Unstable angina non ST elevation myocardial infarction overview

# Overview
Unstable angina and Non ST elevation myocardial infarction (NSTEMI) belong to two different ends of the spectrum of acute coronary syndrome.  Unstable angina is differentiated from NSTEMI by the absence of elevated cardiac biomarkers.  The basic pathology in both the conditions involves a non-occlusive thrombus formation from a previously disrupted atherosclerotic plaque causing inadequate blood supply to the heart muscle.

# The Spectrum of Acute Coronary Syndromes
Acute coronary syndromes (ACS) is a term that encompasses:
- Unstable angina (UA),
- Non-ST-segment elevation myocardial infarction (NSTEMI), and
- ST-segment elevation myocardial infarction (STEMI).
While all three usually result from atherosclerotic plaque rupture and subsequent thrombus formation in one of the main epicardial coronary arteries, with subsequent inadequate blood supply to meet the oxygen and metabolic demands of the myocardium. Other possible etiologies of this imbalance such as coronary artery narrowing alone, coronary spasm, or coronary dissection.
Unstable angina, NSTEMI and STEMI are distinguished pathophysiologically as to whether or not the thrombus is occlusive (as in the case of STEMI) or non-occlusive (as in the case of UA and NSTEMI).
- If an electrocardiogram (EKG) is performed at the time that an occlusive coronary artery thrombus is formed, it will usually show ST-segment elevation in the leads which correspond to the territory of myocardium in which blood supply has been disrupted (see Electrocardiogram).
- If an EKG is performed at the time that a non-occlusive thrombus is formed, it may or may not show signs of ischemia (see Electrocardiogram).
Frequently, Unstable Angina and NSTEMI are indistinguishable on inital evaluation as these two conditions are at different spectrums of ischemia.  If the ischemia is significant to cause myocardial damage, there will be an elevation of Cardiac biomarkers (CK-MB or troponin) and would be classified as an NSTEMI (see Biomarkers).  Often, these may not be detected for up to 12 hours in the bloodstream, which emphasizes the need for thorough evaluation.

# Definition

### Unstable Angina
Unstable angina is defined as new onset angina pectoris (or chest pain which is ischemic in origin) with the following features: a) occurs at rest or with lesser degrees of exertion than stable angina, b) lasts less than 30minutes, c) follows a crescendo pattern (i.e., occurs more frequently than previous), and d) there no sign of myocardial necrosis unlike in STEMI or NSTEMI, and there is no release of biomarkers of myonecrosis (CK or troponin).             

### Non ST Elevation Myocardial Infarction
Non-ST Elevation MI (NSTEMI) presents with clinical features of UA along with the evidence of myocardial necrosis like elevated serum levels of cardiac biomarkers (i.e., creatine kinase (CK), MB isoenzyme of CK (CK-MB) and Troponins I and T). Troponins are fairly sensitive and specific for myocardial necrosis. For the diagnosis of NSTEMI to be made, the troponin elevation must occur in the context of ischemic chest pain, however the diagnosis should not be made based on laboratory findings alone, as there are other possible etiologies for elevated troponins. 

# Classification
Braunwald in 1989 proposed a classification for unstable angina based on severity and clinical circumstances.  This classification was employed in various clinical trials and studies to determine its prognostic importance and clinical usefulness.  In recent years with the more detailed understanding of the pathophysiology of unstable angina and the discovery of improved markers of myocardial injury, acute phase proteins and hemostatic markers, especially cardiac troponin I and troponin T, it was suggested to extend Class IIIB (angina at rest within the past 48 hrs) of the original classification, by subclassifying it into troponin negative and troponin positive patients.

# Pathophysiology

### Unstable Angina
Unstable angina occurs when myocardial oxygen demand exceeds myocardial oxygen supply at rest or with minimal exertion. This supply/demand mismatch can be caused by conditions that increase oxygen demand or reduce oxygen supply.

### Non ST Elevation Myocardial Infarction
As alluded to in prior sections, unstable angina and NSTEMI are at different ends of the spectrum of the same disease.  While there is no way to determine which patients presenting with unstable angina will ultimately progress to NSTEMI, the distinction between the two entities is clear.   Often, for patients presenting prior to the four hour window before cardiac biomarkers are positive (namely CK-MB), the EKG in context of the patient's chest pain will be marker for whether patient has STEMI versus UA/NSTEMI and needs to urgently undergo percutaneous revascularization.

