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Non-ST-elevation acute coronary syndrome

Non-ST-elevation acute coronary syndrome from emergency rule-out of myocardial infarction through risk stratification, invasive timing, antithrombotic therapy and its duration, nonatherosclerotic causes, and secondary prevention.

Unstable angina, NSTEMI, and myocardial injury: the definitions

Acute coronary syndrome (ACS) is a continuum of three conditions: unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). The 2025 American College of Cardiology/American Heart Association (ACC/AHA) ACS guideline bases the initial diagnosis on the clinical history, the electrocardiogram (ECG), and cardiac troponin (cTn). Patients move along the continuum during a single presentation. A subtotal thrombus can occlude and convert NSTEMI into STEMI within minutes, and a transiently occluded artery can reopen, leaving only ST depression or T-wave inversion by the time the first ECG is recorded.

The Fourth Universal Definition of Myocardial Infarction (2018) separates three concepts that are often merged at the bedside. Myocardial injury is any cTn value above the 99th percentile upper reference limit (URL). Injury is acute when serial values show a rise and/or fall and chronic when values are stable. Myocardial infarction (MI) is acute myocardial injury with clinical evidence of acute ischemia: ischemic symptoms, new ischemic ECG changes, new pathological Q waves, imaging evidence of new loss of viable myocardium or new regional wall-motion abnormality in an ischemic pattern, or coronary thrombus at angiography or autopsy. Troponin alone establishes injury; it never establishes infarction.

NSTEMI is acute myocardial infarction without persistent ST-segment elevation meeting STEMI criteria. The culprit is usually a partially occlusive or intermittently occlusive thrombus, distal embolization of thrombus and plaque debris, or a total occlusion supplied by collaterals. The presenting ECG shows ST depression, T-wave inversion, transient ST elevation, or no diagnostic change. Unstable angina is myocardial ischemia at rest or with minimal exertion, or crescendo angina, without a cTn rise above the 99th percentile. High-sensitivity assays detect smaller infarctions, so a share of what was once unstable angina is now classified as NSTEMI, and unstable angina has become an uncommon diagnosis with a lower short-term risk than NSTEMI.

Myocardial injury and the clinical types of myocardial infarction, from the Fourth Universal Definition of Myocardial Infarction (2018). URL, upper reference limit; SCAD, spontaneous coronary artery dissection; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting.

The 2025 ACC/AHA guideline addresses type 1 infarction and states that the evaluation of chest pain and the management of type 2 MI, spontaneous coronary artery dissection (SCAD), and myocardial infarction with nonobstructive coronary arteries (MINOCA) are covered in separate documents: the 2021 AHA/ACC multisociety chest pain guideline, the 2019 AHA statement on MINOCA, and the 2018 AHA statement on SCAD.

Type 1 versus type 2 myocardial infarction

Type 2 MI is ischemic necrosis caused by an imbalance between supply and demand in the absence of an acute atherothrombotic event. The imbalance may arise in a patient with fixed coronary stenoses, in whom tachycardia or hypotension produces subendocardial ischemia distal to a stable plaque, or in a patient with normal coronary arteries, in whom the precipitant alone is sufficient. Coronary spasm, coronary embolism, and SCAD are classified as type 2 mechanisms in the Fourth Universal Definition because they are not atherothrombotic, although they are primary coronary events and are managed as such.

The distinction has therapeutic consequences. Type 1 MI is treated with dual antiplatelet therapy (DAPT), parenteral anticoagulation, and an invasive strategy. In type 2 MI, the precipitant is treated; antithrombotic therapy can be harmful when the precipitant is gastrointestinal bleeding, and an invasive strategy is reserved for patients in whom the clinical picture leaves type 1 MI as a realistic possibility or in whom underlying coronary disease would change management. Many patients with type 2 MI have coronary disease that is not known at presentation, and secondary prevention follows once it is documented.

Mechanisms of type 2 myocardial infarction. Type 2 MI requires evidence of ischemia; the same precipitants can also cause nonischemic acute myocardial injury, which is diagnosed when ischemic symptoms, ECG changes, and imaging evidence are absent.

Nonischemic causes of troponin elevation are classified as myocardial injury, not infarction. Acute causes include myocarditis, Takotsubo syndrome, pulmonary embolism, sepsis, cardiac contusion, cardiotoxic drugs, stroke and subarachnoid hemorrhage, strenuous endurance exercise, defibrillation, and catheter ablation. Chronic elevation is common in chronic kidney disease, heart failure, left ventricular hypertrophy, and infiltrative disease, and in older adults without known heart disease. The pattern on serial testing and the clinical context separate these from type 1 infarction; the absolute concentration does not. Patients with type 2 MI and nonischemic injury have high all-cause mortality, largely from the underlying illness, and the troponin elevation is a marker of that risk.

Epidemiology and natural history of NSTE-ACS

More than 1 million patients are hospitalized with ACS each year in the United States, and an estimated 7 million people worldwide are diagnosed with ACS annually. NSTEMI has outnumbered STEMI in contemporary registries for two decades: STEMI incidence has fallen with smoking reduction and statin use, whereas NSTEMI has been sustained by an aging population with diabetes, kidney disease, and multivessel coronary disease, and by the detection of smaller infarctions with high-sensitivity troponin assays. Patients with NSTEMI are older and have more comorbid conditions than patients with STEMI.

The early phase carries the highest risk. The threatened artery is open or intermittently open, and the thrombus can propagate and occlude, so recurrent infarction and death cluster in the first days. Short-term mortality is lower for NSTEMI than for STEMI, but by 6 months to 1 year the difference narrows, because NSTEMI occurs in older patients with more extensive disease and more noncardiac illness. About 1 in 5 patients with ACS is readmitted within 30 days of discharge.

Women present with ACS on average about 10 years later than men and with a greater burden of risk factors. They are less often correctly diagnosed, less often receive guideline-directed medical therapy, and less often undergo revascularization when it is indicated. Women more often have nonobstructive coronary arteries at angiography, and SCAD, coronary spasm, and coronary microvascular dysfunction account for a larger share of their infarctions.

Pathophysiology: plaque rupture, plaque erosion, and thrombus

Type 1 MI begins with disruption of an atherosclerotic plaque. Plaque rupture is a break in the thin fibrous cap of a lipid-rich necrotic core (a thin-cap fibroatheroma). Exposure of tissue factor and collagen to flowing blood triggers platelet adhesion and aggregation and activation of the coagulation cascade, and the resulting thrombus is platelet-rich at its head and fibrin-rich at its tail. Macrophage-derived proteases weaken the cap, and rupture occurs most often at the shoulders of the plaque, where mechanical stress concentrates. Rupture is the most common substrate of fatal infarction.

Plaque erosion is loss of endothelium over a fibrous, proteoglycan-rich plaque with an intact cap and little lipid. Neutrophil activation with release of DNA-histone networks (NETosis) and endothelial apoptosis are implicated. The thrombus is platelet-rich and often nonocclusive, and erosion is relatively more frequent in younger patients, women, smokers, and NSTE-ACS than in STEMI. Optical coherence tomography (OCT) distinguishes erosion from rupture. A calcified nodule, an eruptive nodule of calcium protruding through the cap, is a less common substrate in older patients with heavily calcified arteries.

The consequences depend on the thrombus and the territory. Partial or intermittent occlusion produces subendocardial ischemia and NSTE-ACS. Embolization of platelet aggregates and plaque debris into the microcirculation produces patchy microinfarction and troponin release even when the epicardial artery remains patent. Vasoconstriction from platelet-derived thromboxane A2 and serotonin adds dynamic narrowing. Collateral flow, ischemic preconditioning, and spontaneous fibrinolysis determine whether occlusion becomes transmural infarction. These mechanisms explain the therapeutic targets: aspirin and P2Y12 inhibitors for platelet activation, anticoagulants for thrombin generation, revascularization for the residual stenosis, and statins and anti-inflammatory therapy for plaque stabilization.

Multiple ruptured or vulnerable plaques are often present at the time of ACS, and nonculprit lesions account for a large share of recurrent events in the following years. This is the rationale for complete revascularization of significant nonculprit stenoses in stable patients and for intensive lipid lowering after ACS.

