reviewed clinical trials presented at all major international cardiology conferences, including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), Transcatheter Cardiovascular Therapeutics (TCT), American Heart Association (AHA) and the European Heart Rhythm Association (EHRA) among others. Trials considered to have the highest impact and broad relevance across the field of clinical cardiology, with a strong likelihood to change or impact clinical practice, were included.

Results

Over 80 key cardiology clinical trials were identified across the spectrum of clinical cardiology in 2025. Important updates in percutaneous coronary intervention were reviewed, including advances in antiplatelet strategies challenging the traditional one-year paradigm of dual antiplatelet therapy (TARGET FIRST, MASTER DAPT), alongside key developments in percutaneous coronary intervention (PCI) and drug-coated balloon (DCB) technologies (SELUTION DeNovo, AGENT IDE). Structural heart disease trials included important updates in transcatheter valve intervention and related therapies (DAPA-TAVI, FAITAVI, BHF PROTECT-TAVI), as well as key data in left atrial appendage closure (CLOSURE-AF). Major advances were also reported in heart failure and cardiomyopathy (SUMMIT, MAPLE-HCM, DIGIT-HF), together with important preventive cardiology outcomes data (VESALIUS-CV).

Conclusion

This review offers a concise synthesis of the key clinical cardiology trials published or presented over the past year, with relevance for both clinicians and cardiovascular researchers.

Key Summary Points

Over 80 major cardiology clinical trials from 2025 were reviewed, highlighting advances across coronary, structural, heart failure, and preventive cardiology.

Shortened dual antiplatelet therapy strategies were generally safe and reduced bleeding, though immediate aspirin withdrawal remains uncertain.

Key interventional studies demonstrated ongoing innovation in percutaneous coronary intervention (PCI) techniques, drug-coated balloons, and novel stent technologies.

Important progress was reported in structural heart interventions, heart failure therapies, and cardiometabolic prevention strategies.

These findings collectively inform evolving clinical practice and are likely to influence future cardiovascular guidelines.

Introduction

During 2025, several key clinical trials with the potential to influence and change contemporary cardiovascular practice were presented at major international scientific meetings and published in high-impact journals. These studies spanned a broad range of cardiovascular subspecialties and reflected ongoing advances in pharmacologic therapy, device-based interventions, and care delivery strategies. Major data releases occurred at the annual meetings of American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC) congress, Transcatheter Cardiovascular Therapeutics (TCT), American Heart Association (AHA) Scientific Sessions, European Heart Rhythm Association (EHRA) Congress, Society for Cardiovascular Angiography and Interventions (SCAI), TVT–The Heart Summit (TVT), and Cardiovascular Research Technologies (CRT). In this review, the authors provide a concise summary of the most important cardiovascular clinical trials presented and/or published during 2025, encompassing all major subspecialties including acute coronary syndromes, percutaneous and structural intervention, electrophysiology, heart failure, cardiometabolic disease, and prevention.

Methods

Trials included in this review were identified through systematic evaluation of late-breaking clinical trial sessions, featured research presentations, and selected oral abstract sessions from major international cardiovascular meetings held during 2025, including ACC, EuroPCR, ESC, TCT, AHA, EHRA, SCAI, TVT, and CRT. Additional studies were identified through targeted searches of PubMed, MEDLINE and Cochrane Library for randomised clinical trials and pivotal observational studies published during the same period. Search terms included acute coronary syndrome, interventional cardiology, heart failure, atrial fibrillation, electrophysiology, and cardiovascular prevention. Selection was based on methodological quality, clinical relevance, and potential to inform clinical practice or future guideline recommendations, with inclusion of selected early-phase or mechanistic studies where findings were considered hypothesis-generating. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Advances in Coronary Syndromes, Shock and Antiplatelet Strategies

Anti-platelet and Anticoagulation Strategies Updates

Standard guidelines recommend 12 months of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI) [1], but an important unresolved issue is whether this duration remains necessary in the era of potent P2Y12 inhibitors and modern drug-eluting stents, given the associated bleeding risk. Recent trials have therefore examined whether shorter DAPT strategies can maintain ischaemic protection while reducing bleeding, with potential implications for future treatment standards. Recent trials [2–4] support the safety of shortened DAPT. This evidence base has been further examined over the past year.

In the Early Discontinuation of Aspirin after PCI in Low-Risk Acute Myocardial Infarction (TARGET-FIRST) trial, 1942 patients with ST-segment elevation myocardial infarction (STEMI) or Non-ST-segment elevation myocardial infarction (NSTEMI), who underwent complete revascularisation and achieved 1 month of uneventful DAPT, were randomised to P2Y12 monotherapy versus a further 11 months of DAPT. At 11 months, treatment with P2Y12 inhibitor monotherapy was non-inferior compared to standard therapy regarding the primary endpoint, a composite of death, myocardial infarction (MI), stent thrombosis, ischaemic stroke, or significant bleeding [2.10% vs. 2.18%; (95% CI − 1.39 to 1.20); p = 0.021]. A significant advantage was seen in the secondary endpoint of moderate to severe bleeding [2.65% vs. 5.57%; (95% CI 0.29–0.75); p = 0.002] [5].

In the One-month dual antiplatelet therapy followed by prasugrel monotherapy at a reduced dose: the 4D-ACS randomised trial, 656 South Korean ACS patients undergoing PCI with a drug eluting stent (DES) (mean age 61 years; 83% male) were randomised to 1-month DAPT with aspirin plus prasugrel (10 mg or 5 mg in patients who are elderly or low weight), followed by prasugrel monotherapy (5 mg) versus 12-month DAPT with aspirin plus prasugrel (5 mg). At 12 months, the net adverse clinical events (NACE) composite [death, MI, stroke, target vessel revascularisation (TVR) and significant bleeding] was lower in the 1-month DAPT group [4.9% vs. 8.8% (95% CI 0.27–0.95); p = 0.034]. Major bleeding (BARC 3–5) was markedly lower (0.6% vs. 4.6%; p = 0.007) while there were similar ischaemic outcomes between strategies [6].

The Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Standard DAPT Regimen (MASTER DAPT) trial included 4579 patients with high bleeding risk who had undergone PCI with a biodegradable polymer-coated stent and were randomized to abbreviated DAPT (n = 172, median ~ 34 days) versus prolonged DAPT (n = 182, median ~ 192 days). Abbreviated DAPT was associated with a similar incidence of total net adverse clinical events (NACEs) [214 vs. 227 events; (95% CI 0.78–1.16); p = 0.64] and total major adverse cardiac and cerebral events (MACCE) [156 vs. 160 events; (95% CI 0.76 to1.20); p = 0.69] but lower incidence of major or clinically relevant bleeding [180 vs. 240 events; (95% CI 0.64–0.94); p = 0.011] [7].

In the Duration of Dual Antiplatelet Therapy in Acute Coronary Syndromes (DUAL-ACS) trial 5052 patients with ACS, managed either conservatively, with PCI or with coronary artery bypass grafting (CABG), were randomised to 3 months DAPT followed by P2Y12 monotherapy versus 12 months DAPT. After a 15-month follow-up period, the shortened DAPT strategy was associated with a numerically lower rate of all-cause mortality (2.7% vs. 3.4%; HR 0.78; 95% CI 0.57–1.07) and less major bleeding (3.2% vs. 4.0%; HR 0.78; 95% CI 0.58–1.06) without a significant increase in recurrent MI or cardiovascular (CV) death. However, the study was underpowered, and outcomes were not statistically definitive [8].

These recent trials support the safety of shortened periods of DAPT in patients with ACS, but it is uncertain whether immediate withdrawal of aspirin leaving only P2Y12 inhibitor monotherapy can safely reduce bleeding without increasing ischaemic events. In the multicentre, open-label, assessor-blinded Early Withdrawal of Aspirin after PCI in Acute Coronary Syndromes (NEO-MINDSET) trial, 3410 patients with ST-elevation or non-ST-elevation ACS who underwent successful PCI with DES were randomised within 4 days to immediate withdrawal and potent P2Y12 inhibitor monotherapy (ticagrelor or prasugrel) only versus standard DAPT (aspirin plus potent P2Y12 inhibitor for 12 months). At 12 months, P2Y12 inhibitor monotherapy failed to meet non-inferiority criteria for the primary composite endpoint of death, MI, stroke, or urgent TVR [7.0% vs. 5.5%, absolute risk difference 1.47% (95% Cl − 0.16 to + 3.10); p = 0.11 for non-inferiority], although it was associated with less major or clinically relevant non-major bleeding (2.0% vs. 4.9%, absolute risk difference − 2.97%; 95% CI − 4.20 to − 1.73). Thus, immediate aspirin withdrawal is not currently supported, although it remains an area of ongoing research interest [9].

The optimal choice of antiplatelet therapy after finishing DAPT following PCI with DES is still unclear. In the Efficacy and Safety of Clopidogrel versus Aspirin Monotherapy After Percutaneous Coronary Intervention (SMART-CHOICE 3) study, 5506 patients at high ischaemic risk who had completed standard DAPT after PCI were randomised to clopidogrel 75 mg OD versus aspirin 100 mg OD monotherapy (median 17.5 months from PCI to randomisation). Clopidogrel therapy was associated with a 29% reduction in the primary composite endpoint of all-cause death, MI, or stroke at a median follow-up of 2.3 years [4.4% vs. 6.6%; HR 0.71; (95% CI 0.54–0.93); p = 0.013] driven by reduction in all-cause death (2.5% vs. 4.0%) and in MI (1.0% vs. 2.2%) with no difference in stroke (1.3% vs. 1.3%). Despite improved efficacy, there was no difference in major bleeding [3.0% vs. 3.0%; HR 0.97; (95% CI 0.67–1.42)] supporting the role of clopidogrel, within the limitations open study design, as the treatment of choice in patients with high ischaemic risk post-standard DAPT therapy [10].

The Aspirin Plus Oral Anticoagulation in Chronic Coronary Syndrome (AQUATIC) study, randomised 872 patients with chronic coronary syndrome (CCS) at high atherothrombotic risk receiving long-term oral anti-coagulant (OAC) (median age ~ 72 years; stent placed > 6 months earlier) to aspirin 100 mg daily plus OAC versus placebo plus OAC. At median follow up (2.2 years), addition of aspirin to OAC was associated with a higher incidence of the primary endpoint, a composite of CV death, MI stroke, systemic embolism, coronary revascularization, or acute limb ischemia [16.9% vs. 12.1%; HR 1.53; (95% CI 1.07–2.18); p = 0.02] and more than threefold increase in major bleeding [10.2% vs. 3.4%; HR 3.35; (95% CI 1.87–6.00); p < 0.001] supporting the view that long-term aspirin in combination with OAC should be avoided in this population [11].

Restoring coronary artery patency quickly in STEMI is critical to limit infarct size and adverse outcomes, yet prehospital platelet inhibition with oral therapies has not consistently improved early reperfusion or clinical outcomes, creating a need to consider other early antiplatelet strategies [12]. In the Zalunfiban at First Medical Contact for ST-Elevation Myocardial Infarction (CELEBRATE) study, 2467 patients with suspected STEMI presenting within 4 h of symptom onset (mean 63 years, 21% female) were randomized to a single subcutaneous injection of the novel glycoprotein IIb/IIIa inhibitor Zalunfiban (0.11 mg/kg or 0.13 mg/kg) versus placebo at first medical contact, on top of standard care. Pooled Zalunfiban significantly improved the 30-day hierarchical composite outcome, including death, stroke, recurrent MI, stent thrombosis, heart failure, and larger infarction [adjusted odds ratio 0.79; (95% CI 0.65–0.98); p = 0.028], with a higher proportion of patients free of major adverse events (13.3% vs. 9.8%) suggesting potential benefit of early potent platelet inhibition alongside contemporary reperfusion therapy. Severe or life-threatening bleeding was similar between groups (1.2% vs. 0.8%; p = 0.40), although mild to moderate bleeding occurred more often with Zalunfiban [13].

