Known Unknowns: Unpacking Controversies and Uncertainties in the 2025 Guidelines for Management of Acute Coronary Syndromes.

purpose of reviewThe 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for managing patients with acute coronary syndromes (ACS) is the first major update since the 2013-2015 ST-elevation myocardial infarction (STEMI) and non-ST elevated myocardial infarction (NSTEMI) guidelines. It brings both conditions together into a single framework. This review covers the most important new and revised recommendations and points out where evidence is still lacking. RECENT

findingsNew findings show that several significant updates are based on recent large-scale trials. The use of bivalirudin with high-dose infusion after percutaneous coronary intervention (PCI) is now given a Class I recommendation for primary PCI in the case of STEMI, as a result of the BRIGHT-4 trial. Complete revascularization is also now recommended as Class I for stable STEMI patients who have multivessel disease, according to the COMPLETE trial. For a selected group of patients with refractory cardiogenic shock resulting from a myocardial infarction, the percutaneous microaxial flow pump has received a new Class IIa recommendation from the DanGer Shock trial, while the intra-aortic balloon pump and extracorporeal membrane oxygenation are classified as Class III for routine use. Intracoronary imaging (intravascular ultrasound and optical coherence tomography) is now given a Class I recommendation for complex PCI, based on the data of the RENOVATE-COMPLEX-PCI, OCTOBER, and OCTIVUS trials. The guidelines also suggest specific low-density lipoprotein cholesterol (LDL-C) targets, and non-statin drugs should be added if the LDL-C level remains above 70 mg/dL even when maximum statin therapy is used. Regarding antiplatelet therapy, ticagrelor or prasugrel is now preferred to clopidogrel in the case of ACS-PCI, and it is formally recommended to switch to P2Y12 monotherapy at one month in patients at high risk for bleeding as an alternative to standard DAPT. The updates indicate a shift towards more potent antiplatelet therapy at hospital presentation, use of radial access when feasible, more use of imaging-guided PCI, stricter lipid targets, and more refined antiplatelet approaches at the time of discharge. That said, significant gaps in the evidence still exist. It has not yet become clear whether physiology-guided revascularization of non-culprit arteries in patients with STEMI or NSTEMI is better than angiography-guided PCI-a question that is currently being investigated in the randomized COMPLETE-2 trial. The optimal time to provide mechanical circulatory supper in cases of cardiogenic shock remains uncertain. The recent neutral findings from intracoronary imaging studies such as OPTIMAL and IVUS-CHIP might alter the existing Class I recommendation. Lastly, new data from the HOST-EXAM, and SMART CHOICE 3, studies suggest that P2Y12 monotherapy may be better than aspirin for the long-term prevention of major adverse cardiovascular events, and this could influence future guideline recommendations for long term antiplatelet therapies in the chronic phase.