Symptoms and physical examination in NSTE-ACS

The typical symptom is retrosternal pressure, tightness, or heaviness, often radiating to the arm, neck, or jaw, at rest or with minimal exertion, lasting more than 10 to 20 minutes, and accompanied by dyspnea, diaphoresis, nausea, or lightheadedness. Unstable angina presents in three forms: rest angina, usually prolonged; new-onset angina of at least moderate severity; and crescendo angina, in which previously stable angina becomes more frequent, longer, or provoked by less exertion. The 2021 chest pain guideline recommends describing symptoms as cardiac, possibly cardiac, or noncardiac and discourages the term "atypical," which has been misread as benign.

Chest discomfort is the most common symptom in both sexes, reported by about 79% of men and 74% of women with ACS. Compared with men, women with ACS more often report pain between the shoulder blades (odds ratio 2.15), nausea or vomiting (odds ratio 1.64), and dyspnea (odds ratio 1.34), usually together with chest discomfort rather than in its place. Older adults, patients with diabetes, and patients with chronic kidney disease more often present with dyspnea, weakness, confusion, or syncope, and their ACS is recognized later. Pain that is pleuritic, positional, reproduced by palpation, or lasting only seconds lowers the probability of ischemia without excluding it.

The examination in uncomplicated NSTE-ACS is often normal. Its purpose is to identify complications and alternative diagnoses. Hypotension, cool extremities, and altered mentation indicate cardiogenic shock. Pulmonary rales, a third heart sound, and jugular venous distension indicate heart failure and define the Killip class, a component of the GRACE score. A new or worsening mitral regurgitation murmur indicates papillary muscle dysfunction. Unequal arm pressures or pulse deficits suggest aortic dissection, a pericardial rub suggests pericarditis, and unilateral leg swelling with hypoxemia suggests pulmonary embolism.

Life-threatening and common alternative diagnoses in patients evaluated for NSTE-ACS.

ECG findings in non-ST-elevation ischemia

The 2025 ACC/AHA guideline recommends acquisition and interpretation of a 12-lead ECG within 10 minutes of first medical contact or hospital arrival (Class 1) and serial ECGs when the first tracing is nondiagnostic, particularly when suspicion is high, symptoms persist, or the patient deteriorates (Class 1). In the National Cardiovascular Data Registry, 11% of patients ultimately diagnosed with STEMI had a nondiagnostic first ECG, and 72.4% of them had a diagnostic tracing within 90 minutes. Comparison with a prior tracing distinguishes new from chronic abnormalities.

ECG findings in suspected NSTE-ACS. Ischemic thresholds from the Fourth Universal Definition of Myocardial Infarction as adapted in the 2025 ACC/AHA ACS guideline (Table 3). LAD, left anterior descending artery.

Many patients with NSTE-ACS have a normal ECG or nonspecific ST-T changes, and a normal ECG does not exclude ACS. Circumflex occlusions are electrically silent on the standard 12 leads in a substantial minority of cases, which is why the guideline recommends posterior leads V7 to V9 when isolated ST depression of 0.5 mm or more appears in V1 to V3. ST elevation of 0.5 mm or more in V7 to V9 (1 mm in men younger than 40 years) indicates posterior infarction, and the patient is managed as STEMI. Right-sided leads are recorded when inferior injury is suspected.

Not every acute coronary occlusion meets STEMI voltage criteria. Hyperacute T waves, the de Winter pattern, posterior injury, and modified Sgarbossa findings identify occlusions within the NSTE-ACS population. The term occlusion MI has been proposed to emphasize that the therapeutic question is whether the artery is occluded; current US and European guidelines retain the STEMI and NSTE-ACS classification and recognize these patterns within it. ST depression from left ventricular hypertrophy with repolarization abnormality, digoxin, hypokalemia, bundle branch block, and rate-related changes in supraventricular tachycardia mimics ischemia and is interpreted against prior tracings and the clinical setting.

High-sensitivity troponin: assay concepts and limits

Cardiac troponin I and T are the biomarkers of choice for myocardial injury, and the 2025 ACC/AHA guideline recommends measurement as soon as possible, preferably with a high-sensitivity assay (Class 1). A high-sensitivity assay (hs-cTn) measures cTn with a coefficient of variation of 10% or less at the 99th percentile URL and detects measurable concentrations in at least 50% of healthy men and women. This analytic precision is what permits rapid algorithms: a concentration below the limit of detection or a very small change over 1 to 2 hours carries meaning that conventional assays cannot provide.

The 99th percentile URL is specific to each assay and is derived from a healthy reference population. Women have lower concentrations than men, and sex-specific 99th percentiles are available for most assays. Troponin I and troponin T values are not interchangeable, and concentrations from different troponin I assays are not interchangeable, because the assays use different antibodies and calibrators. High-sensitivity results are reported in nanograms per liter (ng/L) as whole numbers, which avoids decimal errors.

Manufacturer-designated 99th percentile upper reference limits for two widely used US high-sensitivity assays (Architect values rounded from 26.2, 15.6, and 34.2 ng/L). Every other assay has its own limits, given in its package insert.

A delta, the absolute change between two samples, separates acute from chronic injury. Absolute deltas perform better than relative (percentage) changes at low concentrations, and the delta that defines a significant change is assay specific. With high-sensitivity assays, a change within the normal range below the 99th percentile can signal ischemia. With conventional assays, repeat sampling is performed 3 to 6 hours after the first sample; with high-sensitivity assays, 1 to 2 hours (both Class 1). A single-sample rule-out strategy is valid only when the sample is drawn at least 3 hours after symptom onset.

Troponin is elevated without ACS in several common settings. In chronic kidney disease, baseline concentrations are higher, troponin T more often than troponin I, and the diagnosis of acute MI rests on the delta and the clinical picture. Atrial fibrillation with rapid ventricular response raises troponin through demand ischemia and nonischemic injury. Older adults have higher baseline values, and many exceed the 99th percentile without acute disease. Heart failure, sepsis, pulmonary embolism, stroke, and skeletal muscle disease (for troponin T) also raise concentrations.

Creatine kinase MB (CK-MB) and myoglobin add no diagnostic value when high-sensitivity troponin is available and are no longer recommended for the diagnosis of MI. Reinfarction early after an index event, when troponin is still elevated, is diagnosed by an increase of more than 20% in serial cTn values in the Fourth Universal Definition.

Rapid rule-out and rule-in pathways with high-sensitivity troponin

Clinical decision pathways (CDPs) combine the ECG, the history, and hs-cTn at presentation (0 hours) and at 1 or 2 hours. They avoid admission or further testing in 21% to 43% of eligible patients, with a sensitivity of 99% to 100% for index-visit MI and for major adverse cardiovascular events (MACE) at 30 days. The 2021 chest pain guideline names several validated pathways: the European Society of Cardiology (ESC) 0/1-hour and 0/2-hour algorithms, the High-STEACS pathway, the HEART Pathway, the ADAPT and EDACS pathways, and the No Objective Testing Rule. Each institution adopts one pathway matched to its assay.

The ESC algorithms sort patients into three groups. Rule-out applies when the presentation concentration is very low and symptoms began more than 3 hours earlier, or when the concentration is low and the 1-hour or 2-hour change is small. Rule-in applies when the presentation concentration is high or the change is large. Patients in neither group enter the observe zone, in which a third sample at 3 hours and further testing determine management. Ruled-out patients have a very low risk of MI, but the algorithm does not exclude unstable angina, and patients with a high clinical suspicion or recurrent pain undergo further evaluation.

Assay-specific cutoffs of the ESC 0/1-hour and 0/2-hour algorithms (2023 ESC ACS guideline, supplementary Table S4). The very low single-sample rule-out applies only when chest pain began more than 3 hours before the sample. The cutoffs apply irrespective of age, sex, and kidney function and cannot be transferred from one assay to another.

Rapid algorithms are applied only after STEMI and other life-threatening diagnoses have been excluded, only in patients with suspected ACS (not in unselected patients with sepsis or stroke), and only with the assay for which they were validated. About 1% of patients have a late troponin rise, so serial testing continues when suspicion remains high or pain recurs. Time zero is the time of the first blood draw; the second sample is drawn at 1 or 2 hours whether or not the first result has returned.