Patients presenting with MI complicated by cardiogenic shock (CS) have high rates of reinfarction and mortality. Impaired drug absorption and metabolism of oral antiplatelet therapies in shock may delay effective platelet inhibition creating an unmet need for faster antiplatelet strategies. In the Intravenous Cangrelor versus Crushed Ticagrelor in Acute Myocardial Infarction With Cardiogenic Shock (DAPT-SHOCK-AMI) study, 605 patients with MI and CS (mean 65 years, 22.6% female) undergoing primary PCI were randomised to IV cangrelor crushed oral ticagrelor, in addition to aspirin. IV Cangrelor achieved the primary laboratory endpoint of more effective platelet inhibition by the end of PCI (100% vs. 22.1%, p < 0.0001), improved TIMI 3 flow (83% vs. 74%, p = 0.009) and reduced PCI complications (7.4% vs. 14%; p = 0.09), but did not significantly reduce the primary clinical endpoint of all-cause death, MI, or stroke at 30 days (37.6% vs. 41.0%; (95% CI − 11.2 to 4.3%); p for non-inferiority = 0.13). Despite the improved platelet inhibition, there was no difference in major bleeding (6.4% vs. 5.2%; p = 0.53). While early clinical results were neutral, the trial confirmed that oral antiplatelets are poorly absorbed in shock states. Planned landmark 5-year blinded outcome analyses will investigate if the early pharmacodynamic advantages of cangrelor translate into longer-term mortality benefit [14].

Two major trials have studied ticagrelor-based strategies after CABG and focused on the balance between ischaemic protection and bleeding risk. In the Ticagrelor and Acetylsalicylic Acid versus Acetylsalicylic Acid Only after Isolated CABG in ACS (TACSI) trial, 2201 patients undergoing isolated CABG for ACS were randomised to 12 months DAPT (ticagrelor and aspirin) or aspirin alone. DAPT did not reduce the composite of death, MI, stroke, or repeat revascularisation [4.8% vs. 4.6%; (95% CI 0.72–1.56); p = 0.77] and was associated with higher rates of major bleeding [4.9% vs. 2.0%; (95% CI 1.52–4.11)]. Of note, event rates were lower (4.7%), and ticagrelor discontinuation was higher (8.9%) than expected, leaving the trial underpowered to detect possible efficacy differences in the first 3 months. In the Ticagrelor-based De-escalation of Dual Antiplatelet Therapy After Coronary Artery Bypass Grafting (TOP-CABG) trial, 2300 patients undergoing first-time CABG were randomised 1:1 to shortened DAPT (3 months aspirin and ticagrelor followed by 9 months aspirin) versus standard DAPT (12 months). Shortened DAPT was non-inferior for the primary endpoint of graft occlusion at 1 year [10.79% vs. 11.19%; (95% CI − 3.13 to + 2.52)] and was associated with significantly less clinically relevant bleeding [8.26% vs. 13.19%; (95% CI 0.48–0.81); p < 0.001]. These trials suggest that patients post-CABG may be best managed by aspirin alone if bleeding risk is high or, if using DAPT, to de-escalate to aspirin monotherapy after 3 months rather than 12 months.

An additional practical consideration is the transition from dual to single antiplatelet therapy. In routine practice, this is influenced by evolving ischaemic and bleeding risk, adherence, and follow-up, and may not reflect the controlled conditions of clinical trials. These factors support an individualised rather than protocol-driven approach to DAPT de-escalation.

Use of Beta-Blockers in Coronary Syndromes

Beta-blocker therapy after MI has been a longstanding guideline recommendation based on older trials conducted before modern reperfusion strategies and potent medical therapies. Contemporary trials in patients with preserved or mildly reduced left ventricular ejection fraction (LVEF) have challenged this practice [2].

In the Treatment with Beta-Blockers after Myocardial Infarction without Reduced Ejection Fraction (REBOOT-CNIC) study, 8505 patients with recent acute MI managed with invasive care and a predischarge LVEF > 40% were randomised to beta-blockers versus no beta-blocker therapy. Beta-blocker therapy did not reduce the primary composite of all-cause death, nonfatal reinfarction, or hospitalization for heart failure over a median follow-up of 3.7 years [22.5 vs. 21.7 events per 1000 patient-years (95% CI 0.89–1.22); p = 0.63]. Individual components including all-cause mortality, reinfarction, and heart failure were also similar between groups [15].

The Beta-Blockers after Myocardial Infarction in Patients without Heart Failure (BETAMI-DANBLOCK) study, pooled two RCTs, BETAMI and DANBLOCK, and included 5 574 patients post-MI (mean age ~ 64 years; ~ 22% women) with preserved or mildly reduced left ventricular ejection fraction, but no clinical heart failure, who were randomized to long-term beta-blockers versus no beta-blocker therapy (median follow-up ~ 3.2 years). Beta-blockers modestly reduced the composite of all-cause death or major adverse cardiovascular events (MACE) [14.2% vs. 16.3%; HR 0.85; (95% CI 0.75–0.98); p = 0.03], driven mainly by fewer recurrent MIs [5.0% vs. 6.7%; HR 0.73; (95% CI 0.59–0.92)], while all-cause mortality was similar between groups [16].

To reconcile divergent individual trial results the individual-patient data meta-analysis, Beta-Blockers after Myocardial Infarction with Normal Ejection Fraction study, pooled 17,801 patients from five open-label randomized trials (REBOOT, REDUCE-AMI, BETAMI, DANBLOCK, and CAPITAL-RCT) with recent MI, LVEF > 50%, and no other indication for beta-blockers, who were randomly assigned to beta-blocker therapy versus no beta-blocker and followed for a median of 3.6 years. Beta-blockers did not significantly reduce the primary composite of all-cause death, recurrent MI, or heart failure [8.1% vs. 8.3%; (95% CI 0.87–1.07); p = 0.54]; individual components including all-cause mortality and heart failure were similarly neutral. A subgroup meta-analysis of patients with mildly reduced ejection fraction (40–49%) from these trials demonstrated a significant benefit of beta-blockers on the composite endpoint (HR 0.75; p = 0.03), suggesting that mild systolic dysfunction may still identify a population that benefits from beta-blocker therapy [17].

Cardiogenic Shock

Although cardiogenic shock following STEMI continues to be associated with a high mortality despite advances in revascularization and supportive care, the potential role for routine early mechanical circulatory support has been controversial.

The Danish–German Cardiogenic Shock (DanGer Shock) trial which randomised 355 adults with STEMI-related cardiogenic shock (median LVEF ~ 25%) to early implantation of the Impella CP^® microaxial flow pump plus standard care versus standard care alone previously reported Impella use to be associated with reduced mortality at 180 days [2]. Long-term follow-up data published this year reported that this mortality reduction was sustained for up to 10 years [52.5% vs. 68.8%, HR 0.70; (95% CI 0.54–0.92)], equating to a mean 600 additional days alive. However, a higher incidence of adverse events including bleeding, limb ischaemia, and acute kidney injury was noted underscoring the need for careful patient selection and procedural refinement [18].

The intra-aortic balloon pump (IABP) SHOCK II trial previously reported no significant reduction in mortality with IABP versus no IABP in acute MI-related cardiogenic shock [19]. The Early Intra-Aortic Balloon Support for Heart Failure-Related Cardiogenic Shock (ALTSHOCK-2) study randomised 101 patients who were eligible for heart replacement therapies with HF-CS (SCAI stages B–D; median age 60 years, 20% women) to early IABP (n = 53) versus standard care (n = 48). The trial was stopped early due to futility with early IABP again failing to improve the primary endpoint of survival or successful bridge to durable heart replacement therapy [81% vs. 75%; HR 0.72; (95% CI 0.31–1.68); p = 0.45]. These findings are in keeping with IABP SHOCK II and do not support the routine use of early IABP use, even in patients eligible for heart replacement therapies [20].

Acute Coronary Syndrome Diagnostics

An interesting study evaluated whether an artificial intelligence approach to the presenting electrocardiogram could enhance early risk stratification. In the deep learning electrocardiogram model for risk stratification of coronary revascularization need in the emergency department study, a convolutional neural network was first trained on 144,691 United States of America (US) emergency department (ED) visits and tested on 35,995 separate US ED visits. The model was then externally validated in Europe (18,673 ED visits) where it showed good prediction of need for revascularisation [area under the receiver-operating characteristic curve (AUROC) 0.81] and detection of type 1 MI (AUROC 0.85) outperforming clinician ECG interpretation (0.70 and 0.74) and approaching high-sensitivity troponin T-based diagnosis (0.85 and 0.87) [21].

Advances in Percutaneous Coronary Intervention (PCI)

Advances in PCI continue to focus on key areas of evolving evidence and ongoing debate, including the role of drug-coated balloons as an alternative to stent implantation, the development of novel stent platforms to improve long-term vessel function, and optimisation of strategies for complex coronary disease. In this section, we highlight recent studies according to the specific gaps in knowledge they address, such as device selection, lesion preparation, imaging-guided PCI, and revascularisation strategy and discuss how these findings may influence current and future treatment standards.

Drug Coated Balloons (DCBs)

DCBs are an emerging alternative to stent implantation in PCI, delivering antiproliferative drug therapy without leaving a permanent scaffold. An important unresolved issue is whether DCBs can safely replace DES in de novo coronary artery disease, particularly in larger vessels where radial support may still be required, particularly in vessels greater than 3 mm. The previously discussed Drug-coated balloon angioplasty with rescue stenting versus intended stenting for the treatment of patients with de novo coronary artery lesions (RECCAGE-FREE-1), did not meet the prespecified non-inferiority criterion of paclitaxel based DCB strategy in de novo coronary artery disease (CAD) compared to DES, thus results of the SELUTION DeNovo trial were eagerly anticipated [2]. This prospective, multi-centre trial, randomised 3441 patients (mean age 67 years: 25% female) with acute and chronic coronary syndromes prior to lesion preparation, to SELUTION DCB (Cordis) versus DES. Importantly, patients with STEMI, left main disease, chronic total occlusion (CTO), previous PCI or saphenous vein graft PCI were excluded [22]. At 1 year, the SELUTION DCB strategy was reported to be non-inferior for the primary endpoint of target-vessel failure [composite of death, target-vessel MI, and clinically driven target-vessel revascularisation (5.3 vs. 4.4% (95% CI − 0.55 to 2.38); p = 0.02 for non-inferiority]. However, a relatively wide 50% non-inferiority margin was applied, TVR was higher with DCB (3.3 vs. 2.1%) and there was a high cross-over of DCB requiring rescue DES (20%). Given these uncertainties, a DES strategy still appears the preferable approach in this CAD subset.

In a more established application of DCBs (treatment of ISR), the SELUTION SLR™ 014 In-stent Restenosis (SELUTION4ISR) trial, randomised 208 patients (median age 68 years: 19% female), with ISR to a DCB strategy (the SELUTION SLR™ 014 ballon) versus standard of care (zotarolimus/everolimus-eluting DES or POBA) [2]. Importantly, intravascular imaging (IVUS or OCT) was required for inclusion to ensure ISR did not extend to 5 mm of the proximal or distal stent edge. At 1 year, the SELUTION DCB was reported to be non-inferior to standard of care for the primary endpoint of TVF [15.2% vs. 13.5%, HR: 1.14 (95% CI 0.69–1.90); p non-inferiority = 0.608]. However, within the standard of care group, target lesion failure (TLF) was markedly lower for DES than plain old balloon angioplasty (POBA) (7.1% vs. 43.6%), suggesting that the bundling of both strategies into a single comparator group was inappropriate and makes drawing of conclusions difficult [23].

The previously discussed Agent Paclitaxel Coated PTCA Balloon Catheter for the Treatment of Subjects With In-Stent Restenosis (AGENT IDE) study (n = 600: mean age 68 years; 26% female), reported an 11% absolute reduction in TLF with DCB versus POBA in patients with in-stent restenosis (ISR) length < 26 mm and reference vessel diameter > 2.0 to ≤ 4.0 mm [2]. This year, 2-year follow up data were presented, reporting a sustained reduction in TLF with DCB (27% vs. 34%; HR 0.56; 95% CI 0.40–0.80; p = 0.04) [24]. The consistency of these longer-term results is reassuring.

