Basic Information

Acute coronary syndrome (ACS) represents a spectrum of clinical disorders that includes unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). Although the severity of disease will vary between the three subsets of ACS, they share a common clinical presentation and pathophysiology. This syndrome is typically caused by atherosclerotic coronary artery disease (CAD). In this spectrum, UA and NSTEMI are represented electrocardiographically by the absence of ST-segment elevation in the appropriate clinical setting (i.e., chest discomfort). NSTEMI is represented by the addition of positive cardiac biomarkers. STEMI is characterized by ST-segment elevation or presumed new left bundle branch block on electrocardiogram (ECG) in the appropriate clinical setting. ACS should be thought of as a continuous spectrum as UA will often progress to a myocardial infarction if left untreated (Table 1). Because of this continuum, the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines have grouped UA and NSTEMI into a single category called non–ST-elevation ACS (NSTE-ACS).

Synonyms

1. Unstable angina

2. NSTEMI

3. STEMI

4. Acute myocardial infarction

Epidemiology & Demographics

Incidence

In the U.S., cardiovascular disease accounts for approximately 801,000 deaths each year. The estimated annual incidence of heart attack in the U.S. is 580,000 new attacks and 210,000 recurrent attacks. Approximately 70% of myocardial infarctions are listed as NSTEMI, with the remainder being listed as STEMI. Patients with NSTE-ACS have more cardiac and noncardiac comorbidities than patients with STEMI. The underlying etiology, atherosclerotic CAD, is the number one cause of mortality.

Predominant Sex and Age

In evaluating chest pain, male gender and older age are important clinical factors that can identify ACS as a potential cause. In a 2005-2011 study sponsored by National Heart, Lung, and Blood Institute, the average age-adjusted first MI or fatal coronary heart disease rates per 1000 population in patients age 35 to 84 years of age were 3.7 for white men, 5.9 for black men, 2.1 for white women, and 4.0 for black women. As noted in this study, heart disease affects African Americans disproportionately, with more than 39,000 deaths from heart disease in 2013. Heart disease is the number one killer of women. It takes more lives than all forms of cancer combined.

Risk Factors

Hypertension, diabetes mellitus, dyslipidemia, tobacco use, and family history of premature CAD (CAD in a male first-degree relative younger than 55 years or a female younger than 65 years) are all associated risk factors for CAD. Refer to the topic “Angina Pectoris” for an extensive list of risk factors. Presence of these risk factors causes damage to the vascular endothelium and progression of atherosclerotic coronary artery plaques.

Physical Findings & Clinical Presentation

1. •

   Symptoms often, but not always, include chest discomfort described as a pressure that may radiate to the shoulders, neck, jaw, or back. Typical angina is substernal in location, brought on by emotional or physical stress, and relieved with rest and/or nitroglycerin. The pain and discomfort associated with an ACS event is often diffuse rather than localized. It is often associated with diaphoresis.

2. •

   Women, diabetics, the elderly, and postoperative patients often have an atypical presentation for ACS.

3. •

   Unstable angina has three typical presentations:

   1. ○

      Rest angina: angina occurring at rest and prolonged usually for longer than 20 minutes.

   2. ○

      New-onset angina: new-onset angina of at least Canadian Cardiovascular Society (CCS) class III symptoms (Table 2).

      TABLE2 Grading of Angina Pectoris According to CCS Classification
      Adapted with permission from Campeau L. Grading of angina pectoris (letter), Circulation 54:522–523, 1976. © 1976, American Heart Association, Inc.From: Braunwald E et al.: ACC/AHA guidelines for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina), J Am Coll Cardiol 36:970-1062, 2000.

