Pathophysiology | Physical Examination | Diagnosis | Symptoms | Treatment – Prevention • Invasive vs. Conservative • Medical Therapy | Special Situations
An acute coronary syndrome occurs when atherosclerotic coronary plaque becomes unstable, leading to a series of events that eventually results in partial or total thrombotic occlusion of a coronary artery. Acute coronary syndromes are categorized into unstable angina, non-ST segment elevation myocardial infarction and ST segment elevation myocardial infarction. The terms “transmural,” “non-transmural,” “Q wave MI” and “non-Q wave MI” are no longer recommended. The differences between the types of acute coronary syndromes are discussed below.
Unstable Angina Pectoris
Three different presentations of unstable angina exist:
- Exertional angina of new onset (even if relieved with rest and requiring a consistent amount of exertion to produce symptoms, angina is considered unstable when it first occurs)
- Exertional angina that was previously stable and now occurs with less physical exertion
- Anginal symptoms at rest without physical exertion
In unstable angina, the cardiac enzymes remain normal or are only very minimally elevated.
Non-ST Segment Elevation Myocardial Infarction
Anginal symptoms at rest that result in myocardial necrosis as identified by elevated cardiac biomarkers (see Cardiac Enzymes Topic Review) with no ST segment elevation on the 12-lead ECG.
ST Segment Elevation Myocardial Infarction
Anginal symptoms at rest that result in myocardial necrosis, as identified by elevated cardiac biomarkers (see Cardiac Enzymes Topic Review) with ST segment elevation on the 12-lead ECG.
Pathophysiology – CAD - Unstable Angina/Non-STEMI
The “vulnerable plaque” that formed from the atherosclerotic process is responsible for acute coronary syndromes and, ultimately, coronary artery thrombosis; see Atherosclerosis Topic Review. A substance known as “tissue factor” is located within the necrotic core of the plaque. When exposed to the bloodstream, tissue factor activates the clotting cascade, and thrombosis occurs.
Tissue factor is exposed when the fibrous cap that covers the plaque becomes disrupted or ulcerated. This disruption of the fibrous cap is called “plaque rupture” or “plaque erosion.” Surprisingly, plaque rupture and thrombosis frequently occur at the site of modest coronary stenosis (< 50% luminal narrowing); therefore, even if stress test results are normal, the risk for an ACS is still present. Recall that stress testing is the most sensitive method to detect stenosis of 70% or greater.
Some atherosclerotic plaques have a more stable fibrous cap. Others are thin and considered vulnerable. A clinically useful means to distinguish these types of plaque is not currently available.
Unstable angina has a lower incidence of coronary thrombosis compared with non-ST segment elevation MI or ST segment elevation MIand is more often the result of fixed atherosclerotic stenosis. Plaque rupture or erosion resulting in coronary occlusion is the predominant mechanism in Non-STEMI and STEMI.
Physical Examination – CAD - Unstable Angina/Non-STEMI
Physical examination findings are relatively non-specific and similar to that described in the Stable Angina Topic Review. They are usually only present during the anginal episode, making this a less helpful means of diagnosis. When examined during an anginal attack, the heart rate and blood pressure may be elevated due to increased sympathetic tone.
A S4 heart sound may be present during myocardial ischemia due to the lack of adenosine triphosphate production impairing left ventricular relaxation. Recall that myocardial relaxation is an active process requiring adenosine triphospate, or ATP, which is reduced during ischemia, and a S4 heart sound occurs when a non-compliant, stiffened left ventricle receives blood after atrial contraction because it is unable to relax adequately.
During inferior ischemia, posteromedial papillary muscle dysfunction can cause mitral regurgitation, resulting in a holosystolic murmur at the cardiac apex radiating to the axilla; see Heart Murmurs Topic Review. This rarely occurs during anterior or lateral ischemia because the anterolateral papillary muscle has dual supply from the left anterior descending and circumflex coronary artery.