Novel DES Designs

The DynamX Bioadaptor (Elixir Medical) stent comprises three cobalt-chromium helical strands, initially held together at joints by a bioresorbable PLLA polymer, thereby providing DES-like radial support. The polymer elutes drug over ~ 3 months then fully resorbs by 6 months, allowing the helical strands to separate or "uncage" and acquire independent movement restoring vessel vasomotion. In the previously discussed INFINITY-SWEDEHEART study (2400 patients, mean age 68 years, 24% female), DynamX Bioadaptor was found to be non-inferior versus Resolute Onyx (Medtronic) for TLF at 1 year [2]. Interestingly, 2-year follow up, presented this year at TCT, now reported reduced TLF with the DynamX Bioadaptor [1.47% vs. 2.81%; HR 0.52 (95% CI 0.29–0.93)] [25]. These data highlight the potential of this novel stent design and further outcome data at 5 years are eagerly awaited.

Complex Revascularisation

An important unresolved question in complex coronary artery disease is the optimal revascularisation strategy, particularly the evolving role of PCI compared with (CABG in the era of modern DES and using physiological guidance. In the previously discussed Fractional Flow Reserve (FFR)–Guided PCI as Compared with Coronary Bypass Surgery (FAME 3) trial, FFR-guided PCI of triple vessel disease (TVD) failed to achieve non-inferiority versus CABG for primary outcome of death, stroke, MI, or repeat revascularisation at 1 year [26]. In contrast, in 5-year follow-up data reported this year, available for 96% of the PCI group (n = 724) and 94% of the CABG group (n = 696), there was no significant difference in the prespecified hard endpoint of death, stroke or MI for PCI versus CABG [16% vs. 14%; 95% CI: 1.16 (0.89–1.52)] [27]. Of note, the 5-year analysis did not include repeat revascularisation in the composite 5-year endpoint, and revascularisation was more common with PCI at 5 years (16% vs. 8%). Nevertheless, death/stroke or MI rates with PCI in FAME-3 were lower versus historic data from the SYNTAX trial (16% vs. 22%) whereas CABG outcomes remained similar (both 14% in both trials), suggesting a clinically meaningful advance with the latter DES design and FFR guidance [26].

The Nordic–Baltic–British Left Main Revascularisation (NOBLE) study, randomised patients with unprotected LMS disease (n = 1184, mean age 66.2 years: female 22%) to treatment with PCI or CABG and, as previously discussed, demonstrated no difference in all-cause mortality at 5 years (9% vs. 9%, p = 0.68). Very long term follow up data are rarely available yet are important given the known risk of late vein graft failure. It was thus of great interest that the NOBLE authors presented 10-year data this year, which confirmed no difference in all-cause mortality with PCI versus CABG [23% vs. 25%, HR 0.93; (95% CI, 0.74–1.18); p = 0.56] [28] and, interestingly, in a subgroup analysis of patients presenting with ACS, PCI conferred a lower mortality (HR, 0.57; 95% CI, 0.32–0.99; p = 0.047) (Fig. 1). These key data are reassuring and will help inform guideline recommendations for patients with unprotected LMS disease.

Fig. 1.

NOBLE trial (10-year follow-up) [28]. Primary endpoint and time-dependent landmark analysis. A Cumulative incidence of all-cause mortality. B Landmark analysis of all-cause mortality for the periods 0–5 years and 5–10 years. CABG coronary artery. (Published with permission from Meril Life Sciences.)

Current guidelines in CTO PCI recommend native coronary artery reconstruction in the context of saphenous vein graft (SVG) failure (class IIa) but this guidance is based on observational data only. The PeRcutaneous cOronary Intervention of Native Coronary arTery Versus Venous Bypass Graft in Patients With Prior CABG (PROCTOR) study, randomised 218 patients presenting with SVG failure (mean age 73 ± 7 years; 84% men, mean time from CABG of 18 years) to PCI of the native coronary artery versus SVG PCI (with heart team consensus that both PCI strategies were feasible) [29]. Surprisingly, native vessel PCI was associated with a significantly higher incidence of the primary endpoint of MACE at 1 year [34% vs. 19%: HR: 2.14 (95% CI 1.25–3.65); p = 0.006] driven mainly by higher PCI related MI (13% vs. 1%; HR 14.85; 95% CI 1.95–112.96) but with no difference in all-cause mortality (HR 1.59; 95% CI 0.45–5.64; p = 0.472). While the study may have been underpowered (it had planned to enrol 584 patients) these data may lead to a change in guidelines with SVG PCI (supported by embolic protection) now the preferred treatment option. However, longer follow-up are still of interest as more SVG-PCI than native-PCI failures might be expected over 3–5 years.

Calcium Modification, Intravascular Imaging and Radiation Protection

There are limited data directly comparing calcium modification techniques. The Shockwave Lithoplasty Compared to Cutting Balloon Treatment in Calcified Coronary Disease (Short-Cut) trial randomised 413 patients (mean 72 years, ~ 75% male) with stable and chronic coronary syndromes and significant calcification (by angiogram or IVUS, mean lesion length 29 mm, 50% with 360° arc) to lesion preparation with cutting balloon (0.5 mm smaller than the reference vessel diameter) versus intravascular lithotripsy (IVL) sized 1:1 with reference vessel diameter [30]. Use of cutting balloon was non-inferior to IVL for the primary endpoint of IVUS defined post-procedural MSA (8.0 ± 2.4 mm² vs. 8.6 ± 2.5 mm², p non-inferiority = 0.007) and there were no significant differences in stent expansion, dissection, perforation, balloon rupture or 30-day MACE but was less expensive (mean procedural cost difference US$3632). Subgroup analysis reported cutting balloon without planned up-front rotational atherectomy did not reach non-inferiority for minimal stent area although stent expansion was similar (Fig.I2).

Fig. 2.

Shockwave intravascular lithotripsy delivers localised acoustic pressure waves through a balloon-based catheter to modify calcified coronary lesions. When the balloon is inflated at low pressure, emitters within the catheter generate pulsatile sonic waves that propagate through the vessel wall, selectively fracturing intimal and medial calcium while minimising injury to surrounding soft tissue. (Published with permission from Shockwave Medical)

The Value of IVL Compared To OPN Non-Compliant Balloons for Treatment of RefractorY Coronary Lesions (VICTORY) trial, randomised 882 patients with acute or chronic coronary syndromes (STEMI excluded) and significant coronary calcification on angiogram or Optical Coherence Tomography (OCT) to high pressure OPN ballon versus Intravascular Lithotripsy (IVL) [30]. The OPN balloon was as effective as IVL for the primary outcome of OCT-defined post-procedure stent expansion (85% vs. 84%; p < 0.0001) with no differences in 30-day MACE (MI, TVR or death) but shorter procedural time and potentially cost.

Most data supporting FDA approval of IVL come from predominantly male cohorts. The EMPOWER-CAD study [31] enrolled 399 women undergoing PCI with IVL for acute or chronic coronary syndromes (excluding shock or restenosis). The primary effectiveness endpoint (stent delivery with < 30% residual stenosis) was achieved in 86.9%. The 30-day target lesion failure rate was 12.1%, driven mainly by periprocedural MI. Although non-randomised, these findings support the efficacy and safety of IVL in women.

The previously discussed, the Optical CoherenCe Tomography-gUided Coronary Intervention in Patients With Complex Lesions (OCCUPI) Trial, compared use of OCT versus angiography alone for PCI in complex lesions. A planned post hoc analysis focusing on patients presenting with ACS (n = 790; mean age 62.5 years; 18% female) was presented this year [32]. At 1-year, OCT was associated with significant reduction in the primary outcome of major adverse cardiac events [a composite of cardiac death, MI, stent thrombosis, or ischaemia-driven TVR) (4.9% vs. 9.5%: (95% CI: 0.29–0.87); p = 0.011] and greater post-stent Minimal Lumen Diameter (MLD) (2.78 mm vs. 2.62 mm; p < 0.001). This study adds further weight to the already robust data supporting imaging-guided PCI.

Occupational radiation exposure is of increasing concern for interventional cardiologists. The ATTENUATE study, was a single-centre observational study (all-comers) which randomised 1000 procedures to the use of a RADPAD protection drape versus conventional protection alone [33]. Use of the RADPAD was associated with significant 50.7% reduction in the primary endpoint of dose-area product-normalized operator dose (3.119 vs. 6.324 uSv/Gy cm²; p < 0.0001). Dose reduction was seen whether radial or femoral approach and whether coronary or structural cases. Of note, the RADPAD group had lower overall fluoroscopy times 4.4 versus 5.6 min (p < 0.0001) but it is unclear if this reflected procedural efficiency gains or chance. This important study confirms substantial scatter radiation mitigation and supports routine use to lower long-term operator risks (Fig. 3).

Fig. 3.

The RADPAD radiation protection drape is a sterile, disposable shielding device positioned between the X-ray source and the operator to reduce scatter radiation exposure during fluoroscopically guided procedures. Composed of bismuth and antimony attenuation materials, it absorbs scatter radiation without interfering with image quality when placed outside the imaging field. 5400—RADPAD^® Subclavian Shield. (Published with permission from Worldwide Innovations & Technologies, Inc.)

Advances in Structural Interventions

Advances in structural heart interventions continue to address several important outstanding clinical and technical challenges, including improving access to aortic valve replacement, optimising adjunctive pharmacotherapy and procedural strategies in transcatheter interventions, and refining patient selection for increasingly complex structural procedures. In this section, we highlight recent studies according to the specific gaps in evidence they address, such as system-level barriers to care, device selection and design, and management of co-existing cardiac conditions.

Aortic Interventions

Digital Innovation

Despite increasing availability, up to half of patients with severe aortic stenosis (AS) and a guideline directed indication for transcather aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) do not receive one, hence the rate of AVR within 90 days of diagnosis has been identified as a key system-level performance indicator. The Electronic Provider Notification (EPN) to Facilitate the Recognition and Management of Severe Aortic Stenosis: DETECT AS trial hypothesised that sending clinicians EPNs of patient-specific guideline recommendations [34] when an echo result demonstrated severe AS would improve the rate of AVR. In a single-blinded, cluster randomised study within the Massachusetts General Hospital network, 144 providers (496 patients) were assigned to receive EPNs versus 141 providers (443 patients) assigned to usual care. Receiving an EPN was associated with a 29.5% increase in the primary outcome of AVR rate at 1 year (48.2% vs. 37.2%; OR 1.62 95% CI 1.13–2.32) with even greater benefit in older patients (> 80 years; OR 2.00 95% CI 1.17–3.41) and female patients (OR 2.78 95% CI 1.69–4.57). Limitations include the generalisability of EPNs in less integrated healthcare systems, and the risk of EPN alert fatigue, although it was reassuring in DETECT-AS that the impact of EPNs appeared to increase rather than decrease over time. [35].

Adjunctive Pharmacotherapy

The effectiveness of sodium glucose cotransporter-2 inhibitors (SGLT-2i) in patients with severe AS is unknown. The Dapagliflozin in Patients Undergoing Transcatheter Aortic-Valve Implantation (DapaTAVI) trial randomised 1257 patients (median age 82.4 years) with severe AS who had undergone TAVR, a history of heart failure hospitalisation (HFH), and one (LVEF ≤ 40% or diabetes or eGFR 25–75 mls/min/1.73 m²) to dapagliflozin 10 mg versus ‘standard care’. At 1 year, dapagliflozin was associated with a 5.1% absolute risk reduction in the primary composite of death or HFH or urgent heart failure (HF) visit (15% vs. 20.1%; HR 0.72 95% CI 0.55–0.95), mainly driven by a 37% reduction in HFH or urgent HF visit (0.63 95% CI 0.45–0.88), although it led to increased genital infection (1.8% vs. 0.5%; p = 0.03) and hypotension (6.6% vs. 3.6%; p = 0.01). One important methodological weakness of the trial was the omission of a placebo-controlled arm which may have exaggerated the treatment effect in the novel study group. Nevertheless, DapaTAVI provides strong evidence that in patients with severe AS undergoing transcatheter aortic valve intervention (TAVI), dapagliflozin reduces clinically meaningful heart failure endpoints. [36].

Sedation Strategy

The impact of periprocedural sedation strategy on outcomes following transfemoral TAVI remains uncertain. The DOUBLE-CHOICE trial randomised 752 patients to a minimalist approach (local anaesthesia, invasive monitoring discouraged) versus conventional conscious sedation strategy (target Richmond Agitation Score 0 to − 2, invasive monitoring at clinician discretion). The minimalist approach was non-inferior for the primary composite endpoint of 30-day death, vascular complications, bleeding, infection or neurological events (22.9% vs. 25.8%; HR 0.88, 95% CI 0.65–1.18; p = 0.003 for non-inferiority) with no significant differences in individual components, although it was associated with significantly higher patient-reported anxiety and stress (p < 0.001), and 19.5% of patients required crossover to standard sedation, most commonly due to discomfort, underscoring the importance of careful patient selection.

