Felicita Andreotti

Background and Aim: Evidence-based medicine is dynamic. We appraised recent evidence on the management of acute coronary syndromes (ACS). Methods: A PRISMA scoping review of randomized controlled trials (RCTs) published in PubMed/MEDLINE between January 2025 and March 2026 was conducted. Only trials involving ≥ 500 ACS patient-years and reporting total or cardiovascular death, myocardial infarction, stroke and clinically relevant safety events were included. Comorbid atrial fibrillation and shock were excluded. Data extraction was prespecified. Results: Ten RCTs on antiplatelet therapy, percutaneous coronary intervention (PCI) and beta-blocker treatment were retained and analyzed for bias. Within the limits of each trial, the following messages emerge. After ACS-PCI, very early (day 4) antiplatelet monotherapy may not provide adequate anti-ischemic protection compared to 12-month dual antiplatelet therapy (DAPT; NEO-MINDSET trial). In ACS-PCI patients at low ischemic risk, 1-month DAPT followed by P2Y12 inhibitor alone can reduce major or clinically relevant nonmajor bleeding compared to 12-month DAPT, without apparent loss of anti-ischemic protection (TARGET-FIRST and 4D-ACS trials). For ACS patients receiving 12-month DAPT, ischemic and bleeding outcomes seem not to differ significantly when aspirin is given once or twice daily (ANDAMAN trial), nor when DAPT is clopidogrel-based or ticagrelor-based within specific populations (Canadian Bayesian pragmatic TC4 trial). In ACS patients undergoing coronary bypass, 12-month ticagrelor-based DAPT compared to aspirin alone enhances major bleeding risk without apparent anti-ischemic benefit (TACSI trial). Complete versus culprit-only revascularization leads to lower 3-year rates of ischemic events in older ACS patients with multivessel disease across renal function strata (FIRE trial). For ACS patients with multivessel disease, immediate complete revascularization failed to reach non-inferiority compared to pre-discharge complete revascularization (OPTION-STEMI trial). For patients with a left ventricular ejection fraction above or equal to 40% after myocardial infarction, beta-blocker treatment compared to none, over a follow-up ≥ 3.5 years, improved outcomes in BETAMI-DANBLOCK but not in REBOOT-CNIC. Conclusions: The data retained by this scoping review have implications that impact common clinical-practice decisions.

Aims: To evaluate the association of PCSK9-targeting therapies with mortality and cardiovascular events in stable or clinically stabilized randomized trial populations. Methods: We systematically reviewed randomized trials comparing alirocumab, evolocumab or inclisiran with placebo or active control. The review was registered in PROSPERO (CRD420261395609). Treatment effects were pooled as incidence rate ratios (IRRs) using random-effects models. The primary outcome was all-cause mortality. Prespecified subgroup analyses were based on trial-level known atherosclerosis status, as defined by enrollment criteria. Results: Thirty-two trials enrolled 77,178 participants. Individual atherosclerosis status could not be determined beyond trial-level eligibility criteria. Mortality estimates were predominantly informed by large cardiovascular outcome trials. All-cause mortality was lower with PCSK9-targeting therapy (IRR 0.88, 95% CI 0.82–0.95). Estimates favored PCSK9-targeting treatment in both trials requiring known atherosclerosis for enrollment (IRR 0.90, 95% CI 0.83–0.98) and trials without such an enrollment requirement (IRR 0.78, 95% CI 0.62–0.97; interaction p = 0.21). PCSK9-targeting treatment additionally reduced myocardial infarction, stroke, and coronary revascularization rates. Leave-one-out estimates remained directionally consistent. Conclusion: PCSK9-targeting therapies were associated with lower all-cause mortality and fewer ischemic events across trial populations. The predominant contribution of large cardiovascular outcome trials enrolling populations with known atherosclerosis and using PCSK9 antibodies limits the ability to infer a survival benefit in populations not selected on the basis of atherosclerosis status and across individual therapies, particularly inclisiran.