When the left ventricular end-diastolic pressure, or LVEDP, increases during myocardial ischemia, that pressure can be transmitted backward to the pulmonary veins and into the pulmonary vasculature, causing transient pulmonary edema that results in dyspnea and rales on lung examination.
Diagnosis – CAD - Unstable Angina/Non-STEMI
The diagnosis of unstable angina and non-STEMI is predominantly based on the ECG and cardiac enzymes. Physical examination, as previously described, is non-specific.
The ECG tracing can have multiple abnormalities, but, by definition, there is no ST segment elevation. The most common finding is ST segment depression. This ST segment depression is horizontal or down-sloping in shape. The T waves may be inverted, usually symmetrically.
Surprisingly, unstable angina and non-STEMI can both occur, even with a completely normal ECG; this makes diagnosis quite a challenge. Observation in the hospital for cardiac enzymes in context of serial ECGs (usually 6-8 hours apart) is required to completely exclude unstable angina and non-STEMI, as the ECG changes can be dynamic (come and go) and the findings normal initially. Also, cardiac enzymes (troponin and creatine kinase) require 3 to 4 hours after the injury before showing significant elevation; see Cardiac Enzymes Topic Review).
During non-STEMI, there will be elevation of the cardiac enzymes, indicative of myocardial necrosis. During unstable angina, however, there is no — or only very minimal — elevation. This is the main distinguishing feature between the two diagnoses.
Symptoms – CAD - Unstable Angina/Non-STEMI
The symptoms of occlusive coronary artery disease can manifest as chronic stable angina pectoris or angina as a part of an ACS — both of which are similar, with the latter frequently occuring at rest. Substernal chest pressure with radiation to the medial portion of the left arm or left jaw is the classic description.
Angina can be described as a “tightness,” “discomfort, not pain,” “squeezing,” “indigestion,” “heaviness” or an “elephant sitting on my chest.” Levine sign is when a patient places his or her fist in the center of the chest to describe the sensations of squeezing and tightness with angina.
The pain from angina is gradual in onset and must last for at least 5 minutes. Also, the pain is diffuse and difficult to localize to one part of the chest; the description of a large vs. small area of pain can help distinguish from musculoskeletal issues.
Less common presentations include only shoulder pain, pain down both arms, left wrist pain, right-sided chest or jaw pain, radiation to the right arm, mid-thoracic back pain and only dyspnea without chest pain. Rarely, the pain of angina is described as sharp.
Some associated symptoms that occur simultaneously with the classic anginal symptoms above include dyspnea, diaphoresis (cold sweats), fatigue/weakness, nausea and dizziness. Women, elderly patients and patients with diabetes tend to have more atypical presentations of angina.
Many non-cardiac disease states can cause chest pain, as well. Important features that would suggest non-cardiac causes of chest pain include worsening with inspiration (pleuritic pain), the duration of the pain (< 5 minutes), a small pinpoint area of pain (angina is more diffuse) and no relief with nitroglycerine. Esophageal spasm — a relatively uncommon cause of chest pain — can be relieved with nitroglycerine, causing it to mimic symptoms of angina. Sharp, shooting chest pains lasting a few seconds to a minute are common and usually musculoskeletal related.
When an atherosclerotic plaque ulcerates and thrombosis occurs, an ACS develops and the above-mentioned anginal symptoms can occur at rest. In this setting, the pain is frequently more severe and has a longer duration.
Treatment – CAD - Unstable Angina/Non-STEMI
Primary prevention refers to controlling cardiovascular disease risk factors to stop the first CV event from occurring. Secondary prevention refers to therapy aimed at reducing the risk for ACS in a patient with diagnosed CAD or a coronary risk equivalent.
Primary prevention consists predominantly of controlling CVD risk factors such as LDL cholesterol, tobacco use, hypertension and obesity. Because the baseline risk for a CV event is lower in a primary prevention patient than in a secondary prevention patient, the absolute benefit of reducing risk factors is less.