HEART score for emergency chest pain

The HEART score was derived for undifferentiated chest pain in the emergency department. It assigns 0, 1, or 2 points to each of five elements (history, ECG, age, risk factors, and troponin) for a total of 0 to 10. In a prospective validation in 2,440 unselected patients at 10 Dutch hospitals, MACE within 6 weeks occurred in 1.7% of patients with a score of 0 to 3, 16.6% with 4 to 6, and 50.1% with 7 to 10. The c-statistic for HEART (0.83) exceeded those of the Thrombolysis in Myocardial Infarction (TIMI) score (0.75) and the GRACE score (0.70) in that population, which reflects the purpose of each: TIMI and GRACE were derived in patients with established ACS, HEART in patients with undifferentiated chest pain.

HEART score elements. The normal limit is the 99th percentile URL of the assay in use. LVH, left ventricular hypertrophy. ST elevation meeting STEMI criteria removes the patient from the HEART pathway.

Six-week major adverse cardiac event rates by band from the prospective validation cohort. The score is a risk estimate for undifferentiated chest pain; it does not apply to patients with ST elevation, hemodynamic instability, or an established diagnosis of ACS.

The HEART Pathway. The HEART Pathway combines a HEART score of 3 or less with nonelevated troponin at 0 and 3 hours to identify patients for discharge without stress testing or angiography. In a single-center randomized trial of 282 patients, the pathway reduced objective cardiac testing at 30 days from 68.8% to 56.7%, increased early discharge from 18.4% to 39.7%, and shortened length of stay by about 12 hours, with no major adverse cardiac events at 30 days in patients identified for early discharge. With high-sensitivity assays, the troponin element is adapted to the 0/1-hour or 0/2-hour sampling of the institutional pathway.

Other emergency department tools. The Emergency Department Assessment of Chest Pain Score (EDACS) combines age, sex, risk factors, and symptom characteristics with 0-hour and 2-hour troponin. The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) rule estimates the probability of ACS from a single presentation troponin, ECG ischemia, and clinical features. The 2021 chest pain guideline treats all validated CDPs as acceptable and does not rank them.

Noninvasive testing after ACS is excluded. For patients with acute chest pain at low risk (an estimated 30-day risk of death or MACE below 1%), urgent diagnostic testing for coronary artery disease is not needed. For intermediate-risk patients with no known coronary artery disease and a negative or inconclusive evaluation for ACS, the 2021 guideline gives coronary CT angiography a Class 1 (Level A) recommendation to exclude atherosclerotic plaque and obstructive disease, and stress testing (exercise ECG, stress echocardiography, stress positron emission tomography or single-photon emission CT, or stress cardiac MRI) a Class 1 recommendation to diagnose ischemia. Randomized emergency department trials, including ROMICAT-II, showed that coronary CT angiography shortened length of stay compared with standard evaluation and identified patients for safe discharge.

Risk stratification with GRACE and TIMI

Once ACS is diagnosed, risk scores estimate short- and long-term risk and inform the timing of angiography. The 2025 ACC/AHA guideline states that the GRACE and TIMI risk scores are well validated and may help guide therapeutic decisions, that GRACE outperformed subjective physician assessment for prediction of death or MI, and that there is insufficient evidence that routine use of risk scores reduces events. Scores are not diagnostic tools: they apply to patients in whom ACS is suspected or confirmed.

GRACE. The GRACE in-hospital model uses eight variables available at presentation: age, heart rate, systolic blood pressure, serum creatinine, Killip class, cardiac arrest at admission, ST-segment deviation, and elevated cardiac biomarkers. The point version sums weighted values; the GRACE 2.0 model replaces the points with continuous functions and estimates death and death or MI at 6 months, 1 year, and 3 years. In NSTE-ACS, a point score of 108 or less corresponds to in-hospital mortality below 1%, 109 to 140 to 1% to 3%, and above 140 to more than 3%. The threshold of 140 is the one used in TIMACS and VERDICT and in the high-risk criteria of US and European guidelines.

Point version of the GRACE in-hospital mortality model. Age, heart rate, systolic pressure, and creatinine are scored in bands (for example, age 70 to 79 years scores 75 points and systolic pressure 100 to 119 mm Hg scores 43); Killip class II to IV adds 20, 39, or 59 points; cardiac arrest adds 39, ST deviation 28, and elevated biomarkers 14.

TIMI. The TIMI risk score for unstable angina and NSTEMI assigns 1 point to each of seven variables. In the TIMI 11B derivation cohort, the 14-day rate of death, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization rose from 4.7% with a score of 0 or 1 to 40.9% with a score of 6 or 7. TIMI is quicker to calculate and less discriminating than GRACE, and it omits heart failure, hemodynamics, and kidney function, the strongest determinants of short-term death.

TIMI risk score for unstable angina and NSTEMI and the TIMI 11B 14-day rate of all-cause death, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.

Other markers refine risk. Heart failure on examination, chest radiograph, or lung ultrasound is a strong predictor and is captured by Killip class. Higher troponin concentrations predict higher risk. Natriuretic peptides identify patients at increased risk of death, heart failure, and recurrent events. Left ventricular ejection fraction, measured before discharge (Class 1), guides therapy and risk. Cardiogenic shock is present in 7% to 10% of patients with ACS and dominates every score.

Bleeding risk: ARC-HBR and CRUSADE

Major bleeding after ACS is associated with mortality comparable to that of recurrent infarction, and the features that raise ischemic risk (older age, kidney dysfunction, anemia, low body weight, diabetes, heart failure) also raise bleeding risk. Bleeding risk shapes access site, anticoagulant choice, dosing, P2Y12 inhibitor potency, and DAPT duration. It does not justify withholding an indicated invasive strategy.

The Academic Research Consortium for High Bleeding Risk (ARC-HBR) defines high bleeding risk after PCI as a risk of Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding of 4% or more, or of intracranial hemorrhage of 1% or more, at 1 year. The 2025 ACC/AHA guideline adopts the ARC-HBR criteria; one major or two minor criteria identify high bleeding risk.

Academic Research Consortium high bleeding risk criteria as reproduced in the 2025 ACC/AHA ACS guideline (Table 22). eGFR, estimated glomerular filtration rate.

The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) score estimates in-hospital major bleeding in NSTEMI from eight variables: baseline hematocrit, creatinine clearance, heart rate, sex, signs of heart failure, prior vascular disease, diabetes, and systolic blood pressure. It was derived before radial access and contemporary P2Y12 inhibitors became standard, and its main use is to identify patients in whom access, dosing, and anticoagulant choice are adjusted. The PRECISE-DAPT score, which addresses out-of-hospital bleeding on DAPT, is described with DAPT duration below.

Timing of invasive angiography: immediate, early, and selective

Two decisions follow the diagnosis. The first is a routine invasive approach, with coronary angiography and intent to revascularize, versus a selective invasive approach, with angiography only for recurrent ischemia or high-risk noninvasive findings. The second, when angiography is planned, is its timing. In a collaborative meta-analysis of randomized trials, a routine invasive approach reduced death or MI by 18% (odds ratio 0.82) and MI by 25% (odds ratio 0.75) compared with a selective approach, with the benefit concentrated in patients with elevated biomarkers. Women derive as much benefit as men in the presence of similar risk predictors.

Selection and timing of an invasive strategy in NSTE-ACS, after the 2025 ACC/AHA guideline (Section 6.1 and Figure 8). Patients who are not candidates for revascularization because of comorbidity or preference are managed medically. LVEF, left ventricular ejection fraction.

Trials of strategy. The early trials (FRISC II, TACTICS-TIMI 18, and RITA-3) established that routine angiography reduces death or MI and recurrent ischemia, with benefit confined largely to patients with ST depression or elevated troponin. ICTUS, in 1,200 troponin-positive patients with intensive medical therapy in both arms, found no difference in death, MI, or rehospitalization at 1 year (22.7% versus 21.2%); procedure-related MI was more frequent with early invasive management. These results underlie the Class 1 recommendation that either approach is acceptable in low-risk patients.