      Class	Description of Stage
      I	“Ordinary physical activity does not cause … angina,” such as walking or climbing stairs. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation.
      II	“Slight limitation of ordinary activity.” Angina occurs on walking or climbing stairs rapidly; walking uphill; walking or stair climbing after meals; in cold, in wind, or under emotional stress; or only during the few hours after awakening. Angina occurs on walking 0.2 blocks on the level and climbing 0.1 flight of ordinary stairs at a normal pace and under normal conditions.
      III	“Marked limitations of ordinary physical activity.” Angina occurs on walking 1 to 2 blocks on the level and climbing 1 flight of stairs under normal conditions and at a normal pace.
      IV	“Inability to carry on any physical activity without discomfort—anginal symptoms may be present at rest.”

   3. ○

      Increasing angina: previously diagnosed angina that has become distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by ≥1 CCS class to at least CCS class III severity).

4. •

   “Anginal equivalents” may include dyspnea, nausea, vomiting, and fatigue.

5. •

   ECG for NSTE-ACS may reveal ST-segment depression and/or T-wave inversion. ECG for definition of STEMI will reveal at least 1-mm ST-segment elevation in two contiguous leads or new left bundle branch block in the appropriate clinical presentation.

6. •

   Physical exam findings alone are insufficient for the diagnosis of ACS. It is, however, important to assess the patient’s hemodynamic stability and volume status. The patient may be diaphoretic and tachycardic. Signs of heart failure may be present, which include elevated jugular venous pressure (JVP), presence of an S3 gallop, and peripheral edema. The degree of heart failure with MI can be represented by the Killip classification, with the greater the Killip classification, the greater the mortality noted:

   1. ○

      Killip Class 1 is no heart failure.

   2. ○

      Killip Class 2 includes individuals with rales, elevated JVP, and S3 on exam.

   3. ○

      Killip Class 3 includes individuals with frank pulmonary edema.

   4. ○

      Killip Class 4 describes individuals in cardiogenic shock or hypotension with evidence of vasoconstriction noted.

Etiology

Atherosclerotic CAD is the underlying etiology. The hallmark of ACS is the vulnerable atherosclerotic plaque, which typically has a thin fibrous cap and a large lipid core. This vulnerable plaque ultimately ruptures, which leads to platelet activation and aggregation, leading to thrombus formation. STEMI typically results from complete thrombotic occlusion of a coronary artery, whereas NSTE-ACS often has partial occlusion. Angiographically, it is often the intermediate coronary artery lesions (30% to 50% diameter vessel stenosis) that lead to subtotal or total vessel occlusion in two thirds of STEMI cases.

Differential Diagnosis

Chest pain mimicking ACS may be the result of various underlying disorders, some of which are also accompanied by ECG changes and/or cardiac biomarker release. Examples include acute pulmonary embolism, acute aortic dissection, pericarditis, myocarditis, costochondritis, pneumonia, tension pneumothorax, perforating ulcer, or Boerhaave syndrome. Refer to topics “Angina Pectoris,” “Coronary Artery Disease,” and “Myocardial Infarction” for extensive differential diagnoses of chest pain.

Workup

Focused history and physical exam, 12-lead ECG, cardiac biomarkers, and chest radiograph (CXR). Initial biomarkers may not be positive early in the disease process. Often serial biomarkers are drawn every 6 to 8 hours for a total of three sets for the purposes of ruling out myocardial infarction (MI), or until peak to determine the severity of an established MI. Echocardiogram may reveal new regional wall motion abnormalities or newly depressed LV function or aneurysm formation. Fig. 1 summarizes the evaluation of patients for acute coronary syndrome.

Laboratory Tests

1. •

   Cardiac biomarkers, which include creatine kinase (CK), its MB isoenzyme, myoglobin, and troponin I or T, will be positive in the setting of NSTEMI or STEMI. See Fig. 2, A for timing of release of each biomarker. Troponin I is the most sensitive biomarker for cardiac myocyte damage and also predicts 42-day mortality in ACS. Troponin I is considered the gold standard biomarker for diagnosis of myocardial infarction (Fig. 2, B). There are several clinical conditions that may cause myocardial injury and cause elevations in cardiac biomarkers, including acute pulmonary embolism, heart failure, end-stage renal disease, and myocarditis. Elevations of troponin may be seen for 2 weeks after the onset of myocardial necrosis.

