Acute coronary syndrome (ACS) mostly arises from so-called vulnerable coronary plaques, particularly prone for rupture. Vulnerable plaques comprise a specific type of plaque, called the thin-cap fibroatheroma (TFCA). A TCFA is characterized by a large lipid-rich necrotic core, a thin fibrous cap, inflammation, neovascularization, intraplaque hemorrhage, microcalcifications or spotty calcifications, and positive remodeling. Vulnerable plaques are often not visible during coronary angiography. However, different plaque features can be visualized with the use of intracoronary imaging techniques, such as intravascular ultrasound (IVUS), potentially with the addition of near-infrared spectroscopy (NIRS), or optical coherence tomography (OCT). Non-invasive imaging techniques, such as computed tomography coronary angiography (CTCA), cardiovascular magnetic resonance (CMR) imaging, and nuclear imaging, can be used as an alternative for these invasive imaging techniques. These invasive and non-invasive imaging modalities can be implemented for screening to guide primary or secondary prevention therapies, leading to a more patient-tailored diagnostic and treatment strategy. Systemic pharmaceutical treatment with lipid-lowering or anti-inflammatory medication leads to plaque stabilization and reduction of cardiovascular events. Additionally, ongoing studies are investigating whether modification of vulnerable plaque features with local invasive treatment options leads to plaque stabilization and subsequent cardiovascular risk reduction.

Dual antiplatelet therapy has long been the standard of care in preventing coronary and cerebrovascular thrombotic events in patients with chronic coronary syndrome and acute coronary syndrome undergoing percutaneous coronary intervention, but choosing the optimal treatment duration and composition has become a major challenge. Numerous studies have shown that certain patients benefit from either shortened or extended treatment duration. Furthermore, trials evaluating novel antithrombotic strategies, such as P2Y₁₂ inhibitor monotherapy, low-dose factor Xa inhibitors on top of antiplatelet therapy, and platelet function- or genotype-guided (de-)escalation of treatment, have shown promising results. Current guidelines recommend risk stratification for tailoring treatment duration and composition. Although several risk stratification methods evaluating ischaemic and bleeding risk are available to clinicians, such as the use of risk scores, platelet function testing , and genotyping, risk stratification has not been broadly adopted in clinical practice. Multiple risk scores have been developed to determine the optimal treatment duration, but external validation studies have yielded conflicting results in terms of calibration and discrimination and there is limited evidence that their adoption improves clinical outcomes. Likewise, platelet function testing and genotyping can provide useful prognostic insights, but trials evaluating treatment strategies guided by these stratification methods have produced mixed results. This review critically appraises the currently available antithrombotic strategies and provides a viewpoint on the use of different risk stratification methods alongside clinical judgement in current clinical practice.

Objectives To validate the Global Registry of Acute Coronary Events (GRACE) risk score and examine the extent and impact of the risk–treatment paradox in contemporary patients with acute coronary syndrome (ACS). Methods Data from 5015 patients with ACS enrolled in the FORCE-ACS registry between January 2015 and December 2019 were used for model validation. The performance of the GRACE risk score for predicting in-hospital and 1-year mortality was evaluated based on indices of model discrimination and calibration. Differences in the delivery of guideline-recommended care among patients who survived hospitalisation (n=4911) per GRACE risk stratum were assessed and the association with postdischarge mortality was examined. Results Discriminative power of the GRACE risk score was good for predicting in-hospital (c-statistic: 0.86; 95% CI: 0.83 to 0.90) and 1-year mortality (c-statistic: 0.82; 95% CI: 0.79 to 0.84). However, the GRACE risk score overestimated the absolute in-hospital and 1-year mortality risk (Hosmer-Lemeshow goodness-of-fit test p<0.01). Intermediate-risk and high-risk patients were 12% and 29% less likely to receive optimal guideline-recommended care compared with low-risk patients, respectively. Optimal guideline-recommended care was associated with lower mortality in intermediate- and high-risk patients. Conclusions The GRACE risk score identified patients at higher risk for in-hospital and 1-year mortality, but overestimated absolute risk levels in contemporary patients. Optimal guideline-recommended care was associated with lower mortality in intermediate-risk and high-risk patients, but was less likely to be delivered with increasing mortality risk.