Trials of timing. In TIMACS (3,031 patients), angiography at a median of 14 hours did not reduce death, MI, or stroke at 6 months compared with a median of 50 hours, but it reduced the composite in the third of patients with a GRACE score above 140 (hazard ratio 0.65) and reduced death, MI, or refractory ischemia overall (9.5% versus 12.9%). In VERDICT (2,147 patients), angiography within 12 hours did not improve the overall outcome compared with angiography within 48 to 72 hours, and the GRACE-above-140 subgroup showed a similar direction (hazard ratio 0.81). Pooled data show no overall reduction in death or MI with earlier angiography; a delayed invasive strategy within 48 to 72 hours does not appear to increase MACE in patients without high-risk features.

Randomized trials of strategy and timing in NSTE-ACS. Rates are invasive or earlier strategy versus comparator.

The 2025 ACC/AHA guideline lists relative contraindications to a routine invasive approach: high bleeding risk on DAPT, severe thrombocytopenia (platelets below 50 × 10⁹/L), advanced kidney disease not on dialysis, acute kidney injury, life expectancy below 1 to 2 years, advanced dementia, known coronary anatomy that precludes PCI or CABG, and patient preference. These patients are managed with medical therapy and a selective approach. The trials of timing enrolled stable patients; the very-high-risk group was largely excluded, and the recommendation for immediate angiography rests on the high event rate in these patients and on extrapolation from STEMI.

Fibrinolytic therapy is not used in NSTE-ACS. In patients with ST depression only, except when true posterior STEMI is suspected, fibrinolysis is harmful (Class 3: Harm) because it increases hemorrhagic stroke and major bleeding without benefit.

Anti-ischemic, analgesic, and early supportive therapy

Oxygen. Supplemental oxygen is recommended when oxygen saturation is below 90%, to raise it to 90% or more (Class 1), and is not recommended when saturation is 90% or more (Class 3: No Benefit). In DETO2X-AMI, oxygen at 6 L/min in 6,629 patients with suspected MI and saturation of 90% or more did not reduce 1-year mortality or rehospitalization with MI, including in the subgroup with saturations of 90% to 94%.

Nitrates. Sublingual nitroglycerin relieves ischemic pain, and intravenous nitroglycerin is used for persistent pain, hypertension, or pulmonary edema. Nitrates are avoided with systolic pressure below 90 mm Hg or 30 mm Hg or more below baseline, suspected right ventricular infarction, and recent phosphodiesterase-5 inhibitor use. They relieve symptoms and do not reduce mortality. Pain that persists despite nitrates is an indication for urgent angiography, not for escalating analgesia.

Opioids. Morphine and fentanyl are reserved for pain refractory to maximal anti-ischemic therapy. Opioids delay gastric emptying and absorption of oral P2Y12 inhibitors and delay their antiplatelet effect, although the clinical relevance of this pharmacodynamic finding is disputed. Opioids are not used to mask ongoing ischemia that warrants angiography. Nonaspirin nonsteroidal anti-inflammatory drugs are avoided because they increase MACE.

Beta-blockers and calcium channel blockers. The 2025 ACC/AHA guideline recommends initiation of an oral beta-blocker within 24 hours in patients without contraindications (Class 1), at a low dose with slow escalation as heart rate and blood pressure allow. Contraindications are acute heart failure (Killip class II to IV), a low-output state or risk of cardiogenic shock, PR interval longer than 0.24 seconds, second- or third-degree atrioventricular block without a pacemaker, severe bradycardia, and active bronchospasm. Patients with an initial contraindication are reassessed after 24 hours. COMMIT showed that aggressive early intravenous and oral metoprolol reduced reinfarction and ventricular fibrillation but increased cardiogenic shock, mostly in the first 24 hours, which is why intravenous beta-blockers are not given to patients with heart failure or borderline hemodynamics. A nondihydropyridine calcium channel blocker (verapamil or diltiazem) relieves ischemia when beta-blockers are contraindicated, in the absence of left ventricular dysfunction, heart failure, or atrioventricular block, and is the treatment of choice for vasospasm. Immediate-release nifedipine without a beta-blocker is avoided because reflex tachycardia increases ischemia.

Statins. High-intensity statin therapy is recommended in all patients with ACS (Class 1) and is started during the hospitalization regardless of baseline low-density lipoprotein cholesterol (LDL-C).

Analgesic and anti-ischemic dosing for ischemic chest pain, from the 2025 ACC/AHA ACS guideline (Table 6).

Aspirin and P2Y12 inhibitor choice

Aspirin. Aspirin is given as soon as possible at presentation, irrespective of the final management strategy, as a nonenteric-coated loading dose of 162 to 325 mg chewed for faster absorption, followed by 75 to 100 mg daily (Class 1). Patients already taking aspirin receive the loading dose. Maintenance doses of 300 to 325 mg daily are no more effective than low doses and cause more bleeding. Patients reporting aspirin hypersensitivity undergo desensitization whenever possible, and the P2Y12 inhibitor loading dose is not delayed.

Clopidogrel. In CURE (12,562 patients with NSTE-ACS, most managed medically), clopidogrel added to aspirin reduced cardiovascular death, MI, or stroke from 11.4% to 9.3% (relative risk 0.80), with more major bleeding (3.7% versus 2.7%). Clopidogrel is a prodrug activated by hepatic cytochrome P450 enzymes, principally CYP2C19. Carriers of loss-of-function alleles have less platelet inhibition and more ischemic events after PCI, and high on-treatment platelet reactivity is present in 30% to 40% of patients treated with clopidogrel after PCI.

Ticagrelor and prasugrel. Both are more potent and faster in onset than clopidogrel. In PLATO (18,624 patients with ACS, including medically managed patients), ticagrelor reduced vascular death, MI, or stroke at 12 months (9.8% versus 11.7%; hazard ratio 0.84) and all-cause death (4.5% versus 5.9%). Overall major bleeding did not differ (11.6% versus 11.2%), but major bleeding unrelated to CABG was more frequent (4.5% versus 3.8%). Ticagrelor causes dyspnea in about 10% to 15% of patients, usually transient, and ventricular pauses. Maintenance aspirin doses above 100 mg reduce its efficacy. In TRITON-TIMI 38 (13,608 patients with ACS undergoing PCI after the anatomy was known), prasugrel reduced cardiovascular death, MI, or stroke (9.9% versus 12.1%; hazard ratio 0.81) and stent thrombosis (1.1% versus 2.4%). Major bleeding (2.4% versus 1.8%) and fatal bleeding (0.4% versus 0.1%) were more frequent. Patients with prior stroke or transient ischemic attack had net harm, and patients 75 years or older or weighing less than 60 kg had no net benefit at the standard dose.

Ticagrelor versus prasugrel. In ISAR-REACT 5 (4,018 patients with ACS planned for invasive evaluation), death, MI, or stroke at 1 year occurred in 9.3% with ticagrelor and 6.9% with prasugrel (hazard ratio 1.36), with no difference in BARC major bleeding (5.4% versus 4.8%). The trial was open label, prasugrel was given after the anatomy was known in NSTE-ACS, and the prasugrel dose was reduced to 5 mg in patients 75 years or older or weighing less than 60 kg. The 2025 ACC/AHA guideline does not prefer one agent over the other; the 2023 ESC guideline states that prasugrel should be considered in preference to ticagrelor in patients with ACS who proceed to PCI (Class 2a).

Recommendations in NSTE-ACS (2025 ACC/AHA). An oral P2Y12 inhibitor is given with aspirin to all patients with ACS (Class 1). Prasugrel or ticagrelor is recommended in patients undergoing PCI (Class 1). Ticagrelor is recommended in patients managed without planned invasive evaluation (Class 1); prasugrel has not shown benefit in medically managed patients. Clopidogrel is recommended when prasugrel or ticagrelor is unavailable, not tolerated, or contraindicated (Class 1), and it is the P2Y12 inhibitor used with oral anticoagulation. Prasugrel is not given to patients with prior stroke or transient ischemic attack (Class 3: Harm).