   

2. •

   Testing for B-type natriuretic peptide (BNP) has a class IIb recommendation in the 2014 NSTE-ACS guidelines for use as a prognostic tool in patients presenting with an MI. BNP >80 portends a high risk of death at initial presentation of a STEMI.

3. •

   A complete fasting lipid panel and Hgb A1c should be obtained during the hospital admission for further risk stratification.

Risk Models and Risk Scores

Risk models and scores such as TIMI (see “Risk Assessment” in “Myocardial Infarction” topic), PURSUIT, and GRACE based on clinical, ECG, and laboratory data at presentation help to discriminate patients at high risk versus low risk for short- and intermediate-term adverse outcomes (Fig. 2, C).

Imaging Studies

1. •

   A CXR to assist in evaluating for volume status and for other possible causes of chest discomfort.

2. •

   In patients for whom ECG and cardiac biomarkers are nondiagnostic but the suspicion for ACS is high given the history, an echocardiogram may be helpful to assess left ventricular (LV) function and regional wall motion abnormalities.

3. •

   Coronary CT angiography can be performed in patients with possible ACS, a normal 12-lead EKG result, negative troponin results, and no history of coronary artery disease (Class IIa).

4. •

   Cardiac stress testing (treadmill ECG, imaging stress studies using echocardiography or nuclear modalities) may further help to diagnose and risk stratify these patients. (See “Coronary Artery Disease” in Section I.)

5. •

   Coronary angiogram/cardiac catheterization will reveal coronary artery luminal irregularities/stenotic lesions. In patients with ACS who undergo coronary angiography, approximately 25% will have one vessel disease, 25% will have two vessel disease, 25% will have three vessel disease, 10% will have left main disease, and 15% will have coronary stenosis of <50% or normal coronaries.

The overall goal for patients with NSTE-ACS is to relieve myocardial ischemia and to prevent recurrent cardiovascular events. Antithrombotic therapy is needed to reduce thrombus burden, prevent further thrombosis, and improve coronary artery flow. Revascularization is needed to prevent further events and improve flow within the coronary artery lumen. For patients with STEMI, the goal is immediate reperfusion therapy, whether it is chemical (i.e., thrombolysis) or mechanical (i.e., percutaneous coronary intervention [PCI]), and time from onset of ischemia to revascularization is an important prognostic factor. STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 minutes of first medical contact (Figs. 3 and 4). At non–PCI-capable hospitals where the first medical contact to balloon time is more than 120 minutes, thrombolytic therapy should be given if no contraindications are present; thrombolytics should not be administered 24 hours after initial diagnosis of STEMI. Absolute contraindications to thrombolytic therapy include the following: history of hemorrhagic cerebrovascular accident (CVA), history of CVA, dementia or central nervous system damage within the past year, head trauma or brain surgery within the past 6 months, or intracranial neoplasm. Other contraindications include suspected aortic dissection, internal bleeding within the past 6 weeks, active bleeding or known bleeding disorder, and traumatic CPR within the past 3 weeks.

Nonpharmacologic Therapy

1. •

   STEMI is a medical emergency and requires immediate reperfusion therapy; the best outcomes are seen in cardiac catheterization with primary PCI. Guidelines call for a goal door-to-balloon time of ≤90 minutes.

2. •

   Patients with NSTE-ACS should be risk stratified in conjunction with the cardiology consult service. Risk scores such as the TIMI and GRACE scores can be used to decide between an early invasive strategy and an ischemia-guided strategy. Overall, an early invasive strategy is associated with better outcomes in patients with higher risk (i.e., TIMI score >3 or GRACE >140) and involves cardiac catheterization followed by revascularization with PCI or coronary artery bypass grafting (CABG) within 4 to 24 hours of presentation. An ischemia-guided strategy involves aggressive medical management and revascularization only if ischemia recurs or is documented on noninvasive testing. This should only be reserved for selected patients with low-risk scores (TIMI score 0-2). The early invasive strategy can be further stratified by timing:

   1. 1.