Self-Expanding versus Balloon-Expanded Valves

In factorial design DOUBLE-CHOICE also randomised 835 patients with severe AS and anatomy deemed equally suitable for self-expanding valves (SEVs) to Acurate neo2™ (Boston Scientific, USA) versus Evolut Pro/Pro + /FX™ (Medtronic, USA) TAVI. Use of Acurate neo2 was associated with reduction in the primary composite endpoint (death, stroke, more-than-moderate paravalvular regurgitation, or permanent pacemaker implantation) (15.4% vs. 30.4%; HR 0.47, 95% CI 0.34–0.64), driven mainly by lower rates of pacemaker implantation (11.2% vs. 26.5%). The clinical relevance is uncertain because the Acurate neo2™ has since been withdrawn following unfavourable outcomes in other clinical trials and concerns regarding valve under-expansion [37], but some learning may be gained regarding aspects of valve design, particularly radial force and conduction system interaction, to optimise future self-expanding TAVI platforms. [38].

Bystander Coronary Disease

The optimum strategy for managing concomitant coronary artery disease (CAD) in patients with severe AS undergoing TAVI remains unclear. The multicentre Angiography versus physiology-guided PCI in patients undergoing TAVI: the Functional Assessment in TAVI (FAITAVI) trial randomised 320 patients with at least intermediate CAD (≥ 50% angiographic stenosis in ≥ 2.5-mm vessels) to physiology (FFR) versus angiography-guided PCI. In the FFR-guided arm, PCI was undertaken before TAVI if FFR was ≤ 0.8 but otherwise deferred (if 0.81–0.85, FFR was repeated post TAVI, and PCI undertaken if now indicated). In the angiography arm, PCI was performed for all (≥ 50% lesions before, during or up to 1 month after the TAVI.) As a result, only 77% of the FFR-guided group versus 99% of the angiography-guided group underwent PCI. Use of FFR-guidance was associated with a 44% reduction in the primary composite outcome of death, MI, stroke, major bleeding or TVR (15.2% vs. 25.1%; HR 0.56, 95% CI 0.36–0.89), mainly driven by reduced mortality (2.4% vs. 7.7%; HR 0.31 95% CI 0.1–0.96). An important study limitation is the use of ≥ 50% rather than ≥ 70% stenosis. The investigators justified a ≥ 50% threshold based on observational data suggesting a larger myocardial territory at risk in severe AS may favour more liberal revascularisation, but further research is required to confirm whether physiology guidance remains preferable to angiographic guidance for more typical ≥ 70% stenoses in this setting. [39].

Embolic Protection Devices

TAVI carries a peri-procedural stroke risk of approximately 2–4% [40]. The role of cerebral embolic protection (CEP) devices to reduce the procedure related risk of stroke remains uncertain. The landmark Routine Cerebral Embolic Protection during Transcatheter Aortic-Valve Implantation (BHF PROTECT TAVI) trial randomised 7635 patients in 33 UK centres with severe aortic stenosis to undergo TAVI with the Sentinel™ (Boston Scientific, USA) CEP versus TAVI without CEP. Use of CEP did not reduce the primary endpoint of clinically apparent stroke within 72 h of the procedure (2.1% vs. 2.2%; p = ns), disabling stroke (1.2% vs. 1.4%), death (0.8% vs. 0.7%) or vascular complications (8.1% vs. 7,7%). Thus PROTECT TAVI established that routine use of CEP does not reduce the procedural incidence of stroke [41].

Valve Innovations

Formal head-to-head comparisons of newer transcatheter heart valve (THV) platforms with innovative designs such as Myval™(Fig. 4; Meril Life Sciences, India) versus established THV such as SAPIEN3™(Edwards, USA) are clinically important. The SAPIEN 3 versus Myval transcatheter heart valves for transcatheter aortic valve implantation (COMPARE-TAVI 1) trial randomised 1031 patients with severe AS (median age 81 years, 0% bicuspid valves and 4% valve in valve TAVI) to transfemoral TAVI with Myval/Myval Octahor (20–32 mm) versus SAPIEN3 (29 mm)/SAPIEN3 Ultra (20 mm, 23 mm, 26 mm). Myval met non-inferiority criteria for the primary composite outcome of death, stroke, moderate–severe AR or moderate–severe haemodynamic THV deterioration at 1 year (14% vs. 13%; p non-inferiority = 0.019) although Myval was associated with more moderate–severe AR (4% vs. 1%), permanent pacemaker (PPM) implant (21% vs. 12%) and de novo AF (14% vs. 8%) [42]. The findings are consistent the previously published LANDMARK study which reported non-inferiority of the Myval versus SAPIEN and Evolut platforms [43], and, while the increased need for PPM is of some concern, the wider choice of Myval platforms which may reduce cost and widen access to TAVI is helpful.

Fig. 4.

The Myval™ Transcatheter Heart Valve (THV) is designed for transcatheter aortic valve replacement (TAVR) procedures. (Published with permission from Meril Life Sciences.)

In patients with unfavourable anatomy or previous surgical bioprosthesis THV implantation risks coronary obstruction. Bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary obstruction (BASILICA) is a technique which has shown promise at reducing the risk of coronary obstruction, but its safety had not prospectively investigated. The Electrosurgical Leaflet Modification to Prevent Coronary Obstruction During Transcatheter Aortic Valve Replacement in Failing Native and Bioprosthetic Valves (TELLTALE) study prospectively enrolled 90 patients undergoing TAVI for severe native or bioprosthetic valve AS with prohibitive surgical risk and CT evidence suggesting high risk of coronary obstruction for undergo a BASILICA strategy (single arm study design). The median coronary height was 8.2 mm, valve to coronary distance 3.4 mm and valve to sinotubular junction distance 1.2 mm. The co-primary endpoint was technical success (achieved in all patients) and safety (composite of freedom from death, stroke or coronary obstruction at 30 days), which was achieved in 96% of patients (no deaths but 3 strokes and 1 coronary obstruction). Thus the BASILICA technique appears a feasible and prospective randomised trials are now planned. [44].

While TAVI for severe aortic regurgitation (AR) has shown promise, pre-existing evidence has evaluated off-label use of THVs specifically designed for severe AS. Transcatheter Aortic Valve Implantation with TRILOGY for symptomatic native aortic regurgitation (ALIGN-AR) was a multi-centre, single-arm observational study evaluating the feasibility and safety of the dedicated TRILOGY™(JennaValve Technology, UK) in patients with high surgical risk and severe AR (3 +). The trial enrolled 700 patients with severe AR, high risk for open surgical valve replacement and New York Heart Association Classification of heart failure (NYHA) score more than or equal to 2, examining the co-primary endpoints of (1) 30 day MACE and (2) death at 1 year. The TRILOGY device met the pre-specified performance goal for 30-day MACE (composite of death, stroke, major bleeding, kidney injury, vascular complications, need for further surgical or percutaneous valve interventions, new PPM, or > moderate AR) which occurred in 24.0% (95% CI 20.7–27.3%; p non-inferiority < 0.0001) and the pre-specified performance goal for death at 1 year which occurred in 7.7% (95% CI 5–10.4%; p < 0.0001). ALIGN-AR supports further study of TRILOGY for patients with severe AR and high surgical and randomised studies are now planned. [45].

The NAVITOR™ (Abbot, USA) valve is a SEV THV licensed for severe AS in patients with prohibitive surgical risk. The 30-day and 1-year outcomes of NAVITOR transcatheter Aortic valve in Low-Intermediate risk patients (VANTAGE) enrolled 434 patients with severe AS and at low-intermediate surgical risk (estimated 30-day surgical mortality between 3% and 8%) to a single treatment arm using the NAVITOR valve. Technical success was achieved in 97%, the incidence of the efficacy outcome [occurrence of > moderate paravalvular leak (PVL) at 30 days] was 0% versus a pre-specified performance goal of 6.6% (p non-inferiority < 0.0001) and the incidence of the safety endpoint (death or disabling stroke at 12 months) was 2.3% versus a pre-specified performance goal of 11.3% (p non-inferiority < 0.0001). Mean transvalvular gradient decreased from 42 mmHg at baseline to 4 mmHg at discharge and remained 8 mmHg after 1 year of follow-up, while the incidence of mild PVL at 1 year was 16% and the rate of PPM insertion by 1 year in the total population was 18.7% [46]. While the VANTAGE study valve demonstrates the feasibility of treating low-intermediate risk patients with severe AS, randomised study versus SAVR is still required.

It has been previously shown that, in patients with low surgical risk and trileaflet severe aortic stenosis, the EVOLUT™ self-expanding valve (SEV) THV has comparable 2 year efficacy and safety to SAVR [47]. In a new paper, 5-year Outcomes After Transcatheter or Surgical Aortic Valve Replacement in Low Surgical Risk Patients With Aortic Stenosis, studying the 1414 patients randomised to EVOLUT THV versus SAVR, the TAVI strategy showed no difference in primary endpoint of death or disabling stroke at 5 years (15.5% vs. 16.4%; p = 0.39), all-cause mortality (13.5% vs. 14.9%; p = 0.57), cardiovascular (CV) mortality (7.2% vs. 9.3%; p = 0.15), disabling stroke (3.6% vs. 4.0%; p = 0.57) or reintervention (3.3% vs. 2.5%; p = 0.44). TAVI was associated with less AF (16.3% vs. 41.2%; p < 0.001) but a higher rate of PPM insertion (27% vs. 11.3%; p < 0.001) [48]. While these results are consistent with long-term randomised data using other SEV THV platforms [49, 50] and suggest self-expandable TAVI valves may be equivalent to SAVR in low surgical risk populations over intermediate follow up, given that such patients are typically younger, a longer term (up to 10 years) and large-scale registry evidence is required before TAVI could be considered as standard of care in this setting.

Despite excellent results in tricuspid aortic valve anatomy, the role of SEV THV for treatment of bicuspid aortic valve stenosis remains uncertain, as such patients have typically been excluded from previous randomised control trials (RCT). The single-arm registry Five-Year Outcomes from the EVOLUT Low Risk Bicuspid TAVI Study undertaken in USA 25 centres evaluated 150 patients who received an EVOLUT THV for severe bicuspid aortic valve stenosis ± symptoms (median age of 70.3 years, 90.7% Sievers type 1 valve, median STS score of 1.4%, predicted score of mortality < 3%). Exclusion criteria included dilated ascending aorta (> 45 mm), prohibitive LVOT/leaflet calcification and age < 60 years. At 5 years, the rate of death or disabling stroke was 11.6%, predominantly driven by death (10.3%). While these results compare favourably with the 15.5% 5-year event rate for EVOLUT TAVI in tricuspid anatomy (discussed above), as the populations are different selection bias cannot be excluded [51]. In contrast, a large international propensity-matched analysis from the TriNetX research network studying 12,202 patients with bicuspid AS (2620 TAVI and 9582 SAVR; 1195 matched pairs) reported that TAVI had more than double the incidence of death at a mean of 1.9 years follow-up (HR 2.09, 95% CI 1.51–2.87), albeit firm conclusions cannot be drawn given the absence of detailed information regarding bicuspid valve morphology, transcatheter valve platform, and procedural technique limits [52]. In summary, the divergent findings from these observational studies highlights the need for prospective randomised trials in the bicuspid aortic valve setting.