# Epidemiology and Demographics
Over 9 million patients in the United States alone have angina. An estimated 80,700,000 American adults (one in three) have one or more types of cardiovascular disease (CVD), of whom 38,200,000 are estimated to be age 60 or older. Except as noted, the estimates were extrapolated to the U.S. population in 2005 from NHANES 19992004.

# Risk Stratification
There are several scoring systems which have been devised as methods of identifying high-risk patients presenting with acute coronary syndrome (ACS).  These include, among others, the Braunwald classification system, the Rizik classification system, the TIMI risk score, the GRACE risk score  and the PURSUIT risk score. This evaluation is helpful in selecting the site of care and type of therapy. Physician should document their opinion of the likelihood of ACS in one of the three categories of low, intermediate or high likelihood. Patients with high risk score and/or hemodynamic instability should be managed in coronary care unit while those with intermediate to low risk score and hemodynamic stability can be managed in a step down unit. A continuous ECG monitoring (telemetry) should be used to monitor for arrythmias. Patients with UA have lower short term mortality than NSTEMI or STEMI. Early risk stratification is, therefore, recommended and is based on the initial history, physical exam, ECG, assessment of renal function and cardiac biomarkers.

# Natural History, Complications and Prognosis
Unstable angina / NSTEMI are signs of more severe heart disease.  Natural history is complicated by the development of arrhythmias and heart failure.  In a study it was shown that 14% of the cases of unstable angina can progress to MI.  Sudden death is an infrequent sequel of both UA and NSTEMI.

# Special Groups

## Women
Although women are traditionally at lower risk for CAD as compared to men at all ages, UA/NSTEMI is still common amongst this group and importantly, women can manifest CAD somewhat differently than men. It is also important to keep in mind that women with CAD are, on average, older than men and are more likely to have comorbidities such as hypertension, diabetes mellitus, and heart failure with preserved systolic function; to manifest angina rather than MI; and, to have atypical symptoms of angina and MI.

## Diabetic Patients
75% of all deaths among diabetic patients are due to coronary artery disease.  Diabetic patients with unstable angina or NSTEMI tend to have a more severe disease with worse outcomes.  Long term morbidity and mortality in diabetic patients with no previous cardiovascular disease are the same as that of nondiabetic patients with established cardiovascular disease after hospitalization for unstable coronary artery disease.

## Post-CABG Patients
Post-CABG patients with unstable angina or NSTEMI are associated with a more severe coronary artery disease compared to the patients who have not undergone a bypass surgery.  Medical treatment in this patient population should follow the same guidelines as for UA/NSTEMI in nonpost CABG patients.

## Elderly
Elderly patients represent a group of patients who have more comorbidities and who are both at risk for both CAD as well as for associated complications. However, they do derive equivalent or greater benefit from intervention when compared to younger patients. This group is likely to present with atypical symptoms like dyspnea and confusion rather than chest pain. 
On the other hand, presence of noncardiac comorbidities such as chronic obstructive lung disease, gastroesophageal reflux disease, upper-body musculoskeletal symptoms, pulmonary embolism, and pneumonia is also higher, thus making the diagnosis of UA/NSTEMI challenging. 
Secondly, they are more likely to have altered or abnormal cardiovascular anatomy, increased cardiac afterload due to decreased arterial compliance and arterial hypertension, orthostatic hypotension, cardiac hypertrophy, and ventricular dysfunction, especially diastolic dysfunction. 
Thirdly, elderly patients generally have other cardiac comorbidities and risk factors, such as hypertension, prior MI, HF, cardiac conduction abnormalities, prior CABG, peripheral and cerebrovascular disease, diabetes mellitus, renal insufficiency, and stroke. 
As a result, they are on mulitple medications and hence at risk for drug interactions and polypharmacy. When considering revascularization procedures, general medical and cognitive status, bleeding risk and other risk of interventions, anticipated life expectancy, and patient or family preferences must be considered.