Oral and intravenous antiplatelet dosing in NSTE-ACS, from the 2025 ACC/AHA ACS guideline (Tables 7 and 9).

P2Y12 pretreatment and intravenous antiplatelet agents

Pretreatment is administration of a P2Y12 inhibitor before the coronary anatomy is known. In NSTE-ACS, some patients proceed to CABG, some have no culprit lesion, and some have a nonatherosclerotic cause, so pretreatment exposes patients to bleeding risk that may not be offset by ischemic benefit when angiography is performed promptly. In ACCOAST (4,033 patients with NSTEMI scheduled for angiography within 2 to 48 hours), prasugrel 30 mg given before angiography did not reduce the composite of cardiovascular death, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa bailout at 7 days (hazard ratio 1.02). It increased TIMI major bleeding (hazard ratio 1.90), with threefold more major and sixfold more life-threatening bleeding unrelated to CABG. Upstream ticagrelor has not been shown to improve outcomes compared with administration at the time of PCI; DUBIUS, which compared upstream with downstream P2Y12 inhibitor strategies in NSTE-ACS, was stopped early for futility with low event rates in all arms.

The 2025 ACC/AHA guideline therefore does not support routine pretreatment when angiography is planned within 24 hours, and states that upstream clopidogrel or ticagrelor may be considered when angiography is expected to be delayed beyond 24 hours (Class 2b). The 2023 ESC guideline recommends against routine pretreatment when the anatomy is unknown and early invasive management (within 24 hours) is planned (Class 3) and allows pretreatment when early angiography is not expected.

Cangrelor. Cangrelor is an intravenous, direct-acting, reversible P2Y12 inhibitor with an onset within minutes and offset within 1 hour. In P2Y12 inhibitor-naive patients undergoing PCI, a pooled analysis of the CHAMPION trials showed fewer periprocedural ischemic events than with clopidogrel or placebo, at the cost of more minor bleeding; it has not been compared with ticagrelor or prasugrel for ischemic outcomes. The 2025 ACC/AHA guideline rates it as possibly reasonable in patients undergoing PCI who have not received a P2Y12 inhibitor (Class 2b). Its pharmacology suits patients who cannot absorb oral drugs (intubated, vomiting, or in shock) and patients who may need early surgery.

Glycoprotein IIb/IIIa inhibitors. Eptifibatide and tirofiban are not given routinely in ACS (Class 3: Harm), because upstream and routine use increased bleeding without ischemic benefit in the era of P2Y12 inhibitors. Adjunctive use during PCI is reasonable for large thrombus burden, no-reflow, or slow flow (Class 2a).

P2Y12 inhibitors and CABG. When CABG is indicated, the P2Y12 inhibitor is stopped before elective surgery: clopidogrel 5 days, prasugrel 7 days, and ticagrelor 3 to 5 days. For urgent surgery, interruption of at least 24 hours (ideally) is followed by operation earlier than these intervals when the ischemic risk of waiting is high. Aspirin is continued through surgery, and the P2Y12 inhibitor is resumed when bleeding risk allows, typically 24 to 72 hours after operation.

Parenteral anticoagulation before and during angiography

Anticoagulation interrupts thrombin generation at the culprit plaque and is given to all patients with NSTE-ACS at diagnosis. Intravenous unfractionated heparin (UFH) is recommended (Class 1); its short half-life, titratability, and complete reversal with protamine suit patients going promptly to angiography. When an early invasive approach is not anticipated, enoxaparin or fondaparinux is a recommended alternative to UFH (Class 1). Parenteral anticoagulation is continued until revascularization when revascularization occurs during the same admission (Class 1), because premature discontinuation is followed by rebound thrombin generation and reinfarction, greatest in the first 4 to 8 hours. After uncomplicated PCI, anticoagulation is stopped.

Enoxaparin. In a meta-analysis of 12,171 patients with NSTE-ACS, low-molecular-weight heparin and UFH did not differ significantly in death or MI (2.2% versus 2.3%) or major bleeding. Enoxaparin given intravenously at the time of PCI may be considered as an alternative to UFH (Class 2b). Switching between UFH and enoxaparin around the procedure increases bleeding, so the agent started is continued.

Fondaparinux. In OASIS-5 (20,078 patients), fondaparinux 2.5 mg daily was noninferior to enoxaparin for death, MI, or refractory ischemia at 9 days (5.8% versus 5.7%), nearly halved major bleeding (2.2% versus 4.1%; hazard ratio 0.52), and reduced death at 30 days (295 versus 352 deaths) and 180 days. Guiding-catheter thrombus was more frequent with fondaparinux during PCI (0.9% versus 0.3%), so fondaparinux is not used to support PCI (Class 3: Harm), and patients receiving it are given UFH at the time of PCI. It is the agent with the lowest bleeding risk for medically managed patients and is contraindicated with creatinine clearance below 30 mL/min.

Bivalirudin. Bivalirudin is a direct thrombin inhibitor. In ACUITY, bivalirudin alone was noninferior to heparin plus a glycoprotein IIb/IIIa inhibitor for ischemic events and caused less major bleeding. In the NSTEMI cohort of VALIDATE-SWEDEHEART (3,001 patients, mostly radial access, no routine glycoprotein IIb/IIIa inhibitor), death, MI, or major bleeding at 180 days occurred in 12.1% with bivalirudin and 12.5% with heparin. The 2025 ACC/AHA guideline rates bivalirudin as possibly reasonable as an alternative to UFH in NSTE-ACS PCI to reduce bleeding (Class 2b), in contrast to STEMI, where it is a Class 1 alternative. In MATRIX, bivalirudin did not reduce 30-day ischemic or bleeding events compared with UFH alone. Bivalirudin is the anticoagulant of choice in heparin-induced thrombocytopenia.

Parenteral anticoagulant dosing in NSTE-ACS, from the 2025 ACC/AHA ACS guideline (Table 10). aPTT, activated partial thromboplastin time.

Coronary angiography, physiology, and intravascular imaging in NSTE-ACS

Radial access. A radial approach is preferred to a femoral approach in ACS (Class 1) to reduce bleeding, vascular complications, and death. In the NSTE-ACS cohort of MATRIX (4,394 patients), radial access reduced death, MI, or stroke at 30 days (11.3% versus 13.9%; rate ratio 0.80) and net adverse clinical events (12.2% versus 14.7%). When femoral access is needed, ultrasound guidance reduces complications. In centers where the radial artery is used as a bypass conduit, the access choice is coordinated with the surgical team.

The culprit lesion. The culprit is identified from the angiographic appearance (thrombus, ulceration, haziness, an abrupt cutoff, or reduced TIMI flow), the ECG, and the regional wall motion on echocardiography or ventriculography. In about 1 in 4 patients with NSTEMI, the culprit artery is totally occluded at angiography, most often in the inferolateral territory (right coronary or circumflex artery), which the 12-lead ECG represents poorly. In a meta-analysis of 40,777 patients, an occluded culprit was associated with higher short-term and long-term mortality. When the culprit is uncertain, intravascular imaging identifies plaque rupture, erosion, or thrombus.

Physiology of nonculprit lesions. Fractional flow reserve (FFR) and nonhyperemic indices are reliable in nonculprit vessels; in the culprit vessel during the acute phase, microvascular dysfunction can raise FFR and underestimate the stenosis. In NSTE-ACS patients from FAME (328 patients), FFR-guided PCI reduced stents and MACE at 2 years compared with angiography-guided PCI. In FRAME-AMI (562 patients, about 53% with NSTE-ACS), FFR guidance reduced the number of stents and MACE at 3.5 years, although the trial stopped early. In FAMOUS-NSTEMI (350 patients), FFR reduced revascularization procedures. The 2025 ACC/AHA guideline states that physiological assessment of a nonculprit stenosis may be considered when multivessel PCI is planned (Class 2b).