Treatment of lipid disorders for primary prevention include dietary and lifestyle modifications and medical therapy with HMG-CoA reductase inhibitors. The American College of Cardiology/American Heart Association guidelines released in 2013 recommend high-intensity statin therapy (defined as a > 50% reduction in LDL) without any specific target LDL levels in patients with clinical vascular disease, such as ACS, less than age 75 years. Those older than age 75 years should receive moderate-intensity statin therapy (defined as 30-50% reduction in LDL) without specific targets to achieve. Medications other than HMG-CoA reductase inhibitors to lower LDL levels are not recommended at this time.
Antiplatelet therapy is not recommended for all patients for primary prevention of CVD; however, an individualized approach should be taken. If the risk for bleeding is low, yet there is a significant risk for CVD that does not meet a coronary risk equivalent — putting the patient in the secondary prevention category (see below) — antiplatelet therapy can be considered.
Coronary risk equivalents (10-year risk for cardiac event > 20%) include the following:
- Non-coronary atherosclerotic disease: Peripheral arterial disease, or PAD, carotid artery disease, renal artery disease, abdominal aortic aneurysm
- Type 2 diabetes
- Multiple risk factors: Using the Framingham risk score, a 10-year risk for a cardiac event is greater than 20%
- Chronic kidney disease
Secondary prevention includes antiplatelet therapy and a HMG-CoA reductase inhibitor regardless of the serum LDL cholesterol level. (Smoking cessation, BP control, HDL/triglyceride therapy, exercise and weight loss are discussed elsewhere.
Aspirin therapy has been shown to significantly reduce the risk for ACS in patients with established coronary disease. The data to support this in those with coronary risk equivalents are not as robust, but it is still recommended. There is a risk for major bleeding with aspirin therapy, especially from the gastrointestinal tract. This risk is acceptable considering the CV benefits of aspirin in secondary prevention patients; however, the risk-benefit ratio is not as favorable in primary prevention patients ― with lower baseline CV risk than a secondary prevention patient, but bleeding risk similar. Clopidogrel can be used in aspirin-intolerant patients.
A moderate dose of an HMG-CoA reductase inhibitor such as atorvastatin 40 mg or simvastatin 40 mg, is recommended initially. In most patients with CAD or coronary risk equivalent, the actual goal LDL cholesterol is less than 100 mg/dL. However, if high risk features including prior ACS, poorly-controlled risk factors (hypertension, tobacco use) and type 2 diabetes are present, the goal is less than 70 mg/dL. Both the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial and Treating to New Targets (TNT) trial support these recommendations.
Early Invasive vs. Initial Conservative
An early invasive strategy refers to proceeding to coronary angiography with possible percutaneous coronary intervention — also known as PCI or coronary stenting — within 4 to 24 hours of hospital admission. An initial conservative management consists of medical therapy only, without plans to proceed to coronary angiography and PCI.
Factors that would warrant an early invasive strategy are outlined below:
- Increased cardiac biomarkers (troponin, CK-MB)
- New ST segment depression
- Signs or symptoms of congestive heart failure (rales on examination, hypoxia with pulmonary edema on chest X-ray)
- Hemodynamic instability
- Sustained ventricular tachycardia or ventricular fibrillation
- Recent coronary intervention within 6 months
- Prior coronary artery bypass grafting
- High TIMI risk score
- Reduced left ventricular systolic function (EF < 40%)
- Recurrent angina at rest or with low level activity
- High-risk findings from non-invasive testing
The Invasive vs. Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial showed no difference in the above approaches over 3 years. The third Randomized Intervention Treatment of Angina (RITA-3) trial showed no difference at 1 year, but there was a reduction of death or MI at 5 years in the early invasive arm, seen mainly in high-risk patients. This justifies the approach mentioned above, to only perform angiography/PCI on high-risk patients.