## Chronic Kidney Disease
Chronic kidney disease (CKD) constitutes a risk factor for adverse outcomes after MI. It is a coronary artery disease equivalent as well as a risk factor for progression of CAD.

## Drug and Substance Abusers
Cocaine and methamphetamine are common drugs associated with MI.

## Prinzmetal's Angina
Prinzmetal's angina, also known as variant angina or angina inversa, is chest pain at rest that occurs in periodic cycles. It is unrelated to exertion although can occur with exertion. 
Prinzmetal's angina is caused by vasospasm, a narrowing of the coronary arteries caused by contraction of the smooth muscle tissue in the vessel walls rather than fixed narrowings of the coronary arteries due to atherosclerosis. 
Attacks can be precipitated by an emotional stress, hyperventilation, exercise, or exposure to cold. A circadian variation in the episodes of angina is most often present, with most attacks occurring in the early morning. 
It is characterized by transient ST-segment elevation that spontaneously resolves or resolves with NTG use without progression to MI. The majority of patients have normal exercise tolerance, and stress testing may be negative. 
Because the anginal discomfort usually occurs at rest without a precipitating cause, it may simulate UA/NSTEMI secondary to coronary atherosclerosis.

## Cardiovascular Syndrome X
Cardiovascular syndrome X refers to patients with angina or angina-like discomfort with exercise, ST-segment depression on exercise testing, and normal or nonobstructed coronary arteries on angiography.  This entity should be differentiated from the metabolic syndrome X or metabolic syndrome, which describes patients with insulin resistance, hyperinsulinemia, dyslipidemia, hypertension, and abdominal obesity.  It also should be differentiated from noncardiac chest pain.

# Diagnosis

## History and Symptoms
A person with unstable angina pectoris (UAP) will have a history of angina that has increased in frequency or intensity at the same level of exertion. Anginal pain can manifest in many forms ranging from chest pain to chest pressure to shortness of breath to epigastric pain. UAP is part of the spectrum of acute coronary syndromes (ACS) and requires immediate assessment and management by a qualified physician. The history and symptoms described by a patient with unstable angina can be identical to the symptoms of either NSTEMI or STEMI, both of which carry a poorer prognosis.

### Unstable Angina
UA can have typical or atypical presentations. The 3 classic forms of presentation are: a) Rest angina (angina commencing when the patient is at rest); b) New onset (less than 2 months) severe angina (at least CCS class II); or c) Increasing angina-previously diagnosed angina that has become distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by 1 or more CCS class to at least CCS class III severity).

### Non ST Elevation Myocardial Infarction
NSTEMI generally presents as prolonged, more intense rest angina or angina equivalent. Patients with suspected ACS must be evaluated rapidly. Evaluation should not be done over the phone but in person and in a place where a 12 lead ECG can be obtained. A focused history, examination, ECG and cardiac biomarkers are helpful to determine where the patient will be managed and whether the patient needs to be transferred or referred to a different hospital/setting. Physical examination should focus on identifying the precipitating factors, comorbid conditions, rule out alternative diagnosis and assess hemodynamic status of the patient.

## Physical Examination
Patients with suspected ACS must be evaluated rapidly. The objectives of the initial evaluation are first to identify signs of immediate life-threatening instability and then to ensure that the patient is moved rapidly to the most appropriate setting for the level of care needed based on diagnostic criteria and an estimation of the need for intervention. It is recommended that patients with a suspected ACS with chest discomfort or other ischemic symptoms at rest for more than 20 min, hemodynamic instability, or recent syncope or presyncope to be referred immediately to an ED or a specialized chest pain unit.

## Laboratory Findings

### Blood Studies
Laboratory findings for the diagnosis of unstable angina and NSTEMI include some baseline tests like complete blood count, electrolytes, serum creatinine and measurement of acute-phase proteins.

### Biomarkers
Cardiac markers are biomarkers that are measured to evaluate heart function.  Their levels increase in blood when the heart muscle is necrosed, as in MI. Clinically the most commonly used  cardiac markers include troponins and creatine kinase-MB (CK-MB).  Other markers are lactate dehydrogenase, aspartate transaminase, myoglobin, ischemia modified albumin, pro-brain natriuretic peptide and glycogen phosphorylase isoenzyme.  Cardiac biomarker measurement is one of the initial tests in a patient with heart attack. Unstable angina is associated with negative cardiac biomarkers whereas NSTEMI is associated with elevated cardiac biomarkers.