      Immediate (within 2 hours): Patients with refractory or recurrent angina despite optimal initial treatment, signs or symptoms of heart failure, new or worsening mitral regurgitation, hemodynamic instability, sustained ventricular tachycardia or ventricular fibrillation

   2. 2.

      Early (within 24 hours): No characteristics from the immediate category but new ST-segment depression, a GRACE risk score >140 or temporal change in troponin

   3. 3.

      Delayed invasive: None of the immediate or early characteristics but renal insufficiency, left ventricular ejection fraction of <40%, early post-infarct angina, history of PCI within the past 6 months, prior coronary artery bypass graft, GRACE risk score of 109-140, or TIMI score of 2 or more.

3. •

   Bed rest and continuous ECG monitoring is recommended for all ACS patients. Supplemental oxygen should be administered to patients with arterial oxygen saturation of less than 90%, respiratory distress, or other high-risk features of hypoxemia. Finger pulse oximetry should be utilized to assess arterial oxygen saturation.

Acute General Rx

1. •

   All patients with ACS should receive full-dose non–enteric-coated chewable aspirin of 162 to 325 mg to establish a high blood level for its antiplatelet effects. Thereafter, daily dose of 81 to 325 mg are prescribed and continued indefinitely, with the lower dose of 81 mg showing lower bleeding risk with comparable efficacy.

2. •

   Antithrombotic therapy is critical in treating the underlying pathophysiology of ACS. This consists of administering antiplatelet and anticoagulant agents.

3. •

   Antiplatelet agents inhibit platelet activation and aggregation. Aspirin is a cyclooxygenase inhibitor that blocks platelet aggregation and should be administered to all ACS patients without contraindications.

4. •

   Clopidogrel is a thienopyridine agent that inhibits platelet activation and aggregation. It should be administered in all ACS patients, with the timing dependent on the clinical scenario and management strategy. It requires a loading dose of 300 to 600 mg followed by 75 mg daily. It should be discontinued at least 5 days before CABG. If a patient is unable to take aspirin in the setting of hypersensitivity or major gastrointestinal intolerance, a loading dose of clopidogrel followed by daily maintenance should be started. Other antiplatelet agents that can be substituted instead of clopidogrel include prasugrel, ticlopidine, and ticagrelor. However, maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided after an initial dose; ticagrelor should be used with aspirin 75 to 100 mg per day. Because of a more rapid and consistent onset of action, reversibility, and a reduction in death from vascular causes, MI, or stroke, ticagrelor is preferred over clopidogrel in patients with NSTE-ACS. Prasugrel is not recommended in ACS patients with stroke or transient ischemic attack (TIA), or those patients managed with fibrinolysis because of an increased risk of bleeding complications. Cangrelor is a newer IV ADP-P2Y12 receptor antagonist that may be used initially as a load in the emergency department before an invasive strategy, given its initial action and quick platelet recovery time. As a rule, all ACS patients should have two antiplatelet agents initiated and should be continued up to 12 months regardless of ischemia-guided vs invasive strategy.

5. •

   GP IIB/III a inhibitors may be considered as an intravenous antiplatelet therapy in addition to aspirin for medium- or high-risk patients with NSTE-ACS in whom an invasive strategy is planned (Class IIb). Eptifibatide and tirofiban are preferred agents over abciximab for NSTE-ACS patients; however, for STEMI patients undergoing primary PCI, IV abciximab has the same Class IIa indication as tirofiban and eptifibatide.

6. •

   Anticoagulant agents should be administered to all ACS patients. Options include either unfractionated heparin (UFH), or low-molecular-weight heparin (enoxaparin), or factor Xa inhibitors such as fondaparinux, or direct thrombin inhibitors such as bivalirudin.