When an initial conservative management is undertaken, additional risk stratification must be done to evaluate whether high-risk features that would warrant changing to an invasive approach are present. If any high-risk features as mentioned above develop, an invasive approach should be undertaken. If there are no high-risk features, an evaluation of left ventricular systolic function should be done — either by echocardiography or myocardial perfusion imaging). If the ejection fraction is less than 40%, the patient is at high risk and invasive coronary angiography should be performed. If the ejection fraction is greater than 40%, a stress test with imaging should be performed. If the findings are intermediate or high risk — that is, not low risk — invasive coronary angiography should be performed. For example, an echocardiogram showed an ejection fraction of 45% so a stress test is performed. If normal or only a small defect is seen, medical therapy can be undertaken; however, if a moderate or large area of ischemia is present, invasive coronary angiography is recommended.
The medical management of unstable angina and non-STEMI consists of beta blocker therapy, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), aldosterone antagonists, HMG-CoA reductase inhibitors, calcium channel blockers, nitrates, antiplatelet therapy and anticoagulation therapy. Treatment with fibrinolytics, or tPA, is not recommended for unstable angina and non-STEMI management — and only for STEMI in certain instances; for more details, see STEMI Topic Review.
Although little data exists regarding the efficacy of beta-blockers during unstable angina and non-STEMI, there are an abundance of data for their use during STEMI. ACC/AHA guidelines recommend early intravenous beta-blockers when no contraindication exists and there is angina, hypertension or tachycardia not related to HF. Long-term (lifetime) therapy has been shown to reduce MI incidence and improve mortality.
Angiotensin Converting Enzyme (ACE) Inhibitors/Angiotensin Receptor Blockers (ARBs)
There are also less data to support using ACE inhibitors during unstable angina and non-STEMI than during STEMI, where definite benefit is seen. The ACC/AHA guidelines recommend that ACE inhibitors be given upon hospital discharge in patients with hypertension, diabetes, LV systolic dysfunction (EF < 40%) and/or HF symptoms. There may be a benefit to all patients, but the data are limited; thus, a recommendation to use ACE inhibitors in all patients following unstable angina and non-STEMI is yet to be made. When a patient does not tolerate an ACE inhibitor due to cough, an ARB is a good alternative.
The aldosterone antagonist eplerenone was evaluated in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) trial, leading to the recommendation for use of the agents with an ACE inhibitor prior to hospital discharge after unstable angina and non-STEMI if there is left ventricular systolic dysfunction (EF < 40%) and either diabetes or symptomatic HF present and no contraindication (serum creatinine > 2.5 mL/min and or potassium > 5.0 mEq/L). A class effect is likely present; therefore, spironolactone is frequently used instead of eplerenone due to cost concerns, though there are no direct data to support this practice.
HMG-CoA Reductase Inhibitors
Every patient with unstable angina and non-STEMI should receive at least moderate-dose — and preferably high-dose — statin therapy. The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) and Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial used atorvastatin (80 mg/day given orally) with good results. Statin therapy should be lifetime after a person has an ACS, unless a contraindication exists.
Calcium Channel Blockers
The non-dihydropyridine calcium channel blockers diltiazem and verapamil can be used when there is a contraindication to beta blockers, such as in asthma, and no HF or significant left ventricular systolic dysfunction are present. Sublingual nifedipine is contraindicated due to a reflexive increase in the sympathetic nervous system, which can be harmful.
Nitrates are helpful to treat angina symptoms, hypertension and HF during unstable angina and non-STEMI; however, no clinical data exists to show a mortality benefit and thus their use is individualized. The use of nitrates should not preclude using drugs that do show a mortality benefit.
There are three main categories of antiplatelet therapy.
Aspirin: This acts by blocking the enzyme cyclooxygenase resulting in decreased thromboxane A2 production and platelet inhibition.
Thienopyridines: Also known as P2Y12 receptor blockers, these agents include clopidogrel, prasugrel, ticagrelor and ticlopidine. Clopidogrel has delayed onset of action, no means of reversing the effects, and a significant percentage of people simply do not respond to this therapy. Prasugrel and ticagrelor have fast onsets of action and few if any non-responders, but carry a higher risk for bleeding. Prasugrel is not recommended if there is a prior history of TIA or stroke, as it may cause harm (class III).