Intravascular imaging. Intravascular ultrasound (IVUS) or OCT is recommended to guide stenting of left main or complex lesions (Class 1). Imaging defines vessel size, plaque burden, calcium, and landing zones before stenting and confirms expansion, apposition, and the absence of edge dissection afterward. OCT has higher resolution and identifies plaque rupture, erosion, thrombus, and calcium thickness, but requires contrast to clear blood and images ostial left main disease poorly. IVUS needs no contrast flush and suits left main and ostial disease and patients with kidney dysfunction. Routine aspiration thrombectomy has no role.

Revascularization in multivessel disease: PCI versus CABG

In NSTE-ACS with multivessel disease, the mode of revascularization (CABG or multivessel PCI) is based on disease complexity and comorbidities, with Heart Team input (Class 1). In stable patients without left main stenosis who are not candidates for CABG and undergo culprit-lesion PCI, PCI of significant nonculprit lesions, at the index procedure or staged, is recommended (Class 1). In SMILE (584 patients with NSTEMI), single-procedure multivessel PCI reduced MACE at 1 year compared with staged PCI, driven by less revascularization. In BIOVASC (1,525 patients with ACS, about 60% NSTE-ACS), immediate multivessel PCI was noninferior to staged PCI at 1 year.

CABG is preferred when the anatomy is complex: left main disease with high anatomic complexity, multivessel disease involving the proximal left anterior descending artery in patients with diabetes, and multivessel disease with reduced left ventricular function, as in stable disease. The SYNTAX score quantifies anatomic complexity, and the Society of Thoracic Surgeons score estimates operative risk. In NSTE-ACS, the timing of CABG is individualized: stable patients usually wait for P2Y12 inhibitor washout; patients with ongoing ischemia, left main disease, or hemodynamic instability undergo surgery urgently. When the culprit is clear and the rest of the anatomy favors CABG, culprit-only PCI followed by staged CABG is an option for patients with ongoing ischemia.

In NSTE-ACS complicated by cardiogenic shock, routine PCI of nonculprit arteries at the index procedure is harmful (Class 3: Harm), on the basis of CULPRIT-SHOCK, in which culprit-only PCI reduced death or kidney replacement therapy at 30 days.

Cardiogenic shock, mechanical complications, and left ventricular thrombus

Cardiogenic shock complicates 7% to 10% of ACS and is less frequent in NSTE-ACS than in STEMI, but patients with NSTEMI and shock are older and have more left main and multivessel disease. Emergency revascularization of the culprit vessel by PCI or CABG is indicated irrespective of time from symptom onset (Class 1). Routine intra-aortic balloon pumping and venoarterial extracorporeal membrane oxygenation do not improve survival (Class 3: No Benefit). The microaxial flow pump recommendation (Class 2a) derives from DanGer Shock, which enrolled only STEMI patients; its application to NSTEMI shock is extrapolated. Patients with ongoing angina, hemodynamic instability, uncontrolled arrhythmias, or shock are admitted to a cardiac intensive care unit (Class 1).

Mechanical complications (papillary muscle rupture, ventricular septal rupture, free-wall rupture, and contained rupture) are less frequent after NSTEMI than after transmural STEMI but occur, particularly with circumflex occlusion and posteromedial papillary muscle rupture. Sudden hypotension, pulmonary edema, or a new murmur leads to immediate echocardiography and management in a center with cardiac surgery (Class 1), with short-term mechanical circulatory support as a bridge (Class 2a). Left ventricular thrombus is uncommon after NSTEMI and follows large anterior or apical infarction; it is treated with anticoagulation for 3 to 6 months, with the antiplatelet regimen shortened accordingly.

Permanent pacing is indicated for sustained Mobitz type II block, high-grade or third-degree atrioventricular block (persistent or infranodal), or alternating bundle branch block after MI (Class 1). An implantable cardioverter-defibrillator for primary prevention is recommended in selected patients with an LVEF of 40% or less at least 40 days after MI and at least 90 days after revascularization (Class 1); LVEF is reassessed 6 to 12 weeks after discharge when it is reduced.

Duration of dual antiplatelet therapy after ACS

ACS leaves a prothrombotic state that persists for months, and DAPT reduces both stent-related and spontaneous (nonculprit) events. In patients with ACS who are not at high bleeding risk, DAPT with aspirin and an oral P2Y12 inhibitor is administered for at least 1 year (Class 1), whether the patient was treated with PCI, CABG, or medical therapy alone. The default rests on CURE, TRITON-TIMI 38, and PLATO, all of which treated for up to 12 to 15 months. Patients at high bleeding risk were largely excluded from these trials, so the 12-month default applies to patients without high bleeding risk.

Beyond 12 months, DAPT is extended in selected patients who have tolerated it without bleeding. In the DAPT Study (9,961 patients who had completed 12 months of DAPT after drug-eluting stent implantation without a major event), continuing thienopyridine for another 18 months reduced stent thrombosis (0.4% versus 1.4%) and major adverse cardiovascular and cerebrovascular events (4.3% versus 5.9%), including MI (2.1% versus 4.1%). Moderate or severe bleeding increased (2.5% versus 1.6%). All-cause death was 2.0% versus 1.5% (hazard ratio 1.36, borderline significant). In PEGASUS-TIMI 54, ticagrelor 60 mg twice daily added to aspirin in patients 1 to 3 years after MI reduced cardiovascular death, MI, or stroke at the cost of more major bleeding. Two scores formalize the decision: the DAPT score, which asks whether to extend beyond 12 months, and the PRECISE-DAPT score, which asks at the time of PCI whether to shorten.

DAPT score. The DAPT score was derived from the DAPT Study and assigns 1 point each for MI at presentation, prior MI or PCI, diabetes, stent diameter below 3 mm, cigarette smoking, and paclitaxel-eluting stent; 2 points each for heart failure or LVEF below 30% and for vein graft PCI; and −1 point for age 65 to 74 years and −2 points for age 75 years or older. The range is −2 to 10. A score of 2 or more identified patients in whom extended thienopyridine reduced ischemic events (2.7% versus 5.7%) with a small, nonsignificant increase in bleeding (1.8% versus 1.4%). A score below 2 identified patients with little ischemic benefit (1.7% versus 2.3%) and a larger increase in bleeding (3.0% versus 1.4%). Discrimination was modest (c-statistics about 0.64 to 0.70), and the score applies only at 12 months to patients who completed DAPT without a major ischemic or bleeding event.

Event rates are continued thienopyridine versus placebo between 12 and 30 months in the DAPT Study.

PRECISE-DAPT score. The PRECISE-DAPT score was derived from 14,963 patients in eight randomized trials, most treated with aspirin and clopidogrel, to predict out-of-hospital TIMI major or minor bleeding on DAPT. Its five variables are age, creatinine clearance, hemoglobin, white-cell count, and prior spontaneous bleeding, and its range is 0 to 100. The c-index was 0.73 in the derivation cohort, 0.70 in the PLATO validation cohort, and 0.66 in the BernPCI registry. Scores of 10 or less, 11 to 17, 18 to 24, and 25 or more define very low, low, moderate, and high bleeding risk. In the trials that randomized DAPT duration, long DAPT (12 to 24 months) increased bleeding compared with short DAPT (3 to 6 months) only in patients with a score of 25 or more (absolute increase 2.59%, number needed to harm 38). Long DAPT reduced MI, stent thrombosis, stroke, or target vessel revascularization only in patients with a score below 25 (absolute reduction 1.53%, number needed to treat 65). In patients with ACS and a score below 25, the ischemic benefit of long DAPT was larger (absolute reduction 4.13%, number needed to treat 24).

The PRECISE-DAPT nomogram expressed as an equation. Each input is truncated to the nomogram range: age 50 to 90 years (0 to 19 points), creatinine clearance 100 to 0 mL/min (0 to 25 points), hemoglobin 12 to 10 g/dL (0 to 15 points), and white-cell count 5 to 20 × 10⁹/L (0 to 15 points); prior spontaneous bleeding adds 26 points. Creatinine clearance is calculated by the Cockcroft-Gault equation.

Neither score accounts for the P2Y12 inhibitor used, the complexity of the stented anatomy (left main stenting, two-stent bifurcation, multiple stents, or a last remaining vessel), or the need for oral anticoagulation. The ARC-HBR criteria are the definition of high bleeding risk used in the 2025 ACC/AHA guideline, and PRECISE-DAPT is one validated way of quantifying it.