Background and Aims: Emerging data suggest that, in patients with chronic coronary syndromes (CCS), clopidogrel provides superior antithrombotic protection compared with aspirin for secondary prevention, without an associated increase in bleeding risk. The consistency of the observed benefits across ethnicities remains uncertain. Methods: Randomized controlled trials (RCTs) comparing aspirin vs clopidogrel for secondary prevention in patients with CCS were screened. The primary endpoint was trial-defined major adverse cardiovascular events (MACE). Prespecified subgroup interaction by ethnicity (East Asian vs non-East Asian) was performed. Trial sequential analysis was used to assess the statistical power of the results. Results: Seven RCTs were included, encompassing 30 165 patients, of whom 75.1% were East Asians. Median follow-up was 36.0 months. Overall, clopidogrel was associated with significant reductions in MACE (incidence rate ratio [IRR] 0.83, 95% confidence interval [CI] 0.69–0.99) and net adverse clinical events (IRR 0.83, 95% CI 0.69–0.99), compared with aspirin. There were no differences between groups in major bleeding, myocardial infarction, or mortality. The results were consistent in the East Asian population, whereas a significant interaction by ethnicity was observed for MACE (East Asians: IRR 0.76, 95% CI 0.59–0.98; non-East Asians: IRR 1.00, 95% CI 0.74–1.36; Pint = 0.010) and mortality (Pint = 0.014), with no significant benefits observed in non-East Asian patients. The analyses were statistically powered for most outcomes in East Asian populations but for none in non-East Asian populations. Conclusions: In patients with CCS, the overall body of evidence suggests improved outcomes with clopidogrel compared with aspirin, without an apparent effect on mortality. However, a high level of confidence in these findings is currently limited to East Asian populations, and additional evidence is needed to clarify their applicability to non-East Asian patients. Study registration: PROSPERO (CRD420251145176).

For individuals with suspected chronic coronary syndrome, the 2024 ESC guidelines recommend use of a structured estimate of the probability of obstructive coronary artery disease (CAD). This ‘risk factor–weighted clinical likelihood’ (RF-CL) model is recommended as the initial step after history taking and combines age, sex, symptom characteristics, and five clinical risk factors, with coronary calcification data, if available. The resulting numerical estimate indicates an initial ‘pre-test probability’ of obstructive CAD, that has been calibrated to provide improved accuracy compared with previous models. It can help triage patients for appropriate testing and identify individuals with a very low likelihood of obstructive CAD, for whom deferral of further diagnostic tests should be considered. Designed to assess the likelihood of obstructive CAD, the RF-CL model is not designed to predict ischaemia, which may occur in the absence of obstructive coronary disease and could account for patient symptoms. The score is easy and quick to use, with extensive external validation in contemporary populations including European, North American, and Asian cohorts. However, some have questioned the practical application of the RF-CL tool, citing challenges with the specificity and clarity of patient symptoms, definition and weighting of risk factors, as well as the other ‘enrichment factors’ that can enhance the likelihood. The RF-CL model is quantitative up to 45% and then becomes semi-quantitative/qualitative. For patients considered very high likelihood, with an estimated score > 85%, invasive coronary angiography is recommended, although how this score may be reached is not entirely clear. The RF-CL model undoubtedly improves the prediction of obstructive CAD and can ‘de-risk’ a significant number of symptomatic patients safely, reducing unnecessary testing. In the development and application of such a probability estimate, there is a need to strike a good balance between simplicity and usefulness, vs increased sensitivity at the expense of greater complexity. Here, the two sides of this Great Debate are presented, to help the reader better evaluate the practical usefulness of the new RF-CL assessment in predicting the probability of obstructive CAD.