Glycoprotein IIb/IIIa inhibitors: This category includes abciximab, eptifibatide and tirofiban. They agents very strongly inhibit platelet function by blocking the binding of fibrinogen to the activated glycoprotein IIb/IIIa receptor complex.
Regardless of an early invasive versus initial conservative approach, all patients with unstable angina and non-STEMI should receive aspirin and treatment with a P2Y12 receptor blocker. Clopidogrel therapy is frequently used; however, ticagrelor or prasugrel can be given instead of clopidogrel, as there are fewer non-responders to these drugs and a quicker onset of action. Even when no PCI is performed, as in initial conservative management, a P2Y12 receptor blocker should be continued for 12 months.
When an early invasive strategy is used, a glycoprotein IIb/IIIa inhibitor could be given in addition to aspirin and clopidogrel (class IIa, C) based on the patient’s risk. When high-risk features are present, such as delay to angiography and early recurrent anginal chest pains, a glycoprotein IIb/IIIa inhibitor should definitely be utilized prior to angiography. Eptifibatide and tirofiban are the preferred glycoprotein IIb/IIIa inhibitors in this setting. Low-risk patients (TIMI risk score < 2) should not get glycoprotein IIb/IIIa therapy (class III).
Note that abciximab is not recommended for initial conservative therapy based on the fourth Global Utilization of Strategies to Open Occluded Coronary Arteries—Acute Coronary Syndrome (GUSTO IV-ACS) trial, but only if PCI is planned. Eptifibatide and tirofiban can be used for initial conservative therapy (class IIb). If a patient in the initial conservative category develops high risk features and PCI is planned, a glycoprotein IIb/IIIa inhibitor should be started.
Full anticoagulation should be started in all patients with unstable angina and non-STEMI, unless a contraindication exists; however, based on available data and guidelines, the choice of anticoagulant differs between early invasive and initial conservative groups.
When initial conservative management is undertaken, anticoagulation with either unfractionated heparin or low molecular weight heparin (enoxaparin or fondaparinux) should be started if no contraindication exists. The duration of unfractionated heparin therapy should be for 48 hours, but guidelines based on clinical trials state that low molecular weight heparin should be continued for the entire length of hospitalization or 8 days.
When an early invasive strategy is employed, anticoagulation should be with unfractionated heparin, low molecular weight heparin or bivalirudin (Angiomax). Bivalirudin is not recommended for initial conservative management.
Special Situations – CAD - Unstable Angina/Non-STEMI
Although no formal guidelines exist specifically for this ECG change, an early invasive strategy makes sense due to the high-risk nature of proximal left anterior descending artery, or LAD, disease. Wellens’ ECG changes have two types. The first has biphasic T waves in the anterior precordial leads, and the second has deep inverted T waves throughout the precordial leads.
Non-cardiac Chest Pains
There are multiple causes of chest pains, and when the diagnosis is in question, a cardiac etiology must be assumed due to the life-threatening nature of ACS. The term unstable angina is used frequently in patients with chest pain — even if the etiology is in question — as long as the primary reason for observing the patient in the hospital is to assure that an ACS is not present.
Some institutions use platelet assays to identify clopidogrel non-responders. Those patients are treated with prasugrel or ticagrelor instead. These platelet assays are not recommended in the ACC/AHA guidelines, but do not pose any harm.
Arrhythmia During ACS
Ventricular tachycardia and ventricular fibrillation — both life threatening — are common complications of acute coronary syndromes. Although less common, atrial fibrillation and atrial flutter are can be troublesome, as well. The only measures that should be routinely taken to prevent arrhythmias during an ACS include beta blocker therapy and maintaining electrolytes (potassium and magnesium) within normal limits. The prophylactic administration of lidocaine to suppress premature ventricular contractions or prevent ventricular tachycardia/fibrillation is not recommended. Likewise, the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated increased mortality in patients using encainide, flecainide and moricizine to suppress premature ventricular contractions after an ACS.
Anemia During ACS
There are no official guidelines in regards to the threshold for transfusion in patients who are anemic during an ACS. In general, the hematocrit should be maintained at greater than 21% and preferably above 30%.
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