Shortened DAPT, P2Y12 monotherapy, and de-escalation

Bleeding after ACS is most frequent in the first months, and most of the ischemic benefit of DAPT accrues early. Several strategies reduce bleeding after an initial period of DAPT: stopping aspirin and continuing a potent P2Y12 inhibitor, switching from ticagrelor or prasugrel to clopidogrel, and shortening DAPT to 1 month in high bleeding risk. The 2025 ACC/AHA guideline grades them differently.

Bleeding-reduction strategies after ACS and PCI. The 2025 ACC/AHA guideline also recommends a proton pump inhibitor in patients at high risk of gastrointestinal bleeding who take DAPT, an oral anticoagulant, or both (Class 1).

The evidence favors withdrawing aspirin and keeping the potent P2Y12 inhibitor, not the reverse. Prasugrel monotherapy has not been established after ACS, and low-dose prasugrel monotherapy started immediately after PCI in Japanese patients increased early events compared with DAPT. Clopidogrel monotherapy started 1 to 2 months after ACS raised concern for excess MI, possibly because of inadequate platelet inhibition in clopidogrel nonresponders. A proton pump inhibitor reduces gastrointestinal bleeding on DAPT. Omeprazole attenuates the pharmacodynamic effect of clopidogrel through CYP2C19, but a randomized trial showed no increase in ischemic events, and ticagrelor and prasugrel are not affected.

The 2023 ESC guideline also keeps 12 months of DAPT as the default and supports single antiplatelet therapy after 3 to 6 months, or after 1 month in high bleeding risk, as alternatives.

NSTE-ACS in patients who need oral anticoagulation

Atrial fibrillation, venous thromboembolism, and mechanical valves create an indication for oral anticoagulation in a substantial minority of patients with ACS. The trials of ticagrelor and prasugrel excluded anticoagulated patients. The 2025 ACC/AHA guideline recommends discontinuing aspirin 1 to 4 weeks after PCI and continuing a P2Y12 inhibitor, preferably clopidogrel, with an oral anticoagulant (Class 1). A direct oral anticoagulant is preferred over a vitamin K antagonist in eligible patients.

In AUGUSTUS (4,614 patients with atrial fibrillation and recent ACS or PCI, all receiving a P2Y12 inhibitor), major or clinically relevant nonmajor bleeding occurred in 10.5% with apixaban versus 14.7% with a vitamin K antagonist (hazard ratio 0.69), and in 16.1% with aspirin versus 9.0% with placebo (hazard ratio 1.89). Apixaban reduced death or hospitalization (23.5% versus 27.4%), and ischemic events were similar across groups. PIONEER AF-PCI, RE-DUAL PCI, and ENTRUST-AF PCI supported the same principle with rivaroxaban, dabigatran, and edoxaban. Beyond 12 months, oral anticoagulation alone is generally continued, as described in the 2023 chronic coronary disease guideline.

Myocardial infarction with nonobstructive coronary arteries

MINOCA is acute MI by the Fourth Universal Definition with no coronary stenosis of 50% or more in any major epicardial vessel and no overt alternative diagnosis for the presentation. It affects about 5% to 6% of patients with acute MI referred for angiography, and patients are younger and more often women than patients with obstructive disease. The 2019 AHA statement treats MINOCA as a working diagnosis that begins a search for the mechanism: once a specific cause such as myocarditis or Takotsubo syndrome is found, the diagnosis is replaced by that cause. Troponin elevation without ischemic features (nonischemic injury) is not MINOCA.

The angiogram is reviewed for a missed culprit: distal or branch occlusion, a subtle dissection, embolism, or a hazy plaque. Left ventricular angiography or echocardiography defines the wall-motion pattern; a pattern that extends beyond one coronary territory suggests Takotsubo syndrome. Cardiac MRI is the central test. An ischemic pattern of late gadolinium enhancement (subendocardial or transmural, in a coronary distribution) confirms infarction, whereas subepicardial or midwall enhancement indicates myocarditis, and edema without enhancement in a typical ballooning pattern indicates Takotsubo syndrome. MRI is most informative when performed early, ideally within about 2 weeks of presentation. Intravascular imaging (IVUS or, with higher resolution, OCT) at the index angiogram identifies plaque rupture, erosion, or intramural hematoma in many patients with an ischemic MRI pattern. Provocative testing with intracoronary acetylcholine or ergonovine diagnoses epicardial or microvascular spasm, and coronary function testing measures microvascular resistance and coronary flow reserve.

Mechanisms of MINOCA, after the 2019 AHA scientific statement on MINOCA.

Outcomes after MINOCA are better than after MI with obstructive disease but not benign, and recurrent MI and death occur at rates that justify secondary prevention matched to the mechanism. Randomized data on therapy in MINOCA without a defined mechanism are limited; observational registry data associate statins and renin-angiotensin system inhibitors with lower event rates.

Spontaneous coronary artery dissection

SCAD is a nonatherosclerotic, nontraumatic separation of the coronary artery wall by an intramural hematoma, with or without an intimal tear, that compresses the true lumen. It is an important cause of ACS in women younger than 50 years and the most common cause of pregnancy-associated MI. Associated conditions include fibromuscular dysplasia, pregnancy and the postpartum period, connective tissue disease, systemic inflammatory disease, and hormonal therapy, and episodes are often triggered by intense physical exertion or emotional stress.

Angiographic recognition determines management. Type 1 SCAD shows contrast staining of the arterial wall with multiple lumens. Type 2, the most common, shows a long, smooth, diffuse narrowing, often of the mid to distal left anterior descending artery or its branches, with an abrupt change in caliber. Type 3 is focal or tubular narrowing that mimics atherosclerosis and is confirmed by IVUS or OCT. Intracoronary imaging carries a risk of extending the dissection and is used only when the diagnosis is uncertain and the result will change management.

Most dissections heal spontaneously within weeks to months, and PCI in SCAD has lower success and higher complication rates than in atherosclerotic disease, because wires enter the false lumen and stents propagate the hematoma. The 2018 AHA statement therefore favors conservative management in stable patients with preserved flow. Revascularization by PCI or CABG is reserved for ongoing ischemia, hemodynamic instability, ventricular arrhythmia, or left main or proximal two-vessel dissection. Patients managed conservatively are observed in hospital for several days because early extension occurs. Beta-blockers are commonly prescribed after SCAD and were associated with a lower rate of recurrence in an observational cohort; the role of antiplatelet therapy and statins without atherosclerosis is uncertain. Screening for fibromuscular dysplasia with CT or MR angiography from head to pelvis is recommended. Recurrent SCAD occurs in a substantial minority, and future pregnancy is discussed with a multidisciplinary team.

Cocaine- and methamphetamine-associated chest pain and ACS

Cocaine causes coronary vasoconstriction, platelet activation, increased myocardial oxygen demand, and accelerated atherosclerosis; methamphetamine shares these effects and causes cardiomyopathy. Chest pain after stimulant use is evaluated with ECG, serial troponin, and assessment for aortic dissection, and ACS is managed with standard therapy. The acute hyperadrenergic state is treated first with a benzodiazepine, followed by nitrates and a calcium channel blocker for hypertension and vasospasm. Beta-blockers are not given to patients with signs of acute intoxication (euphoria, tachycardia, or hypertension) because of the risk of potentiating coronary spasm (Class 3: Harm in the 2014 AHA/ACC NSTE-ACS guideline); a combined alpha- and beta-blocker such as labetalol may be considered for hypertension or tachycardia after a vasodilator has been given. Recurrent events are common in patients who continue stimulant use, and abstinence is the main secondary prevention measure. Drug-eluting stents are selected cautiously when adherence to DAPT is uncertain.