Diagnostic and treatment strategies for acute coronary syndrome have improved dramatically over the past few decades, but mortality and recurrent myocardial infarction rates remain high. An aging population with increasing co-morbidities heralds new clinical challenges. Therefore, in order to evaluate and improve current treatment strategies, detailed information on clinical presentation, treatment and follow-up in real-world patients is needed. The Future Optimal Research and Care Evaluation in patients with Acute Coronary Syndrome (FORCE-ACS) registry (ClinicalTrials.gov Identifier: NCT03823547) is a multi-center, prospective real-world registry of patients admitted with (suspected) acute coronary syndrome. Both non-interventional and interventional cardiac centers in different regions of the Netherlands are currently participating. Patients are treated according to local protocols, enabling the evaluation of different diagnostic and treatment strategies used in daily practice. Data collection is performed using electronic medical records and quality-of-life questionnaires, which are sent 1, 12, 24 and 36 months after initial admission. Major end points are all-cause mortality, myocardial infarction, stent thrombosis, stroke, revascularization and all bleeding requiring medical attention. Invasive therapy, antithrombotic therapy including patient-tailored strategies, such as the use of risk scores, pharmacogenetic guided antiplatelet therapy and patient reported outcome measures are monitored. The FORCE-ACS registry provides insight into numerous aspects of the (quality of) care for acute coronary syndrome patients.

The Global Registry of Acute Coronary Events (GRACE) scoring system guides the management of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) according to current guidelines. However, broad validation of the sex-specific GRACE 3.0 in-hospital mortality model, and corresponding models for predicting long-term mortality and the personalised effect of early invasive management, are still needed. We used data of 609 063 patients with NSTE-ACS from ten countries between Jan 1, 2005, and June 24, 2024. A machine learning model for 1-year mortality was developed in 400 054 patients from England, Wales, and Northern Ireland. Both the in-hospital mortality model and the new 1-year mortality model were externally validated in patients from Sweden, Switzerland, Germany, Denmark, Spain, the Netherlands, and Czechia. A separate machine learning model to predict the individualised effect of early versus delayed invasive coronary angiography and revascularisation on a composite primary outcome of all-cause death, non-fatal recurrent myocardial infarction, hospital admission for refractory myocardial ischaemia, or hospital admission for heart failure at a median follow-up of 4·3 years was developed and externally validated in participants from geographically different sets of hospitals in the Danish VERDICT trial. The in-hospital mortality model (area under the receiver operating characteristic curve [AUC] 0·90, 95% CI 0·89-0·91) and the 1-year mortality model (time-dependent AUC 0·84, 95% CI 0·82-0·86) showed excellent discriminative abilities on external validation across all countries. Both models were well calibrated and decision curve analyses suggested favourable clinical utility. Compared with score version 2.0, both models provided improved discrimination and risk reclassification. The individualised treatment effect model effectively identified patients who would benefit from early invasive management on external validation. Patients with high predicted benefit had reduced risk of the composite outcome when randomly assigned to early invasive management (hazard ratio 0·60, 95% CI 0·41-0·88), whereas patients with no-to-moderate predicted benefit did not (1·06, 0·80-1·40; p_interaction=0·014). The individualised treatment effect model suggested that the group of patients with NSTE-ACS who benefit from early intervention might be incompletely captured by current treatment strategies. The updated GRACE 3.0 scoring system provides a validated, practical tool to support personalised risk assessment in patients with NSTE-ACS. Prediction of an individual's long-term cardiovascular benefit from early invasive management could refine future trial design. Swiss Heart Foundation, University of Zurich Foundation, Kurt and Senta Herrmann Foundation, Theodor and Ida Herzog-Egli Foundation, and Foundation for Cardiovascular Research-Zurich Heart House.

Aims: A genotype-guided P2Y12-inhibitor de-escalation strategy, switching acute coronary syndrome (ACS) patients without a CYP2C19 loss-of-function allele from ticagrelor or prasugrel to clopidogrel, has shown to reduce bleeding risk without affecting the effectivity of therapy by increasing ischaemic risk. We estimated the cost-effectiveness of this personalized approach compared to standard dual antiplatelet therapy (DAPT; aspirin plus ticagrelor/prasugrel) in the Netherlands. Methods and results: We developed a 1-year decision tree based on results of the FORCE-ACS registry, comparing a cohort of ACS patients who underwent genotyping with a cohort of ACS patients treated with standard DAPT. This was followed by a lifelong Markov model to compare lifetime costs and quality-adjusted life years (QALYs) for a fictional cohort of 1000 patients. The cost-effectiveness analysis was performed from the perspective of the Dutch healthcare system. A genotype-guided de-escalation strategy led to an increase of 57.73 QALYs and saved €808788 compared to standard DAPT based on a lifetime horizon. Probabilistic sensitivity analysis showed that the genotype-guided strategy was cost-saving in 96% and increased QALYs in 87% of simulations. The intervention remained cost-effective in the scenario where prices for all P2Y12 inhibitors were equalized. The genotype-guided strategy remained dominant in various other scenarios and sensitivity analyses. Conclusion: A genotype-guided de-escalation strategy in patients with ACS was both cost-saving and yielded higher QALYs compared to standard DAPT, highlighting its potential for implementation in clinical practice. Trial registration: ClinicalTrials.gov identifier: NCT03823547.