## Electrocardiogram
The EKG in patients with unstable angina can be variable. In some cases, no changes on EKG will be appreciated. In other cases, a resting EKG may show flipped or inverted T waves, ST segment depression, or non-specific ST-T changes.  It is the first line of assessment in any patient suspected of having unstable angina.

## Chest X-Ray
When suspecting UA/NSTEMI a chest X-ray is critical to aid in the exclusion of aortic dissection.  A mediastinal mass consistent with a cancer may be present, but it is unlikely to present with a syndrome of accelerating chest pain.  It is also used to evaluate other causes of chest pain or discomfort like pulmonary infection, pneumothorax, pulmonary hypertension etc.

## Echocardiogram
Left ventricular function and wall motion abnormalities can be assessed promptly using an echocardiogram.  It can also be used to exclude other possible causes of like aortic stenosis and hypertrophic obstructive cardiomyopathy.  Valvular or mechanical complications from MI warrant an immediate transesophageal echocardiography.

## Coronary Angiography
One other image modality that can be used in diagnosing and treating UA/NSTEMI is CT coronary angiography. This is a superior imaging technique with a sensitivity and specificity of 90% and 95% respectively. Depending on the patient's symptoms and degree of suspicion for ACS, early coronary angiography can be performed to make a definitive diagnosis. If there is no evidence of either calcified or noncalcified plaque on coronary angiogram, then it is highly unlikely that the patients symptoms are due to UA/NSTEMI.

# Treatment

## Primary Prevention
Major risk factors for development of coronary heart disease have been established from several long term epidemiological studies.  Various clinical trials have demonstrated that development of coronary diseases can be prevented or the risk of experiencing UA/NSTEMI in patients who have coronary heart disease can be lowered by modifying the main risk factors.

## Immediate Management
Initial management of acute coronary syndrome (ACS) begins with differentiating between the spectrum of ACS which includes STEMI, unstable angina and Non-ST Elevation Myocardial Infarction. Because the symptoms for all these can be similar, a medical evaluation is necessary as mentioned in other sections (see  Pre-hospital Care and  Initial Therapy). Information from the history, physical examination, 12-lead ECG, and initial cardiac biomarker tests can help in differentiating between the above three categories as well as categorize the patient into probable or definite ACS, chronic stable angina or non-cardiac cause of chest pain. Patients with STEMI must be evaluated for immediate reperfusion therapy (see Reperfusion Therapy (Overview of Fibrinolysis and Primary PCI)). Patients with unstable angina/NSTEMI, recurrent symptoms suggestive of ACS and/or electrocardiogram ST-segment deviations, or positive cardiac biomarkers who are hemodynamically stable should be admitted to an inpatient unit for bed rest with continuous rhythm monitoring and careful observation for recurrent ischemia and managed with either an invasive or conservative strategy (see initial conservative versus initial invasive strategies). Immediate management is directed towards relief of chest pain. Nitrates, ASA and morphine are recommended to control the symptoms from possible ACS. Beta blockers, thienopyridines (like clopidogrel and prasugrel) should be administered in the absence of contraindication to their use. Based on the suspicion for likelihood of ACS, anticoagulants and GP IIb/IIIa inhibitors can be started early in the course of presentation. Two strategies in the treatment are early invasive or conservative strategies. Most trials have shown benefit of early invasive therapy with cardiac catheterization and revascularisation procedures. Early invasive therapy is now recommended for patients with UA/NSTEMI and ST segment changes at presentation and/or positive troponins during first 24hrs of presentation.

## Antithrombin Therapy
Anticoagulation, traditionally with unfractionated heparin (UFH), is a cornerstone of therapy for patients with unstable angina/NSTEMI. 
Some of the agents available in this category include unfractionated heparin, low molecular weight heparin, direct thrombin Inhibitors (e.g.,bivalirudin) factor Xa Inhibitors (e.g.,fondaparinux),  and warfarin. These agents are also sometimes referred to as antithrombins, although, it should be noted that they often inhibit one or more proteins in the coagulation cascade before thrombin.