7. •

   In the most recent guidelines, enoxaparin and UFH have both received Class I recommendations for use among ACS patients managed conservatively or invasively.

8. •

   For STEMI, fondaparinux can be used for anticoagulation. It has been shown to decrease bleeding complications as compared with either UFH or LMWH. However, it has a long half-life (15 hours), and thrombosis on catheters has been noted when using only fondaparinux in the cath lab; therefore, it is not recommended as a sole anticoagulation during primary PCI.

9. •

   Bivalirudin is a reversible direct thrombin inhibitor and may be considered as an alternative to UFH and GP IIb/IIIa inhibitors in patients with STEMI (HORIZONS AMI trial) who are undergoing primary PCI (PPCI). When bivalirudin was compared to UFH plus a glycoprotein IIb/IIIa inhibitor in patients with STEMI and PCI, less bleeding and a short- and long-term reduction in cardiac events and overall mortality was observed. With bivalirudin, there is no risk of heparin-induced thrombocytopenia, less bleeding is observed, and the anticoagulant effect can be monitored during intervention by the activated clotting time. Similar results were reported in the use of bivalirudin alone in patients with UA/NSTEMI in the ACUITY trial when compared to enoxaparin/UFH with GP IIb/IIIa arms.

10. •

    Beta-blocker therapy reduces ischemia by decreasing myocardial oxygen demand and oral therapy should be initiated within 24 hours of onset of ACS unless signs or symptoms of heart failure and shock are present or arrhythmias preclude its use. Oral administration, titrated to a heart rate of 50-60 beats/min, is preferred. Intravenous beta-blockers can be administered to STEMI patients who are hypertensive or have ongoing ischemia; they should be avoided if the patients have any of the following:

    1. 1.

       Signs of heart failure,

    2. 2.

       Evidence of a low output state,

    3. 3.

       Increased risk for cardiogenic shock, or

    4. 4.

       Other relative contraindications to beta-blockade (PR interval >0.24 second, second- or third-degree heart block, active asthma, or reactive airway disease).

11. •

    Nitroglycerin is a vasodilator that should be administered to relieve chest discomfort in all ACS patients. It can be administered sublingually at first, up to 3 doses, followed by intravenous administration if symptoms persist. In the setting of an inferior STEMI, it is necessary to rule out a right ventricular (RV) infarct with a right-sided ECG before the administration of nitroglycerin. This is because RV infarcts are preload dependent and nitroglycerin decreases preload through venodilation, which leads to hypotension in this setting. This can be corrected by discontinuing nitroglycerin and starting bolus intravenous fluids. Nitroglycerin provides no mortality benefit in ACS patients.

12. •

    Oxygen should be administered to patients with shortness of breath, signs of acute heart failure, cardiogenic shock, or an arterial oxyhemoglobin saturation of less than 90%. The 2014 ACC/AHA guidelines report no demonstrated benefit for routine use of supplemental oxygen in normoxic patients with NSTE-ACS; rather, emerging data suggest that routine use of oxygen can lead to adverse effects such as increased coronary vascular resistance, reduced coronary blood flow, and increased mortality rate.

13. •

    The 2014 ACC/AHA Guidelines for unstable NSTE-ACS have downgraded the recommendation for morphine use for uncontrolled ischemic chest discomfort from a Class IIa to a Class IIb recommendation due to reports linked to increased adverse events.

14. •

    Calcium channel blockers (nondihydropyridine) may be used in patients with persisting or recurrent symptoms, despite treatment with beta-blockers and nitroglycerin. They work by causing coronary vasodilation and decreasing myocardial oxygen demand. They are useful when beta-blockers are contraindicated and in patients with Prinzmetal variant angina. Calcium channel blockers should not be used in cases of severe LV dysfunction, pulmonary edema, increased risk for cardiogenic shock or advanced heart blocks.