While the landmark PARTNER 3 trial reported superiority of TAVI with the balloon-expandable SAPIEN 3™ (Edwards, USA) versus SAVR at 1 year in patients with severe tricuspid valve AS and low surgical risk [53], by 5 years, outcomes had converged [49]. A new follow-up Transcatheter or Surgical Aortic-Valve Replacement in Low-Risk Patients at 7 years utilised the same composite primary outcome (death, stroke or rehospitalisation related to the procedure, valve, or heart failure) plus a new, hierarchical composite secondary outcome utilising the same outcome events and subjecting them to a win-ratio (WR) analysis. In total, 460 patients from the TAVI group (92.7%) and 391 from the SAVR group (86.1%) were available for analysis. TAVI showed similar outcomes for the primary endpoint (34.6% vs. 37.2%; − 2.6%, 95% CI − 9% to 3.7%) and the win-ratio analysis (WR1.04, 95% CI 0.84–1.30), with no significant difference in death (19.5% vs. 16.8%; p = 0.31), mean aortic valve gradient (13.1 mmHg vs. 12.1 mmHg), valve failure (6.9% vs. 7.5%; p = 0.73) or valve reintervention (6.7% vs. 6.0%; p = 0.72). TAVI was associated with more clinical valve thrombosis (2.8% vs. 0.5%; p < 0.01) and a trend to higher PPM implantation (17.3% vs. 12.8%, p = 0.07) but markedly less atrial fibrillation (AF) (17.7% vs. 43.5%; p < 0.0001) [54]. While the greater withdrawal in the surgical group raises the possibility of attrition bias, the 7-year PARTNER 3 data continue to suggest similar outcomes for balloon-expandable TAVI versus SAVR in appropriately selected low-risk populations with severe AS.

The EARLY TAVR trial previously established that in patients with asymptomatic severe AS prior, early treatment with TAVI versus clinical surveillance reduced the composite of death, stroke or CV hospitalisation [55]. In a subsequent sub-study Incidence and impact of acute valve syndrome before aortic valve replacement: insights from the EARLY TAVR trial those who received early balloon-expandable TAVI (n = 455) were compared with the 388 clinical surveillance patients (86%) who eventually received delayed AVR (98% by TAVI, 2% by SAVR). At 2 years, early TAVI was associated with a 35% trend to reduction in the composite outcome of death, stroke or HFH (6.8% vs. 10.6%; HR 0.65, 95% CI 0.4–1.05; p = 0.08). Notably, 40% of clinical surveillance patients undergoing delayed AVR presented with Acute Valve Syndrome (AVS) defined as one or more of NYHA ≥ 3, syncope, AF, Ventricular arrhythmia, resuscitated cardiac death, HFH, LVEF < 50%, or threefold increase in NT-BNP. Such patients had a two-fold higher risk of death, stroke or HFH at 2 years versus early TAVI (HR 2.14, 95% CI 1.21–3.79).[56] Thus, further studies are warranted to identify patients at highest risk of progression to AVS who might benefit the most from early aortic valve intervention.

Small aortic annuli can present a challenge for TAVI. The Small Annuli Randomised to Evolut or Sapien (SMART) trial, which previously reported favourable results at 1 year, randomised 716 patients with severe AS and small CT derived annular area (< 430 mm²) of whom 87% were female to TAVI with supra-annular SEV using an EVOLUT™ (PRO/PRO+/Fx, Medtronic, USA) versus intra-annular balloon expandable valve (BEV) with SAPIEN (3/3Ultra, Edwards, USA). At 2-year follow-up, supra-annular SEV reported no significant difference in the primary composite endpoint of death, stroke or HFH (17.8% vs. 17.6%, HR 1.01, 95% CI 0.71–1.43) but lower mean gradient (8.5 mmHg vs. 16.1 mmHg; p < 0.001), a lower incidence of prosthetic valve thrombosis (1% vs. 4.5%; p = 0.005) and lower rates of TIA (1.2% vs. 4.2% BEV; p = 0.02).[57]. Ongoing follow-up will determine whether these early haemodynamic differences translate in to improved long-term clinical outcomes.

The ACURATE neo2™ (Boston Scientific, USA) is a supra-annular SEV with a top–down deployment mechanism that delivers a comparatively lower radial force compared with other SEVs. The Safety and Effectiveness Study of the ACURATE Valve for Transcatheter Aortic Valve Replacement (ACURATE IDE) trial previously reported increased death, stroke or HFH at 1 year for the ACURATE neo2 THV (n = 752) versus other commercially available devices (n = 748; SAPEN3/3 Ultra and EVOLUT platforms) [37]. In a retrospective analysis, one mechanism for the disappointing ACURATE neo2 THV appeared to be valve under-expansion which was independently associated with a greater incidence of death from stroke of HFH (HR 1.92, 95% CI 1.27–2.91). Patients with under-expanded valves (n = 135) versus fully expanded valves (n = 489), had a higher incidence of heavy valve leaflet and annulus calcification (OR 1.92, 95% CI 1.27–2.91), although procedural technique did not appear to contribute with pre-dilatation in all patients and post-dilatation rates similar (26.7% vs. 25.2%; p = 0.72). [58] Thus, valve under-expansion appeared predominately due to patient-specific anatomical characteristics rather than modifiable procedural factors.

Mitral and Tricuspid Interventions

Severe mitral valve dysfunction due to mitral annular calcification (MAC) remains a high-risk condition with no established transcatheter therapy and limited surgical options. The Transcatheter Mitral Valve Replacement (TMVR) with Tendyne™ (Abbott, USA) for Severe Mitral Annular Calcification (SUMMIT-MAC) study was a prospective, single-arm feasibility trial enrolling (n = 103) symptomatic patients (NYHA ≥ 2) with severe MAC and significant mitral regurgitation (MR) or mitral stenosis (MS), excluding those with severe left ventricular dysfunction, marked pulmonary hypertension (pHTN), or limited life expectancy, to undergo transapical Tendyne™ implantation. The primary endpoint, freedom from all-cause mortality or HFH at 12 months, was achieved in 60.4% of patients (exceeding the pre-specified performance goal of 43.0%; 50.2–70.0%; p = 0.0002). Technical success was high at 94.2%, all successfully implanted patients having ≤ 1 + MR at 30 days, with improvement in NYHA class (56.9%), and a modest increase in functional capacity (+ 20.6 m increase in 6-min walk distance, 6MWD; p = 0.038). Bleeding was the most frequent complication (27% with any bleed; 7% life threatening) and death occurred in 6.8% and 21% at 30 days and 1 year, respectively. These findings demonstrate the feasibility of Tendyne™ TMVR in severe MAC, but the high event rate highlights the need for randomised studies to refine patient selection and determine comparative benefit [59].

Although previous randomised evaluation of transcatheter tricuspid valve edge to edge repair (TEER) in patients with severe tricuspid regurgitation (TR) did not reduce mortality or HFH at 1 year, some patient-centric outcomes were encouraging [60]. The Two-year Outcomes Of Transcatheter Tricuspid Valve Edge-to-Edge Repair For Tricuspid Regurgitation: (TRILUMINATE) trial reported follow-up of 572 patients with (NYHA ≥ 2), and severe TR randomised to TEER with TRICLIP™ (Abbott, USA) versus best medical treatment. Crossover of medical patients to TEER after 1 year was permitted and occurred in 61.5%. TEER was associated with durable reduction in TR severity (≤ moderate TR 84% vs. 44%) and a small reduction in the annualised rate of HFH (0.19 vs. 0.26 events/year; p = 0.02) but no difference in death or the need for tricuspid valve surgery (albeit that outcomes the treatment effect was likely attenuated by the high number of patients who crossed between the conservative and intervention arm after 1 year [61].

An alternative approach to TEER in treatment of severe symptomatic TR is transcatheter tricuspid valve replacement (TTVR). The Transcatheter Valve Replacement in Severe Tricuspid Regurgitation (TRISCEND) trial randomised 400 patients with severe TR and intermediate or high surgical risk in a 2:1 ratio to unblinded transcatheter insertion of the EVOQUE™ (Edwards, USA) device versus medical therapy (Edwards Lifesciences; Fig. 5). The hierarchical composite endpoint, using the WR method, was death, insertion of a ventricular assist device or heart transplant, post-index valve intervention, HFH, 10-point improvement in KCCQ, 1-point improvement in NYHA or 30-m improvement in 6MWD). At 1 year, TTVR patients achieved marked better reduction of TR to moderate or less (99.1% vs. 16.1%) and favourable primary composite outcome (TTVR WR 2.02; 95% CI 1.56–2.62) driven mainly by improved KCCQ score (23.1% vs. 6.0%) and improved NYHA class (10.2% vs. 0.8%) but with no difference in mortality or HFH, and with increased risk of severe bleeding (16.4% vs. 5.3%; p = 0.003) and PPM implantation (17.4% vs. 2.3%; p < 0.001). [62] Together, the results of TRISCEND and TRILUMINATE demonstrate that, while TEER and TMVR are technically feasible and reduce TR severity, at present, benefit appears confined to improvement in symptoms only [62].

Fig. 5 .

Edwards EVOQUE transcatheter tricuspid valve replacement system. (Published with permission from Edwards Lifesciences)

Left Atrial Appendage Occlusion (LAAO) and Other Interventions

It is unknown whether percutaneous left atrial appendage occlusion (LAAO) devices for patients with AF and high bleeding risk (HBR) are efficacious. The Left atrial appendage closure in patients with atrial fibrillation at high risk of stroke and bleeding compared to medical therapy trial (CLOSURE-AF) randomised 912 patients with AF and HBR (mean CHA2DS2-VASc 5; mean HAS-BLED 3) to LAAO versus best medical therapy (BMT). The LAAO arm utilised mainly the Amplatzer Amulet™ device (42%) (Abbott, USA) or WATCHMAN FLX™ (54%) (Boston Scientific, USA) device and the BMT arm predominantly included use of direct oral anticoagulants (DOACs) (85%). At 3 years, LAAO failed to meet non-inferiority for the primary composite outcome of stroke, systemic embolism, CV death or major bleeding (16.83/100 patient-years versus 13.27/100 patient-years; HR 1.28, 95% CI 1.01–1.62) with consistent results in per-protocol or non-inferiority analysis. Serious LAAO complications included cardiac tamponade (n = 5), device embolisation (n = 1), major bleeding (n = 18), peripheral embolism (n = 1) and death within 7 days of implant (n = 2). Interestingly, the incidence of major bleeding was numerically higher in the LAAO arm (HR 1.21 95% CI 0.86–1.71). CLOSURE-AF thus demonstrates that, in patients with AF and HBR, LAAO confers no benefit compared with standard medical care [63].

The optimal management of intermediate-high risk pulmonary embolism (PE) without haemodynamic instability remains uncertain. Systemic thrombolysis has previously been shown to improve haemodynamic parameters but at the cost of major bleeding [64]. Computed assisted vacuum thrombectomy (CAVT) with the Indigo^® (Penumbra, USA) has been hypothesised to improve cardiac performance without significantly increasing the risk of major bleeding. The STORM-PE trial (RCT of mechanical thrombectomy with anticoagulation vs. anticoagulation alone for acute intermediate-high risk PE) randomised 100 patients to CAVT plus anticoagulation (AC) versus AC alone. At 48 h, CAVT was associated with a mean reduction in the primary endpoint of RV/LV ratio of 0.27 (95% CI 0.12–0.43) and reduction in the key secondary composite outcome (PE-related mortality, recurrent PE, clinical deterioration requiring rescue therapy, and major bleeding at 7 days; 4.3% vs. 7.5%; p = 0.681). In summary, STORM-PE results are encouraging although larger studies are required to confirm hard endpoint clinical effectiveness [65].

Advances in Heart Failure

Heart failure (HF) remains an area of active research, with several recent trials addressing unresolved questions across pharmacological therapy, device-based treatment, and supportive care. Key uncertainties include whether older therapies such as digitoxin retain value in the era of contemporary guideline-directed medical therapy, whether obesity-targeted treatment modifies heart failure with preserved ejection fraction (HFpEF) outcomes, how best to initiate or extend disease-modifying therapy in hospitalised or advanced HF populations, and whether device or lifestyle strategies should alter current standards of care.

Pharmacotherapy

Despite widespread use of guideline-directed medical therapy, the clinical efficacy of the cardiac glycoside digitoxin in patients with heart failure with reduced ejection fraction (HFrEF) has remained uncertain. In the international, double-blind, placebo-controlled DIGIT-HF trial, 1212 patients with chronic HFrEF were randomised to digitoxin versus placebo, in addition to contemporary background therapy, and followed for a median of 36 months. Digitoxin was associated with an 18% relative reduction in the primary composite endpoint of death or first hospital admission for worsening HF (39.5% vs. 44.1%; p = 0.03), although no significant reduction in death (27.2% vs. 29.5%; p = ns) and numerically higher adverse event rates (4.7% vs. 2.8%) [66]. While DIGIT-HF suggests a reduction in heart failure hospitalisation, the absence of a mortality benefit and the signal toward increased adverse events support a cautious interpretation, with any role for digitoxin likely limited to selected patients with persistent symptoms despite optimal therapy.

