ACS is a term that encompasses several conditions: unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI); ST segment elevation myocardial infarction (STEMI); and sudden cardiac death due to myocardial infarction. Cardiac chest pain, or angina, is the typical symptom. In ACS, the chest pain is usually new or progressing compared with prior chest pain. It may increase in frequency, severity, or duration, or occur at rest. Angina that is predictable, exertional, and resolves with rest or nitroglycerin is referred to as stable angina. Stable angina is not ACS. The above patient appears to have a history of stable angina, but is now presenting with unstable angina.

Many individuals will experience ACS without significant chest discomfort. This is especially common among elderly persons, women, and those with diabetes mellitus, all of whom often experience atypical symptoms including dyspnea, presyncope, fatigue/malaise, or nausea/vomiting. So-called diaphragmatic infarcts of the inferior wall often present with symptoms that, on first glance, appear to be gastrointestinal in nature. When pretest probability for ACS is sufficiently high, such atypical symptoms should be interpreted as angina equivalents until proven otherwise: stable angina is exertional chest pain that resolves with rest; unstable angina or MI classically presents with new chest pain, chest pain at rest, or abrupt worsening of stable angina; and symptoms of ACS are frequently atypical.

Acute coronary syndromes result from an acute decrease in myocardial blood flow. Although this can be caused by a number of conditions, it is mostly commonly due to atherosclerotic coronary plaque rupture complicated by acute coronary thrombosis, a process often referred to as atherothrombosis.

Generally speaking, UA, NSTEMI, and STEMI differ in the extent of vascular occlusion and myocardial ischemia. UA and NSTEMI both typically result from partially occlusive thrombosis and transient ischemia, with an NSTEMI occurring when sufficient ischemia is present to induce myocyte necrosis. STEMI is caused by a 100% occlusive thrombus, resulting in prolonged ischemia and transmural infarction. Figure 35-2 represents this graphically. Unstable angina and NSTEMI result from partially occlusive atherothrombosis, and STEMI usually represents 100% thrombotic coronary occlusion.

The electrocardiogram (ECG) is a key component of early risk stratification in patients with suspected ACS and should be performed immediately. The most important value of the ECG is its ability to immediately distinguish between STEMI and UA/NSTEMI. However, the ECG does provide additional prognostic information beyond ST elevations. Unstable angina or NSTEMI may manifest on ECG as ST depressions, T wave flattening, or T wave inversion or as a normal ECG.

The presence of ST depressions and their quantitative depth have been demonstrated as markers of elevated risk in ACS compared with those without ST changes. In the PARAGON study, for example, those with ST depressions > 2 mm had 5.7 times higher 1-year mortality compared with those without ST depressions.¹ The presence of ST segment depressions greater than 1 mm has also been identified as an independent predictor of both in-hospital and five-year mortality in ACS, regardless of treatment strategy, perhaps because they are often seen in older, sicker patients with more diffuse coronary artery disease.² UA/STEMI can take many forms on ECG: deeper ST depressions are associated with worse outcomes in ACS.

Serum markers of cardiac necrosis are useful both for establishing the diagnosis of acute myocardial infarction (MI) and identifying higher risk patients. Using current assays, troponin levels typically become detectable approximately 6 hours after the onset of myocyte necrosis. When significant symptoms and/or ECG changes are present, one should treat the patient as having unstable angina. Waiting for positive biomarkers may lead to unnecessary and costly delays in treatment.

Prospective trials consistently show correlation between quantitative troponin levels and short-term risk. When the clinical presentation is consistent with ACS, even low-level elevations (> 0.1 ng/mL) should be considered a marker of elevated risk and predictive of benefit from an early-invasive approach.³ Not surprisingly, the concurrent findings of elevated troponin and ST depressions in UA/NSTEMI identifies a particularly high-risk subgroup.¹ Higher serum levels of cardiac biomarkers are associated with worse outcomes in ACS.

The above case, which is a fairly typical presentation of acute coronary syndrome, is not consistent with demand ischemia. Demand ischemia is a colloquial term generally used in place of the more formal terminology, “type II MI.” According to the universal definition of myocardial infarction, a type II myocardial infarction is generally one that is not caused by a primary atherothrombotic event.⁴ In such situations, the myocardial ischemia is attributed to a mismatch between oxygen consumption and oxygen supply. There are often no symptoms suggestive of acute coronary syndrome. This is frequently seen in conditions of hemodynamic stress resulting from sepsis, hypotension, hypertension, anemia, arrhythmias, postoperative status, or coronary vasospasm.