Special populations: kidney disease, older age, female sex, diabetes, anemia, and heart failure

Chronic kidney disease. Patients with chronic kidney disease have the highest ischemic and bleeding risks and are the least often treated with an invasive strategy. Contrast-associated acute kidney injury is reduced by minimizing contrast volume, isotonic hydration, and avoidance of nephrotoxins; radial access reduces bleeding. Enoxaparin and bivalirudin are dose-adjusted and fondaparinux is avoided below a creatinine clearance of 30 mL/min, and eptifibatide requires dose reduction. Ticagrelor and prasugrel need no adjustment, but bleeding risk rises with declining function. Advanced kidney disease not on dialysis is a relative contraindication to a routine invasive approach in the 2025 ACC/AHA guideline, and the decision is individualized; observational data suggest benefit from invasive management in moderate kidney disease.

Older adults. Patients 75 years or older account for a growing share of NSTE-ACS and have more atypical presentations, more comorbidity, and more bleeding. Age alone does not exclude an invasive strategy. After Eighty showed fewer MIs and urgent revascularizations with an invasive strategy in patients 80 years or older, without a reduction in death, with a benefit that diminished with increasing age. SENIOR-RITA, in patients 75 years or older (mean age 82 years, one-third frail), found no reduction in cardiovascular death or MI with an invasive strategy, fewer nonfatal MIs, and procedural complications in less than 1%. The decision rests on frailty, cognition, comorbidity, bleeding risk, and patient goals. Drug doses are based on weight and creatinine clearance; prasugrel is reduced to 5 mg daily or avoided, and clopidogrel is a lower-bleeding alternative to potent P2Y12 inhibitors.

Women. Women with NSTE-ACS are older, more often have diabetes and hypertension, report associated non-chest-pain symptoms more often, and are more often undertreated. Sex-specific troponin cutoffs increase the diagnosis of MI in women. Women more often have MINOCA, SCAD, or microvascular disease, but in the presence of the same risk predictors they derive as much benefit from a routine invasive approach as men. Bleeding complications are more frequent in women, which favors radial access and weight-based dosing.

Diabetes. Diabetes increases ischemic risk and the extent of coronary disease. In multivessel disease involving the left anterior descending artery, CABG is generally preferred over multivessel PCI, as in stable disease. In-hospital hyperglycemia is treated with insulin, and hypoglycemia is avoided.

Anemia and transfusion. In MINT (3,504 patients with MI and hemoglobin below 10 g/dL), a restrictive strategy (transfusion for hemoglobin below 7 to 8 g/dL) and a liberal strategy (transfusion to maintain hemoglobin of 10 g/dL or more) led to death or recurrent MI at 30 days in 16.9% and 14.5% (relative risk 1.15; P = 0.07), with cardiac death 5.5% versus 3.2%. On this basis, transfusion to a hemoglobin of 10 g/dL or more may be reasonable in patients with ACS and anemia (Class 2b), in contrast to the restrictive thresholds used in other hospitalized patients.

Heart failure and left ventricular dysfunction. Heart failure at presentation (Killip class II or higher) is among the strongest predictors of death and places the patient in the very-high-risk group, in which immediate angiography within 2 hours is indicated. Ventricular function is measured before discharge (Class 1). In patients with LVEF of 40% or less, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) (Class 1), a mineralocorticoid receptor antagonist when heart failure symptoms or diabetes are present (Class 1), and a beta-blocker are indicated.

Secondary prevention at discharge

Patients remain at increased risk of recurrent events for months to years after ACS, and the therapies started in hospital are continued and intensified after discharge. An early outpatient visit, medication reconciliation, and referral to cardiac rehabilitation before discharge reduce readmission.

Secondary prevention after NSTE-ACS, from the 2025 ACC/AHA ACS guideline. ASCVD, atherosclerotic cardiovascular disease.

Lipid lowering. The guideline thresholds of 70 mg/dL and 55 mg/dL reflect the very high risk of patients after ACS. Ezetimibe lowers LDL-C by 15% to 25%, PCSK9 monoclonal antibodies by about 60%, inclisiran by about 50%, and bempedoic acid by about 20%.

Beta-blockers after the acute phase. The trials of long-term beta-blockade after MI predate reperfusion, high-intensity statins, and modern antiplatelet therapy. In REDUCE-AMI (5,020 patients with MI, coronary angiography, and LVEF of 50% or more), long-term beta-blockade did not reduce death or recurrent MI over a median of 3.5 years (7.9% versus 8.3%; hazard ratio 0.96). REBOOT (8,438 patients with LVEF above 40%) was neutral (hazard ratio 1.04), and a pooled analysis of five trials in 17,801 patients with normal ejection fraction found no reduction in death, MI, or heart failure (8.1% versus 8.3%; hazard ratio 0.97). In contrast, an individual-patient meta-analysis of 1,885 patients with mildly reduced LVEF (40% to 49%) found fewer deaths, MIs, or heart failure events with beta-blockers (hazard ratio 0.75). In ABYSS, among patients a median of 2.9 years after MI with LVEF of 40% or more, interruption of beta-blockers failed to show noninferiority to continuation (23.8% versus 21.1%) and did not improve quality of life. Beta-blockers remain indicated for LVEF below 50%, heart failure, arrhythmia, angina, and hypertension; in patients with preserved LVEF and none of these indications, the long-term benefit is not established.

Colchicine. In COLCOT (4,745 patients within 30 days of MI), colchicine 0.5 mg daily reduced cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to revascularization (5.5% versus 7.1%; hazard ratio 0.77), driven by stroke and urgent hospitalization for angina, and LoDoCo2 showed a similar reduction in chronic coronary disease. In CLEAR SYNERGY (7,062 patients with acute MI, most with STEMI), colchicine did not reduce cardiovascular death, MI, stroke, or ischemia-driven revascularization over 3 years (9.1% versus 9.3%; hazard ratio 0.99) and caused more diarrhea. Colchicine is avoided in severe kidney or hepatic dysfunction and with strong CYP3A4 or P-glycoprotein inhibitors.

Behavioral and psychosocial care. Smoking cessation, with counseling and pharmacotherapy, is the most effective single lifestyle measure after ACS. Dietary counseling, regular physical activity, weight management, and blood pressure and glucose control are delivered through cardiac rehabilitation, which remains underused, particularly by women and underrepresented groups. Depression and anxiety are common after ACS and are associated with worse outcomes; screening is part of discharge planning and rehabilitation.

Return to activity. Sexual activity is resumed when mild to moderate exertion is tolerated without symptoms. Nitrates are contraindicated within 12 hours of avanafil, 24 hours of sildenafil or vardenafil, and 48 hours of tadalafil.

Prognosis after NSTE-ACS

Short-term risk is set by age, heart failure, hemodynamic state, kidney function, ST deviation, troponin concentration, and cardiac arrest, the variables of the GRACE score. Longer-term risk is set by the extent of coronary disease, completeness of revascularization, left ventricular function, diabetes, kidney disease, persistence of smoking, and adherence to secondary prevention. Bleeding complications, particularly in the first months, are associated with a mortality increase comparable to that of recurrent infarction, which is the rationale for bleeding-reduction strategies.

Sources of error in the diagnosis and management of NSTE-ACS

• Attribution of every troponin elevation to ACS: an isolated stable elevation is chronic injury, and a rise without ischemic evidence is acute nonischemic injury; neither is treated with DAPT and anticoagulation.
• Failure to recognize an occlusion equivalent: posterior injury with ST depression in V1–V3, the de Winter pattern, hyperacute T waves, and modified Sgarbossa findings indicate acute occlusion and require emergency reperfusion.
• Application of a rapid troponin algorithm to the wrong assay, to a sample drawn within 3 hours of symptom onset as a single-sample rule-out, or to a patient with ongoing pain or an ischemic ECG.
• Stress testing in a patient with the Wellens pattern: the critical proximal LAD stenosis can occlude during the test.
• Delay of angiography in a patient with refractory angina, heart failure, ventricular arrhythmia, or shock while the risk score is calculated: instability overrides every score.
• Femoral access by default in patients at high bleeding risk, older adults, and women, in whom radial access reduces bleeding most.
• Continuation of triple therapy beyond 1 to 4 weeks after PCI, or use of ticagrelor or prasugrel in triple therapy, in patients who need an oral anticoagulant.
• Discharge of a patient with MINOCA without cardiac MRI or a search for the mechanism, which leaves myocarditis, Takotsubo syndrome, embolism, and spasm unrecognized.

References

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