HFpEF in the setting of obesity has limited disease-modifying options, despite strong links between adiposity, inflammation, symptoms, and recurrent congestion. In the SUMMIT trial, 731 patients with HFpEF and obesity were randomised to once-weekly dose-escalated subcutaneous tirzepatide versus placebo, with a median follow-up of 104 weeks. Tirzepatide was associated with a 38% reduction in the primary composite of CV death or worsening HF (36 vs. 56 patients; HR 0.62; 95% CI 0.41–0.95; p = 0.026) mainly driven by a 56% reduction in worsening HF events (8.0% vs. 14.2%; HR 0.54; 95% CI 0.34–0.85), with improved health status, increased exercise capacity, and an 11.7% greater weight reduction [67]. These data support tirzepatide as a clinically meaningful option for obesity-related HFpEF, while reinforcing the ongoing need to understand how benefits integrate with contemporary background therapy (Fig. 6).

Fig. 6.

Key cardiovascular and metabolic outcomes in the SUMMIT trial

Vericiguat is approved for worsening HFrEF, but its role in stable ambulatory HFrEF receiving contemporary background therapy has been uncertain. The Vericiguat in Ambulatory Heart Failure with Reduced Ejection Fraction Without Recent Worsening (VICTOR) trial randomised 6105 patients with HFrEF and no recent HF hospitalisation to vericiguat versus placebo. Vericiguat did not significantly reduce the primary composite endpoint of CV death or HF hospitalisation at a median 18.5 months (18% vs. 19%; HR 0.93; 95% CI 0.83–1.04; p = 0.22) but, of interest, did show a nominal reductions in CV death (9.6% vs. 11.3%; HR 0.83; 95% CI 0.71–0.97; p = 0.020) and all-cause mortality (12.3% vs. 14.4%; HR 0.84; 95% CI 0.74–0.97) which would support further scrutiny regarding population selection and endpoint drivers [68].

Despite strong evidence supporting sodium–glucose cotransporter-2 inhibitors (SGLT-2i) in chronic ambulatory HF, data on the efficacy and safety of initiating these therapies during hospitalisation for HF have been limited. The Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure–Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF–TIMI 68) trial randomised 2401 patients hospitalised for HF to dapagliflozin 10 mg once daily versus placebo in addition to guideline-directed medical therapy. Dapagliflozin showed a numerically lower but non-significant reduction in primary composite endpoint of CV death or worsening HF at 2 months [10.9% with dapagliflozin vs. 12.7% with placebo; HR 0.86 (95% CI 0.68–1.08); p = 0.20], and numerical reduction in all-cause mortality (3.0% vs. 4.5%; HR 0.66; 95% CI 0.43–1.00) [69]. In addition, a prespecified meta-analysis of randomised trials with in-hospital initiation of SGLT-2i, including DAPA ACT HF-TIMI 68, did report a 29% reduction in early CV death or worsening HF (HR 0.71; 95% CI 0.54–0.93; p = 0.012), and 43% reduction in all-cause mortality (HR 0.57; 95% CI 0.41–0.80; p = 0.001), thus supporting consideration of this strategy in patients with stabilised HF [70].

Heart failure due to chronic Chagas cardiomyopathy carries a poor prognosis but has lacked large prospective randomised evidence supporting standard guideline therapies in this specific aetiology. The Sacubitril/Valsartan versus Enalapril in Heart Failure Due to Chronic Chagas Cardiomyopathy (PARACHUTE-HF) trial randomised 922 patients with confirmed Chagas disease and symptomatic HFrEF to sacubitril/valsartan versus enalapril. Use of sacubitril/valsartan was associated with a 52% increased likelihood of better outcome in the hierarchical primary endpoint of CV death or first HF hospitalisation (at a median of 25 months) or reduction in NT pro-BNP (at 12 weeks) (stratified WR 1.52; 95% CI 1.28–1.82), mainly driven by greater NT-proBNP reduction (30.6% vs. 5.5%) [71].

Despite widespread use of neurohormonal blockade in advanced heart failure, the role of HF specific pharmacotherapy in patients supported with durable left ventricular assist devices (LVADs) remains poorly defined. The multi-centre, randomised, open-label, parallel group study to Evaluate the Use of Sacubitril/Valsartan in HeartMate 3 Left Ventricular Assist Device Recipients (ENVAD-HF) randomised 60 stable HeartMate 3 recipients to sacubitril/valsartan versus standard of care blood pressure management, with a target mean arterial pressure of 75–90 mm Hg. At 12 months, Sacubitril/valsartan showed comparable safety and tolerability with numerically fewer primary safety endpoint events (death, renal dysfunction, hyperkalaemia, or symptomatic hypotension; 2 vs. 5 events; HR 0.42; 95% CI 0.08–2.18; p = 0.30), providing a rationale for a larger adequately powered trial. However, even in this small study, a need for fewer antihypertensive medications and an improvement in Kansas City Cardiomyopathy Questionnaire overall summary score was noted. [72].

Iron deficiency is common in heart failure and is associated with worse outcomes, yet the clinical benefits of intravenous iron therapy on hard CV end points remain uncertain. In the FAIR-HF2 DZHK05 trial, 1105 patients with HFrEF and iron deficiency were randomised at 70 European centres to intravenous ferric carboxymaltose versus saline placebo. At a median of 16.6 months, ferric carboxymaltose, reduced by around 1/5th each of the co primary endpoints of (1) CV death/first HF hospitalisation (2) total HF hospitalisations and (3) CV death/first HF hospitalisation in those with TSAT < 20%, but none reached confirmatory statistical significance under a multiplicity strategy [73]. Despite lack of hard endpoint reduction, improved secondary outcomes including NYHA class and 6MWD were consistent with previous IV iron trials.

Non-pharmacotherapy

Despite established mortality benefit of implantable cardioverter defibrillators (ICDs) in patients with severe left ventricular systolic dysfunction, the role of prophylactic device therapy in post–MI patients with persistent moderate dysfunction and abnormal arrhythmic risk markers remains uncertain. The REFINE-ICD trial, presented as a late-breaking trial at ESC Congress Madrid 2025, screened nearly 2000 patients with prior MI, identifying 597 with left ventricular ejection fraction (36–50%) and high risk Holter ECG features (impaired heart rate turbulence or T-wave alternans) who were randomised to ICD plus optimal medical treatment versus optimal medical treatment alone. Despite the high-risk Holter ECG features identifying a substantially higher-risk population than a parallel registry, ICD use in this population did not reduce all-cause mortality (24.5% vs. 21.3%), cardiac mortality (8.8% vs. 7.6%) or sudden cardiac death (2.6% vs. 3.8%) at a mean of 5.7 years [74], suggesting that additional or alternative biomarkers are needed to identify which post-MI patients with moderate systolic dysfunction might benefit from prophylactic ICD therapy.

Fluid restriction is commonly recommended in chronic HF despite limited prospective evidence for benefit and concerns about adverse effects on quality of life. In the Fluid REStriction in Heart Failure versus Liberal Uptake (FRESH-UP) trial, 504 patients with stable chronic HF were randomised to liberal versus 1500 mL/day restricted fluid intake for 3 months. Although liberal fluid intake (a mean of 1764 mL) did not significantly improve the primary endpoint of health status measured by KCCQ Overall Summary Score (74.0 vs. 72.2 points; adjusted mean difference 2.17; 95% CI − 0.06 to 4.39; p = 0.06), it significantly reduced thirst distress, with no differences in safety outcomes including death, HF hospitalisation, need for intravenous diuretics or acute kidney injury at 6 months. These findings suggest that routine fluid restriction in stable chronic HF offers no clear advantage but may unnecessarily increase patient discomfort [75].

Hypertrophic Cardiomyopathy

Despite the ground-breaking benefits of mavacamten in selected patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), its efficacy in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) has remained uncertain. The phase 3, ODYSSEY-HCM trial randomised 580 adults with symptomatic nHCM to mavacamten versus placebo for 48 weeks. Despite a 58% reduction in NT-proBNP, mavacamten did not significantly improve either of the co-primary endpoints (peak oxygen uptake, between-group difference 0.47 mL/kg/min; p = 0.07; and KCCQ clinical summary score 2.7 points difference; p = 0.06), but was associated with reduced ejection fraction (consistent with the known myosin-inhibitor profile) and more frequent treatment interruptions. Although well tolerated overall, mavacamten does not appear to confer meaningful functional or symptomatic benefit in nHCM, underscoring important pathophysiological differences to obstructive HCM [76].

Despite long-standing reliance on beta-blockers as first-line therapy for symptomatic obstructive hypertrophic cardiomyopathy (oHCM), robust randomised evidence supporting their efficacy is limited, and whether they offer superior benefit as initial monotherapy is a topical question. In the MAPLE-HCM trial, 175 adults with symptomatic oHCM were randomised to targeted cardiac myosin inhibition with aficamten monotherapy versus metoprolol monotherapy for 24 weeks. Aficamten was associated with improvement in peak oxygen uptake (2.3 mL/kg/min difference; p < 0.001) NYHA functional class (51% vs. 26% ≥ 1 NYHA class; p < 0.001), KCCQ clinical summary score (+ 7.8 points difference; p < 0.001), left ventricular outflow tract gradient, NT pro–BNP levels, and left atrial volume index [77]. Given the greater functional, haemodynamic, and symptomatic benefit, these data support a potential paradigm shift to early targeted myosin inhibition rather than betablocker therapy in this population.

Advances in Electrophysiology and Devices

Recent developments in electrophysiology and cardiac device therapy have focused on refining ablation technologies, improving anticoagulation strategies across diverse clinical scenarios, and enhancing outcomes with implantable and pacing-based interventions. This section reviews new evidence addressing practical clinical questions, ranging from the comparative performance and safety of emerging ablation modalities, to tailoring stroke prevention strategies, and optimising patient selection for device therapy and considers how these findings may shape contemporary practice.

Atrial Fibrillation

Pulsed field ablation (PFA) has emerged as an alternative to thermal ablation techniques in the management of atrial fibrillation (AF), with previous registries suggesting encouraging safety and clinical efficacy [78, 79]. The Ground-Breaking Electroporation-based Intervention for PAROXysmal Atrial Fibrillation Treatment (BEAT-PAROX-AF) trial randomised 289 patients (mean age 63.5 years, 42% female) with symptomatic paroxysmal AF, resistant to ≥ 1 antiarrhythmic drug, and class I or IIa indication for pulmonary vein isolation, to PFA versus radiofrequency ablation (RFA) using the CLOSE protocol. PFA achieved a similar incidence in the primary endpoint of single procedure success at 12 months (77.2% vs. 77.6%; 95% CI − 8.2 to 10.1; p = 0.84) but with a shorter mean procedural time (56 vs. 95 min; p < 0.001) and numerically fewer serious adverse events (3.4% vs. 7.6%) [80] confirming its role as a useful alternative to RFA.

In the Pulsed Field or Cryoballoon Ablation for Paroxysmal Atrial Fibrillation study, 210 patients (median age 64 years; 28% female) with symptomatic paroxysmal AF undergoing first-time PVI were randomised to PFA using a pentaspline catheter (Farapulse™) versus cryoballoon ablation (Medtronic™, Arctic Front), with continuous rhythm monitoring via implantable cardiac monitors. PFA was associated with a lower incidence of atrial tachyarrhythmia recurrence between days 91 and 365 post-ablation (Kaplan–Meier cumulative incidence 37.1% vs. 50.7%; p < 0.001 for non-inferiority), while the safety endpoint, a composite of procedure-related complications, was comparable between groups (1% vs. 2%) [81].

Despite these encouraging data, PFA may be associated with a distinct risk profile versus RFA, which is incompletely characterised [82]. The NEMESIS-PFA trial evaluated biomarker changes in 871 patients (mean age 69 years, 29% female) who underwent AF ablation with PFA (88.7%) versus RFA (11.3%). PFA was associated with significantly greater median changes in cardiac troponin (13,551 vs. 128 ng/dL; p < 0.001), haemoglobin (− 2.3 vs. − 1.2 g/dL; p < 0.001), creatinine (1.0 vs. 0.9 mg/dL; p = 0.007), LDH (107.5 vs. 26.5; p < 0.001) and haptoglobin (− 102 vs. − 34 mg/dL; p < 0.001), with all effects demonstrating dose dependence [83]. These findings highlight the need for further evaluation of system-specific collateral effects as PFA use increases.