Interestingly, compared with patients with type I MIs, patients with type II MIs tend to be older, to have comorbid cardiovascular or renal disease and significantly higher mortality rates at 30 days and 1 year of follow-up, which is probably driven in part by a lower likelihood or receiving optimal guideline-directed medical therapy.⁵

In ACS, examination findings suggestive of heart failure are indicative of elevated risk. The physical examination should focus on findings such as elevated jugular venous pressure, tachycardia, the presence of an S3, rales, pleural effusions, cool extremities, and lower extremity edema.

The Killip score is an easy-to-use system that classifies ACS patients based entirely on systolic blood pressure and physical examination findings. It has been demonstrated to predict both short- and long-term mortality in STEMI and NSTEMI. In fact, a Killip score of III/IV has been shown to be the most powerful predictor of mortality in a large study of patients presenting with NSTEMI.⁶ The Killip score affirms the importance of simple, bedside physical examination in an age of ubiquitous, technology-driven testing (Table 35-1). Physical examination findings of heart failure are associated with worse outcomes in ACS.

The goal of risk stratification is to identify patients who are high risk for complications and thus more likely to derive benefit from invasive treatments and more powerful pharmacologic therapies. Several prognostic scoring systems are available that integrate history, physical examination, ECG, and biomarkers to estimate the patient’s risk of serious complications due to ACS.

One of the most well-validated risk predictors is the TIMI (Thrombosis in Myocardial Infarction (TIMI) risk score. It is easily calculated at the bedside using seven variables and can predict risk of death, MI, or the need for urgent revascularization at 14 days. It is also useful in identifying those who will benefit most from an early invasive treatment strategy,⁷ Table 35-2 displays the items that contribute to the score. Figure 35-3 illustrates the increasing risk of adverse events with higher scores.

Risk stratification should be a continuous process throughout one’s hospital stay. The “Dynamic TIMI score” can also be used to integrate the TIMI risk score on admission with clinical variables based on the patient’s hospital course. It includes other factors such as reinfarction, arrhythmia, bleeding, congestive heart failure, stroke, and renal dysfunction. It has been prospectively validated and shown to predict 1-year mortality. A higher Dynamic TIMI risk score, calculated after admission or prior to discharge, helps identify higher risk people who may require closer monitoring or additional interventions.⁸

The TIMI risk score quantifies risk stratification and helps identify those who will benefit from more aggressive therapies. Risk assessment should be an ongoing process throughout one’s hospitalization.

Optimal management, and the decision of how quickly to proceed to angiography with intent to revascularize, depends on risk stratification: those with UA/NSTEMI who are hemodynamically or electrically unstable should proceed to urgent angiography. High-risk UA/NSTEMI patients (TIMI risk score ≥ 3) will benefit from an “early invasive” strategy of angiography and revascularization, simultaneous with dual antiplatelet therapy and anticoagulation. A TIMI score ≥ 3 has been identified as a clear inflection point in the mortality and morbidity curve for UA/NSTEMI. In this case, angiography and revascularization within 24 hours appears to be superior to a delay of 36 hours or more.⁹ Lower-risk UA/NSTEMI patients can often be observed with dual antiplatelet therapy alone (or simply aspirin and heparin), pending further risk stratification.

Standard of care for high-risk patients with ACS is dual-antiplatelet therapy: aspirin plus a platelet adenosine P2Y-12 receptor blocker. Newer P2Y-12 inhibitors, such as ticagrelor or prasugrel, have proven more potent and are generally preferred over clopidogrel, assuming there are no contraindications and that the patient will be treated invasively.

Aspirin has a long history of efficacy supporting its use in the setting of ACS. Current recommendations are for a loading dose of 162 to 325 mg (in the chewable, rapidly absorbable form) in the setting of suspected ACS. The daily dose thereafter should be 81 mg (preferably enteric coated). Maintenance doses higher than 81 mg daily are associated with increased bleeding without an improvement in prevention of ischemia.

Three options for P2Y-12 inhibitors are available: clopidogrel, prasugrel, or ticagrelor. Each has its own unique pharmacokinetics and risk/benefit profile (Table 35-3).