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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 April 1, 2025 e809

therapies and advances in interventional methods would yield different results. Similarly, elevated cardiac biomarkers (CK-MB and older generation troponin assays) identify those who benefit more from a routine invasive strategy; however, it remains unknown whether hs-cTn assays that detect smaller degrees of myonecrosis are as useful for identifying those who benefit from routine coronary angiography. Although women are less likely to have obstructive coronary disease at angiography, they derive as much benefit from a routine invasive approach in the presence of similar risk predictors.4 The GRACE 2.0 risk calculator and TIMI Risk Score for unstable angina/NSTEMI may help identify patients at increased risk of MACE who benefit more from a routine invasive approach (Table 5).1 Relative contraindications to coronary angiography that merit further consideration of the relative risks and benefits of a routine invasive approach are outlined in Table 15. 2.	 Although some trials have demonstrated a reduc-

tion in MACE with a routine invasive approach in NSTE-ACS,1–3 others have not demonstrated a significant benefit when compared with a selective approach that involves further risk stratification.4,7 Although a pooled analysis of 3 randomized trials suggested that the benefit of a routine invasive approach was independent of baseline risk,6 other meta-analyses across studies have suggested that lower risk patients may derive less benefit.4,5,14 In addition, some low-risk patients, particularly those who have normal cardiac biomarkers in whom a diagnosis of an ACS is suspect, may have improved outcomes with a selective invasive approach.4,5 These patients should preferentially undergo noninvasive stress testing or coronary CT angiography prior to hospital discharge to help determine the need for coronary angiography; however, patients with suspected ongoing ischemic symptoms should be considered for coronary angiography. 3.	 Patients with NSTE-ACS who are unstable (eg,

refractory or recurrent angina [despite optimal medical therapy, hemodynamic or electrical instability, acute pulmonary edema or HF, worsening mitral regurgitation]) have been largely excluded from RCTs. Despite a relative paucity of clinical trial data, these patients are at heightened risk of adverse outcomes, and an immediate invasive strategy (<2 hours from hospital admission) with intention to perform revascularization is recommended.8,15 If patients with ACS and unstable features are at a non–PCI-capable hospital, they should be immediately transferred to a PCI-capable facility with a goal of immediate angiography. Clinical features that support immediate coronary angiography with intent to revascularize are listed in Figure 8. 4.	 For patients with NSTE-ACS for whom the decision has been made to proceed with coronary angiography, the benefit of an early invasive versus a delayed invasive approach is unclear.8,9,11,12 In the TIMACS (Timing of Intervention in Acute Coronary Syndromes) trial,11 patients were enrolled within 24 hours of symptoms and randomized to early angiography within 24 hours versus delayed angiography ≥36 hours from time of randomization. In the VERDICT (Very Early vs Deferred Invasive Evaluation Using Computerized Tomography) trial,12 patients were randomized to early angiography within 12 hours versus delayed between 48 to 72 hours from time of diagnosis. Both studies reported no significant difference in MACE between an earlier versus delayed invasive approach in the overall study populations, but there was signal toward a reduction in MACE with an earlier invasive approach in the higher risk patients with a GRACE risk score >140.11,12 In a meta-analysis of RCTs that compared an early versus delayed approach, a mortality benefit was not seen with earlier angiography. However, factors that favored an earlier invasive approach included a GRACE risk score >140, diabetes, age >75 years, and elevated cardiac biomarkers (although formal tests for interaction were not significant).8 Although not evaluated in RCTs, a continuing steep rise in cardiac biomarkers, likely due to ongoing ischemia and myonecrosis despite optimized medical therapy, may also favor earlier coronary angiography. 5.	 In intermediate- or low-risk patients for whom

angiography is planned in NSTE-ACS, timing does not appear to be critical, and a delayed invasive strategy within 48 to 72 hours does not appear to increase future risk of MACE.8,10–12,15 Randomized trial data have not demonstrated an overall significant difference in death or MI between an earlier versus delayed invasive approach in nonselected patients with NSTEMI.8,11,12,16

Table 15.  Relative Contraindications for a Routine Invasive Approach in ACS High risk for bleeding on DAPT Severe thrombocytopenia (platelet count <50 × 109/L) Advanced kidney disease (not on dialysis) Acute renal failure Limited (<1-2 y) life expectancy Advanced dementia Known coronary anatomy that precludes PCI and/or CABG surgery Patient preference ACS indicates acute coronary syndromes; CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; and PCI, percutaneous coronary intervention.

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