There is a paucity of evidence regarding the optimal duration of anticoagulation for patients with AF following catheter ablation (CA)[84]. The Long-Term Anticoagulation Discontinuation After Catheter Ablation for Atrial Fibrillation (ALONE-AF) trial randomised 840 patients (mean age 64 years, mean CHA2DS2-VASc 2.1) without AF recurrence ≥ 12 months post-ablation to discontinuing versus continuing oral anticoagulation. Discontinuing therapy was associated with a lower incidence in the primary endpoint of stroke, systemic embolism or major bleeding at 2 years (0.3% vs. 2.2%; p = 0.02), driven primarily by reduced major bleeding (0% vs. 1.4% difference − 1.4, 95% CI − 2.6 to − 0.2) [85].

The Optimal Anticoagulation for Enhanced Risk Patients Post-Catheter Ablation for Atrial Fibrillation (OCEAN) trial randomised 1284 patients (mean age 66 years, 28% female, mean CHA2DS2-VASc score 2.2) ≥ 12 months post-successful CA to aspirin (70–120 mg once daily) versus rivaroxaban (15 mg once daily). Use of aspirin did not significantly increase the primary endpoint of stroke, systemic embolism or new embolic stroke > 15 mm on magnetic resonance imaging (1.4% vs. 0.8%; p = 0.28), but was associated with numerically less fatal or major bleeding. ALONE-AF and OCEAN support further investigation into an individualised rhythm-guided approach to anticoagulation in patients with relatively low stroke risk following CA.

The Active Monitoring for Atrial Fibrillation (AMALFI) trial investigated whether remote screening in a primary care setting improved the detection and timeliness of AF diagnosis in at-risk individuals. AMALFI randomised 5040 patients aged ≥ 65 years (mean age 78 years; 47% female) with moderate-to-high stroke risk [median CHA2DS2-VASc score 4 (IQR 3–5)] and no prior AF or atrial flutter to 14-day patch-based continuous ECG monitoring versus usual care. At 2.5 years, use of the 14-day patch was associated with 26% increase in AF diagnosis (6.8% vs. 5.4%; p = 0.03), and greater oral anticoagulant use (1.63 vs. 1.14 months; p < 0.001), although no difference in stroke rates [2.7% vs. 2.5%; rate ratio 1.08 (95% CI 0.76–1.53)] [86]. These findings suggest that remote AF screening is feasible in primary care but, in the absence of stroke reduction, is unlikely to prompt guideline change toward routine patch screening at present.

The Therapy for Atrial Fibrillation in Patients with Drug-Eluting Stents (ADAPT AF-DES) trial randomised 960 patients (mean age 71 years, 21% female) with AF, who had undergone PCI with implantation of a drug-eluding stent 12 or more months previously, to non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy (n = 482) versus NOAC plus clopidogrel. At 12 months, NOAC monotherapy was non-inferior for the primary composite endpoint (death, MI, stent thrombosis, stroke, systemic embolism, and major or clinically relevant non-major bleeding; Kaplan–Meier estimate 9.6% vs. 17.2%; absolute difference − 7.6%; 95.2% CI − 11.9 to − 3.3; p < 0.001) [87]. Results from ADAPT AF-DES support current guideline recommendations of NOAC monotherapy in the later post-stent period.

Uncertainty exists surrounding the optimal timing of antithrombotic strategy for patients with AF who undergo PCI. The multicentre OPTIMA-AF trial randomised 1088 patients (mean age 75 years, 20% female) across 75 centres in Japan, with non-valvular AF undergoing PCI for stable angina, unstable angina or silent ischaemia to a shorter 1-month dual therapy (DOAC plus P2Y12 inhibitor) followed by DOAC monotherapy versus 12 months dual therapy followed by DOAC monotherapy [88]. The 1-month dual therapy strategy was non-inferiority for the primary composite endpoint of death or thromboembolic events (4.5% vs. 5.4%; HR 1.20; 95% CI 0.70–2.07; p non inferiority = 0.002) but was associated with significantly lower rates of clinically relevant bleeding (4.8% vs. 9.5%; HR 0.50; 95% CI 0.31–0.80; p = 0.004 for superiority) [89]. Intravascular imaging was used in all PCI procedures and ACS patients were excluded which may limit the generalisability of results but findings support further investigation into shorter antithrombotic regimes in this population.

There is limited randomised evidence to inform stroke prevention strategies amongst individuals with AF who have survived a previous intracerebral haemorrhage (ICH). The Direct oral anticoagulants (DOAC) versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF) trial randomised 319 patients (median age 79 years, 35% female) with spontaneous ICH, an indication for anticoagulation and modified Rankin score ≤ 4 to DOAC (n = 158) versus no anticoagulation (n = 161, antiplatelet therapy in 33%) [90]. Use of DOAC therapy was associated with significantly fewer first incidence ischaemic strokes (1 vs. 20 patients; HR 0.05; 95% CI 0.01–0.36; Fig. 7) and an absolute reduction in the ischaemic stroke event rate by 7.77 events per 100 patient years (NNT 13). However, DOAC therapy did not meet the prespecified non-inferiority criterion for recurrent intracerebral haemorrhage (11 vs. 1 patient; HR 10.89, 95% CI 1.95–60.72; Fig. 8) [90]. Net clinical benefit (all stroke/SE, MI, CV death, major bleed) numerically favoured continuing DOAC (adjusted HR 0.69, 95% CI 0.33–1.40) but did not reach significance and individual level decision making is still required.

Fig. 7.

Central illustration from Veltkamp et al. [90]. Kaplan–Meier analysis of first incident ischaemic stroke in PRESTIGE-AF clinical trial. Images reprinted under Creative Commons CC-BY-NC open access agreement. DOAC direct oral anticoagulant, HR hazard ratio

Fig. 8.

Central illustration from Veltkamp et al. [90]. Kaplan–Meier analysis of first recurrent intracerebral haemorrhage in PRESTIGE-AF clinical trial. Images reprinted under Creative Commons CC-BY-NC open access agreement. DOAC direct oral anticoagulant, HR hazard ratio

Biomarker-based risk scores for stroke and bleeding (ABC-AF) have been validated in AF [91–93], although their impact on clinical outcomes remains uncertain. In the Biomarker-Based ABC-AF Risk Scores for Personalized Treatment to Reduce Stroke or Death in Atrial Fibrillation trial, 3933 patients with AF (median age 73.7 years; 33.6% female) were randomised to an ABC-AF–guided strategy (97.8% OAC use) versus standard care (typically CHADsVAsc; 92.6% OAC use). The study was stopped early due to a non-significant trend toward higher mortality in the ABC-AF arm among patients with CHA₂DS₂-VASc ≥ 3. The ABC-AF risk-score did not reduce the primary endpoint of stroke or death (HR 1.19; 95% CI 0.96–1.48; p = 0.12), and there were no significant differences in stroke, major bleeding, or HF hospitalisation [94]. These findings underscore the need for prospective evaluation of risk stratification and precision medicine tools across diverse clinical settings before routine implementation.

Obesity is recognised as an independent and modifiable risk factor for AF [95] and may reduce success rates of CA, but limited randomised evidence exists to guide optimal management of AF in this population. The Catheter Ablation versus Lifestyle Modification with Antiarrhythmic Drugs to Treat Atrial Fibrillation (PRAGUE-25) trial randomised 203 patients (median age 60 years, 32% female) with symptomatic AF and BMI ≥ 30 kg/m² (mean BMI 34.9 kg/m²) to CA versus lifestyle modification plus antiarrhythmic drugs (LFM + AAD). The CA strategy was associated with significantly higher freedom from AF at 12 months (73% vs. 35%; HR 2.79; p < 0.001), with numerically fewer major complications (1 vs. 4). Of note, LFM + AAD resulted in greater weight loss (− 6.4 kg vs. − 0.35 kg; p < 0.001) [96] emphasising the complementary role of lifestyle intervention in this population.

Management of Other Cardiac Dysrhythmias, Including CIEDs

Existing evidence suggests that outcomes following complex cardiac procedures are superior in high volume centres [97, 98]. Bansal et al. examined the association between hospital procedural volume and post-procedural complications following ventricular tachycardia (VT) ablation among 9298 patients (mean age 65.5 years; 23.5% female) from the 2019 National Inpatient Sample database (a representative 20% sample of all U.S. inpatient hospitalisations). Hospitals were categorised as high-, medium-, or low-volume centres, accounting for 3531, 3606, and 2161 procedures, respectively. Despite a higher comorbidity burden, patients treated at high-volume hospitals experienced significantly lower in-hospital mortality (2.9% vs. 3.5% vs. 3.8%; p = 0.04), cardiac tamponade (0.9% vs. 1.4% vs. 2.2%; p = 0.015), or major bleeding requiring transfusion (2.2% vs. 4.5% vs. 5.7%; p = 0.012) [99]. The observed reduction in mortality and procedural complications at high-volume centres underscores the importance of institutional experience and may support concentrating VT ablation in specialised centres.

The Increasing the Potassium Level in Patients at High Risk for Ventricular Arrhythmias (POTCAST) trial evaluated whether correction of low-normal plasma potassium improves outcomes in patients at high risk of ventricular arrhythmias. A total of 1200 patients (mean age 63 years, 20% female) with an ICD and baseline potassium ≤ 4.3 mmol/L were randomised to potassium-raising therapy (dietary advice, supplementation and/or mineralocorticoid receptor antagonists) plus standard care versus standard care alone. Over a median follow-up of 39.6 months, use potassium-raising therapy which increased plasma potassium by 0.3 mmol/L, was associated with a 22% reduction in the primary composite endpoint of ventricular arrhythmia, appropriate ICD therapy, arrhythmia or HF hospitalisation, or all-cause mortality (22.7% vs. 29.2%; 95% CI 0.61–0.95; p = 0.01), but no difference in rates of potassium-related hospitalisation (~ 1% in both groups) [100], supporting plasma potassium as a safe, modifiable therapeutic target.

The role of myocardial fibrosis in ventricular arrhythmia (VA) amongst endurance athletes is poorly defined. The Ventricular Arrhythmia and Cardiac Fibrosis in Endurance Experienced Athletes (VENTOUX) trial enrolled106 asymptomatic male cyclists/triathletes (age 50 years) who undertook over 10 h/week of exercise for 15 or more years. Participants underwent exercise testing, stress–perfusion late gadolinium enhancement–CV magnetic resonance and implantation of implantable loop recorders (ILR) to detect the primary endpoint of incident VA, with median follow-up of 720 days. Non-sustained ventricular tachycardia and sustained ventricular tachycardia occurred in 20 (18.9%) and 3 (2.8%) of participants, respectively. The risk of incident VA was greater in those with myocardial fibrosis (HR 4.7; 95% CI 1.8–12.8; p = 0.002) and increased left ventricular end-diastolic volume indexed (LVEDVI; HR 1.4, 95% CI 1.1–1.9; p = 0.02), with myocardial fibrosis remaining predictive after adjusting for LVEDVI (HR 4.7, 95% CI 1.7–12.7; p = 0.002) [101]. Further investigation is required to establish whether myocardial fibrosis in this population is intrinsically arrhythmogenic or serves as a surrogate marker of an underlying pathological process.

Conduction system pacing (CSP) may reduce the adverse effects associated with chronic right ventricular pacing in patients with high-grade atrioventricular block (AVB). Authors of the CSPACE: A Randomised Controlled Trial Comparing Right Ventricular Pacing with Conduction System Pacing trial randomised 202 consecutive patients (mean age 77 years, 33% female) with a pacing indication for AVB but no indication for cardiac resynchronisation therapy (CRT) to CSP versus right ventricular septal pacing (RVsP). Procedural success rate was 88.1% and 100%, respectively. CSP significantly reduced the composite endpoint of PICM, upgrade to CRT, HF hospitalisation and all-cause mortality (7.17 vs. 20.69 events per 100 person-years; HR: 0.35; 95% CI: 0.19–0.64; p < 0.001) and while lead revision was required more frequently in the CSP group (7.9% vs. 1%; p = 0.017), results support the role of CSP as the preferred pacing strategy in AVB [102].