Aims: We aimed to develop the European Society of Cardiology (ESC) quality indicators (QIs) for myocardial infarction (MI), from 1 year after hospital discharge, corresponding to transition to the chronic coronary syndrome phases. Methods and results: We collaborated with the European Association of Preventive Cardiology (EAPC) and developed QIs for the long-term management of patients following MI. We applied the ESC methodology for QI development by (i) determining key domains of post-MI care; (ii) developing candidate QIs by performing a systematic review of the literature, and (iii) selecting the final set of QIs using a modified Delphi approach. In total, 18 QIs were identified across seven domains of care including (i) structural framework, (ii) risk assessment and follow-up, (iii) pharmacological management, (iv) rehabilitation, behavioural, and preventive interventions, (v) coronary revascularization, (vi) clinical outcomes, and (vii) patient-reported outcomes. Conclusion: We present the ESC QIs from 1 year after hospitalization for MI, to standardize and address gaps in care for this high-risk group. These QIs are supported by evidence from contemporary literature, endorsed by expert consensus, and aligned with the 2024 ESC guidelines on the management of chronic coronary syndromes. Lay summary: Measures to evaluate and improve the long-term management of patients following a heart attack are needed. In this paper, we identified key aspects of care that can help clinicians, decision-makers and patients improve the quality of care, from one year after a heart attack onwards, and help address inequalities and variations in clinical practice.

Background and Aims: Dual antiplatelet therapy (DAPT) de-escalation strategies improve outcomes after percutaneous coronary intervention (PCI) compared to standard DAPT. However, the potential impact of sex on the safety and efficacy of these strategies is yet to be fully investigated. Methods: Randomized controlled trials comparing de-escalated vs standard DAPT regimens in patients without baseline indication for oral anticoagulation reporting outcomes stratified by sex were included. The co-primary endpoints were trial-defined major adverse cardiovascular events (MACE) and major bleeding. Hazard ratios (HR) with 95% confidence intervals (CI) were computed to account for different follow-up durations. A network meta-analysis including ranking of treatments was performed to explore the comparative effects of different DAPT de-escalation strategies among females and males. Results: Overall, 71 272 patients from 20 trials were included, and 23.3% were female. De-escalation strategies were grouped into (1) DAPT discontinuation, by aspirin or the P2Y12 inhibitor; or (2) P2Y12 inhibitor switch or dose reduction. With DAPT discontinuation vs standard DAPT, a significant interaction between treatment effect and sex was found for both MACE (Pint = .028) and major bleeding (Pint = .015). Indeed, DAPT discontinuation reduced MACE in females (HR, 0.86; 95% CI, 0.75–0.98) but not in males (HR, 1.04; 95% CI 0.93–1.16), while reducing major bleeding in males (HR, 0.60; 95% CI, 0.44–0.82) but not in females (HR, 1.04; 95% CI, 0.76–1.43), compared to standard DAPT. Conversely, no interactions by sex were found with P2Y12 inhibitor switch or dose reduction vs standard DAPT for both MACE (Pint = .668) and major bleeding (Pint = .858). At treatment ranking, aspirin discontinuation ranked best for most outcomes in females, while P2Y12 inhibitor switch to clopidogrel showed the best outcomes in males. Conclusions: Sex may influence the safety and efficacy of antiplatelet de-escalation strategies after PCI, particularly those involving the shortening of DAPT. Aspirin discontinuation may represent the optimal strategy for females, while P2Y12 inhibitor switch to clopidogrel may be most effective for males.

The diagnosis of refractory angina has conventionally been limited to patients with angina and ischaemia secondary to obstructive atherosclerotic epicardial coronary disease who experience persistent symptoms despite optimal pharmacological and revascularization therapies. It is now well-established that angina may also be caused by ischaemia resulting from coronary microcirculatory disorders, coronary vasospasm, and bridging in the absence of obstructive epicardial coronary disease or after “successful” revascularization. This increasingly prevalent and symptomatic group of patients, with both angina and demonstrable ischaemia, have been excluded from the conventional definition of refractory angina. In patients with obstructive epicardial coronary disease, disturbed microcirculatory and vasomotor function, amongst other ischaemic mechanisms, may account for continuing symptoms despite revascularization. Under-recognition of these mechanisms results in inadequate treatment and symptom persistence. In this review, a redefinition of refractory angina is proposed to include the full spectrum of patients experiencing persistent angina despite current maximal guideline-directed medical and revascularization therapies. Systematic approaches for comprehensive investigation are suggested to identify underlying mechanisms of ischaemia and stratify treatments accordingly. The complex needs of patients with refractory angina are likely best addressed by an inter-disciplinary Angina Heart Team with the aim of improving patient symptoms, quality of life, and clinical outcomes.