## Antiplatelet Agents

### Aspirin
Antiplatelet therapy plays a major role in the management of unstable angina/NSTEMI. This class of medication is directed towards one of the following three pathways: decreasing thromboxane A2 formation (aspirin), inhibiting the P2Y12 component of the adenosine diphosphate (ADP) receptor pathway (thienopyridines), direct inhibitors of platelet aggregation (GP IIb/IIIa inhibitors).

### Thienopyridines
Thienopyridines are a class of drugs that inhibit ADP receptor/P2Y 12 and function as antiplatelet agents.

### Glycoprotein IIb/IIIa Inhibitor
Glycoprotein IIb/IIIa (Gp IIb/IIIa) is an integrin complex present on the surface of the platelets.  This complex aids in platelet aggregation during the clotting process by acting as a receptor for fibrinogen.  Gp IIb/IIIa inhibitors are a class of antiplatelet agents that prevent platelet aggregation and thrombus formation by inhibiting the integrin complex.

## Mechanical Reperfusion

### Initial Conservative Versus Initial Invasive Strategies
Two approaches to the use of cardiac catheterization and revascularization in UA/NSTEMI include an initial invasive strategy, involving routine early cardiac catheterization and revascularization with percutaneous coronary intervention (PCI) or coronary bypass grafting (CABG) and a second more conservative approach with initial medical management with catheterization and revascularization only for recurrent ischemia either at rest or on a noninvasive stress test.  The objective of this is to provide a strategy that has the most potential to yield the best clinical outcome and improve long-term prognosis.

### PCI
Coronary angiography is useful for defining the coronary artery anatomy in patients with UA/NSTEMI and for identifying subsets of high-risk patients who can benefit from early revascularization. The benefits of early invasive strategy have been discussed in previous section (see  Initial Conservative Versus Initial Invasive Strategies).  Coronary revascularization with either PCI or CABG helps improve prognosis, relieve symptoms, prevent ischemic complications, and improve functional capacity. In recent years, increased utilization of PCI has been noticed mainly secondary to technical advancements and as a result of this, less complications associated with the procedure.

### CABG
For patients with UA/NSTEMI, when revascularization is required, the choice is between PCI and CABG. In general, the indications for PCI and CABG in UA/NSTEMI are similar to those for stable angina. Based on the results of multiple randomized trials, CABG is recommended for patients with disease of the left main coronary artery and multivessel disease and impaired left ventricular function. However, recent advance in techniques and less complications with PCI have led to use of PCI for isolated left main disease.

## Complications of Bleeding and Transfusion
Advancements in the efficacy and increased utilization of synergistic anti-platelet agents, anticoagulant therapies, and invasive risk stratification in high-risk patients with unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) has led to a 40% decrease in mortality from coronary artery disease (CAD) over the preceding 20 years.  The advanced management of NSTEMI minimizes ischemic events; however the paradigm is that it also increases the risk of bleeding and necessitation for blood transfusion. Recent analyses and randomized controlled trials demonstrate an independent association between bleeding complications, blood transfusions, and poor outcomes among NSTEMI patients. Clinical trials of antithrombotic therapies associated with decreased bleeding complications have demonstrated improvements in short-term and long-term survival.

## Discharge Care

### Medical Regimen
In most cases, the inpatient anti-ischemic medical regimen used in the nonintensive phase should be continued after discharge, and the antiplatelet/anticoagulant medications should be changed to an outpatient/oral regimen. The selection of a medical regimen should be individualized to the specific needs of each patient based on the in-hospital findings and events, the risk factors for CAD, drug tolerability, and recent procedural interventions.

### Post-Discharge Follow-Up
Patients with UA/NSTEMI, specially those with high risk factors during hospital stay, have high mortality which can be as high as 14 fold compared to those with absence of risk factors.

## Long-Term Medical Therapy and Secondary Prevention
Similar to patients with STEMI, patients with UA/NSTEMI also require secondary prevention at the time of discharge. Patients and their families should be educated regarding the specific targets for LDL cholesterol and HDL cholesterol, blood pressure, body mass index (BMI), physical activity, and other appropriate lifestyle modifications.