Advances in Cardiovascular Prevention

Preventative cardiology remains a rapidly evolving field, with several key trials presented during 2025 providing important insights into lipid management, cardiometabolic disease and blood pressure control. Collectively, recent prevention trials highlight a shift towards earlier and more intensive intervention across multiple risk pathways, including lipids, cardiometabolic disease and hypertension.

Dyslipidaemia and Lipid-Lowering Therapies

Statins remain first-line therapy for low density lipoprotein (LDL)–cholesterol reduction [103); however, recent trials have further expanded the evidence base for novel and adjunctive lipid-lowering strategies, particularly in high-risk primary prevention populations.

While the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor, evolocumab, has been shown to reduce the risk of MACE among patients with prior MI or stroke, its role in patients without prior CV events has been unclear. The VESALIUS-CV trial randomised 12,257 high-risk patients with LDL cholesterol ≥ 90 mg/dL but without prior MI or stroke to evolocumab versus placebo. At a median of 4.6 years evolocumab was associated with significant reduction in cardiac death, MI or stroke and 4-point MACE including revascularisation with no increase in safety events. Benefits were seen in those with and without imaging evidence of atheroma. VESALIUS-CV thus supports use of evolocumab in high-risk primary prevention. Importantly, these findings extend the benefits of PCSK9 inhibition beyond secondary prevention, addressing a major evidence gap and supporting earlier, more intensive lipid-lowering in high-risk patients without prior cardiovascular events. This trial may have important implications for future guideline recommendations and risk-stratified prevention strategies [104].

Novel lipid-lowering strategies also continue to expand. Oral PCSK9 inhibition has emerged as a promising alternative to injectable therapies. In the CORAL reef phase 3 trial, 303 adults with heterozygous familial hypercholesterolemia receiving background statin therapy, with or without ezetimibe, were randomised in a 2:1 ratio to once-daily oral PCSK9 inhibitor, enlicitide versus placebo for 52 weeks. Enlicitide resulted in a 59.4% reduction in low-density lipoprotein cholesterol at week 24 (95% CI − 65.6 to − 53.2; p < 0.001), with sustained effects (− 63.5%) at week 52, and significant reductions in non-high-density lipoprotein cholesterol (− 56%), apolipoprotein B (− 51.1%), and lipoprotein(a) (− 27.5%). These findings indicate enlicitide is safe and highly effective for lipid lowering in heterozygous familial hypercholesterolemia, offering a potential alternative to injectable therapies [105].

Severe hypertriglyceridemia markedly increases the risk of acute pancreatitis, yet existing therapies only partially address this risk, highlighting a need for more effective triglyceride-lowering strategies. In the Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk trial (CORE-TIMI 72a and CORE2-TIMI 72b; ClinicalTrials.gov identifiers NCT05079919 and NCT05552326), 1061 adults with fasting triglyceride levels ≥ 500 mg/dL on standard lipid-lowering therapy were randomised to the apolipoprotein C-III inhibitor olezarsen (50 mg or 80 mg monthly subcutaneous) versus placebo for 12 months. Use of olezarsen was associated with large reductions in fasting triglycerides at 6 months (62.9% with 50 mg and 72.2% with 80 mg; p < 0.001), and a markedly lower incidence of adjudicated acute pancreatitis events (HR 0.15; 95% CI 0.05–0.40; p < 0.001, NNT 20), suggesting that olezarsen has a potential as a new therapeutic option for this high-risk population [106].

Cardiometabolic Disease, Diabetes and Obesity

While subcutaneous glucagon-like peptide-1 (GLP-1) agonists reduce CV events in patients with diabetes, it has been uncertain whether similar benefit is present for oral GLP-1 agonists. In the Semaglutide Cardiovascular Outcomes Trial (SOUL), patients with type 2 diabetes and established CV disease or high CV risk were randomised to oral semaglutide versus placebo. At a median of 49.5 months, oral semaglutide was associated with a 14% reduction in the primary composite endpoint of CV death, MI, or stroke [12.0% vs. 13.8%, HR 0.86 (95% CI 0.77–0.96), p = 0.006], with consistent effects across key subgroups. These findings show that the benefits of subcutaneous GLP-1 appear to extend to oral administration also [107].

GLP-1 agonists are effective for obesity management, but comparative efficacy between newer dual-agonist agents and established treatments has been uncertain in patients without diabetes. In the SURMOUNT-5 trial, 751 adults with obesity but without type 2 diabetes were randomised in a phase 3b, open-label design to tirzepatide versus semaglutide for 72 weeks. Tirzepatide gave greater mean percent weight loss (− 20.2% vs. − 13.7%; p < 0.001), larger reductions in waist circumference (18.4 cm vs. 13.0 cm; p < 0.001), and higher proportions of participants achieving clinically meaningful weight-loss thresholds. Further study is required to determine whether this improved obesity management translates into improved CV outcomes [108].

Hypertension and Blood Pressure Control

Despite widespread availability of anti-hypertensive therapy, blood pressure control remains suboptimal in many high-risk patients. Novel long-acting agents and pathway-specific therapies are therefore attracting interest. The KARDIA-3 trial randomised patients with uncontrolled hypertension on 2–4 background antihypertensive agents and established CV disease or high CV risk to subcutaneous zilebesiran (300 mg or 600 mg every 6 months), a small interfering RNA targeting angiotensinogen versus placebo. Zilebesiran 300 mg gave modest reduction in systolic blood pressure (− 5 mmHg at 3 months and − 3.9 mmHg at 6 months) with no additional benefit from 600 mg. Although overall BP lowering did not remain significant after adjustment, those with higher baseline systolic BP ≥ 140 mmHg and taking diuretic showed greater benefit (− 9.2 mmHg at 3 months and − 8.3 mmHg at 6 months) and this subgroup will be studied further in the phase 3 CV outcomes trial. [109].

Aldosterone synthase inhibition was tested in the Baxdrostat Efficacy and Safety in Uncontrolled and Resistant Hypertension (BaxHTN) phase 3 trial which randomised 796 adults with uncontrolled or resistant hypertension on two or more background antihypertensive agents to once daily oral baxdrostat (1 mg or 2 mg) versus placebo for 12 weeks. Baxdrostat, significantly reduced seated systolic blood pressure at week 12 (− 14.5 mmHg) with consistent effects in resistant hypertension and a higher proportion achieving blood pressure control. Although associated with more frequent hyperkalaemia and modest early declines in estimated glomerular filtration rate, BaxHTN suggests that aldosterone synthase inhibition with baxdrostat may provide clinically meaningful blood pressure lowering in patients with hard-to-control hypertension [110].

Poor adherence to antihypertensive therapy is common and contributes to suboptimal blood pressure control, particularly in vulnerable populations, thus scalable strategies to improve adherence are needed. In the Behavioral Economics Trial To Enhance Regulation of Blood Pressure (BETTER-BP), 400 adults with uncontrolled hypertension and poor self-reported medication adherence were randomised to a mobile health–based incentive lottery delivered by text message versus usual care, with passive adherence monitoring and 6-month intervention follow-up. Use of incentive lottery intervention doubled the likelihood of achieving adequate medication adherence at 6 months but did not significantly reduce systolic blood pressure, suggesting that enhanced medication adherence alone may be insufficient to translate into short-term blood pressure reduction in high-risk populations [111].

Special Populations

Women with ischemia and nonobstructive coronary artery disease (INOCA) frequently have persistent symptoms and adverse outcomes, but evidence to guide optimal preventive medical therapy in this population remains limited. The Women’s Ischemia Trial to Reduce Events in Non-obstructive CAD (WARRIOR) randomised 2476 symptomatic, clinically stable women with INOCA and < 50% coronary stenosis to intensive medical therapy (high-intensity statin, a maximally tolerated angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, plus low-dose aspirin) versus usual care with 5-year follow-up. The intensive arm did not significantly reduce the primary endpoint of major adverse CV events (17.8% vs. 16.2%; p = ns), nor did it improve secondary outcomes including quality of life or angina burden [112]. However, the study was severely limited by usual care prescribing leading to almost identical levels of statin, ACEi/ARB and aspirin. WARRIOR highlights the ongoing need for further trials to define optimal management of women with INOCA.

Cardiac allograft vasculopathy is a leading cause of late morbidity and mortality after heart transplantation, but whether intensive lipid lowering with PCSK-9 inhibition can prevent early disease progression is uncertain. In the Cardiac Allograft Vasculopathy Inhibition With Alirocumab (CAVIAR) trial, 114 recent heart transplant recipients with well-matched baseline characteristics were randomised early after transplantation to alirocumab versus placebo, in addition to background rosuvastatin, with serial invasive coronary imaging performed at baseline and 1 year. Use of alirocumab resulted in a 50% reduction in low-density lipoprotein cholesterol (p < 0.001), but this did not reduce the rate of coronary plaque progression or improve physiological measures of coronary or microvascular function at 1 year. Although safe and effective for lipid lowering, CAVIAR suggests that early PCSK-9 inhibition does not attenuate short-term cardiac allograft vasculopathy progression in patients with already relatively low baseline low-density lipoprotein cholesterol [113]. However, longer follow-up and further study across a range of low-density lipoprotein cholesterol levels would be of interest.

Conclusion

This paper has summarised a wide array of key trials in clinical cardiology that were presented and/or published during 2025. In coronary syndromes and antithrombotic management, this year has seen a continued challenge to the traditional paradigm of prolonged dual antiplatelet therapy, with trials such as TARGET-FIRST, MASTER DAPT, DUAL-ACS, and SMART-CHOICE 3 supporting shorter and more individualised strategies following acute coronary syndromes and percutaneous coronary intervention. Additional studies including CELEBRATE and DAPT-SHOCK-AMI have explored novel approaches to early platelet inhibition in STEMI and cardiogenic shock, highlighting both potential benefit and ongoing uncertainty.

Important advances in percutaneous coronary intervention were also observed, with growing interest in drug-coated balloon technologies supported by SELUTION DeNovo and AGENT IDE, alongside longer-term revascularisation data from FAME 3 and NOBLE. In structural intervention, several pivotal trials have provided important insights into transcatheter aortic valve intervention and adjunctive therapy (DAPA-TAVI, FAITAVI, BHF PROTECT TAVI, EARLY TAVR), together with expanding evidence for transcatheter treatment of tricuspid valve disease (TRILUMINATE, TRISCEND) and left atrial appendage occlusion (CLOSURE-AF).

A substantial number of impactful trials were published in heart failure and cardiomyopathy, including SUMMIT, DIGIT-HF, MAPLE-HCM, and PARACHUTE-HF. Finally, in the field of prevention, 2025 has seen major advances in lipid lowering and cardiometabolic therapy, most notably with VESALIUS-CV, supporting earlier and more intensive intervention to reduce future atherosclerotic CV risk.

Looking ahead, the integration of advanced technologies in coronary intervention and heart failure management, as well as deeper investigations into the molecular mechanisms underlying atherosclerosis, will be key areas of focus. These innovations may bring about new therapies that could redefine the prevention and treatment of CV disease, driving further improvements in patient outcomes.

Author Contribution

Matthew Todd was the lead author and was responsible for collating the clinical trials for review, allocating sections among authors, and coordinating the overall structure of the manuscript. He authored the advances in cardiovascular prevention and advances in heart failure sections, as well as the abstract and introduction, and compiled all sections into a single draft, incorporating final edits following review by the supervising consultant and peer reviewers. Mark McKane authored the advances in coronary syndromes, shock and antiplatelet strategies section. Patrick Savage contributed the advances in percutaneous coronary intervention section. Michael Campbell contributed the advances in structural interventions section. Meadhbh Hogg authored the electrophysiology and cardiac devices section. Ian Menown acted as supervising consultant, guiding the overall style and format of the review and providing comprehensive review, editing, and revision of the full manuscript. All authors reviewed and approved the final submission, and the lead author reviewed the final edited version of the manuscript. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article. All authors were involved in the conception and design of the review, acquisition and interpretation of data, drafting and critical revision of the manuscript, and approval of the final version.

Funding

No funding was received for the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Conflict of Interest

Ian Menown—conference sponsorship and/or speaker honoraria from Novartis and Daiichi Sankyo. Ian Menown is an Editorial Board Member of Advances in Therapy. Ian Menown was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Matthew Todd, Patrick Savage, Mark McKane, Meadhbh Hogg and Michael Campbell have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.