15. •

    Patients routinely taking nonsteroidal antiinflammatory drugs (NSAIDs) (except for aspirin), both nonselective as well as COX-2 selective agents, before ACS should discontinue those agents at the time of presentation because of the increased risks of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use.

16. •

    Angiotensin-converting enzyme (ACE) inhibitors may be added and should be used within 24 hours of onset of ACS in all patients with depressed LV function (ejection fraction [EF] <40%) or pulmonary vascular congestion. Angiotensin receptor blockers (ARBs) should be used in patients who are ACE inhibitor intolerant.

17. •

    Refer to topic “Cocaine Overdose” for treatment of cocaine-related ACS.

Chronic Rx

1. •

   Post-ACS medical therapy involves aspirin, statin, beta-blocker, and a second anti-platelet agent such as clopidogrel, ticagrelor, or prasugrel.

2. •

   In patients already on an oral anticoagulant for another diagnosis such as atrial fibrillation, the duration of triple therapy should be minimized. The WOEST trial showed that using clopidogrel along with an oral anticoagulant but without aspirin resulted in a significant reduction in bleeding complications with those patients on a triple therapy of oral anticoagulant, aspirin, and clopidogrel. It is a class IIB recommendation in those patients with atrial fibrillation and a CHADS-VASC score of 2 or greater after coronary revascularization to consider using clopidogrel concurrently with oral anticoagulant but without aspirin.

3. •

   Lipid lowering with statins has been evaluated in trials such as the MIRACL study, in which high-dose atorvastatin 80 mg reduced death, MI, and cardiac events at 16 weeks when administered early, within 24-96 hours after an ACS. The A-Z trial and PROVE IT-TIMI 22 trials demonstrated benefit of early high-intensity statin therapy with LDL targets <70 mg/dl in ACS.

4. •

   ACE inhibitors may be added to treat hypertension and should be used in all patients with depressed LV function (EF <40%) or pulmonary vascular congestion. ARBs should be used in patients who are ACE inhibitor intolerant.

5. •

   An aldosterone blocker should be used in post-MI patients without significant renal dysfunction or hyperkalemia who have an ejection fraction of less than 40% and are already on therapeutic doses of an ACE inhibitor and a beta-blocker.

6. •

   Cardiac rehabilitation and a monitored exercise program should be recommended at the time of discharge.

7. •

   Aggressive risk factor management, including smoking cessation, weight loss, diet and exercise, diabetes control, and so on, for secondary prevention of future events is crucial.

Referral

1. •

   All ACS patients should be cared for in conjunction with the cardiology consult service.

2. •

   When appropriate, referral to a cardiac surgeon may be necessary for CABG.

3. •

   At time of discharge, patients should be considered for cardiac rehabilitation referral.

Comments

1. •

   ACS is common and a leading cause of mortality in the United States.

2. •

   The diagnosis hinges on the basics—history and physical, ECG, biomarkers, and CXR.

3. •

   Remember the potentially fatal non-ACS causes of chest discomfort, which include acute pulmonary embolism and acute ascending aortic dissection.

4. •

   STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 minutes of first medical contact.

5. •

   STEMI patients presenting to a hospital without PCI capability and who cannot be transferred to a PCI center and undergo PCI within 90 minutes of first medical contact should be treated with fibrinolytic therapy within 30 minutes of hospital presentation unless fibrinolytic therapy is contraindicated.

6. •

   Refer to topics “Angina Pectoris” and “Myocardial Infarction” for additional discussion of this subject matter.

Prevention

1. •

   Primary prevention of ACS is based on recognizing the major risk factors for CAD and treating them as appropriate.

2. •

   Patients with depressed LV function (ejection fraction <35%) at least 40 days after an acute MI benefit from an implantable cardioverter defibrillator (ICD) for the prevention of sudden cardiac death.

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Related Content

1. Acute Coronary Syndrome (Patient Information)

2. Angina Pectoris (Related Key Topic)

3. Coronary Artery Disease (Related Key Topic)

4. Myocardial Infarction (Related Key Topic)