Unstable Angina and NSTEMI:
Tailoring Treatment Based on Risk

Emerg Med 36(11):20-38, 2004

For the best outcome in high-risk patients with unstable angina and non-ST-segment-elevation myocardial infarction, the consensus has moved to early and aggressive intervention. The authors discuss identification and management of these patients as well as the management of those at lesser risk.

By Eve Kaiyala, MD, and Deborah B. Diercks, MD

Coronary artery disease (CAD) is the most common cause of cardiovascular disability and death in the United States. Approximately 1.8 million Americans experience acute coronary syndrome (ACS) annually. Of these, 450,000 are admitted through the emergency department for acute myocardial infarction (AMI). In addition, there are approximately 1.4 million hospital admissions annually in the United States for patients with unstable angina (UA) or non-ST- segment-elevation MI (NSTEMI). For patients with UA/NSTEMI, the risk of cardiovascular death or AMI is 6% to 8% during both the initial hospitalization and the following two years.

Studies have shown that emergent evaluation of UA/NSTEMI patients can stratify them into low- and high-risk groups. It is important to manage high-risk patients aggressively to reduce adverse outcomes such as recurrent ischemia, reinfarction, and death.

Complications of MI include arrhythmias (75% to 95% of patients), congestive heart failure (CHF, 60%), cardiogenic shock (10%), ventricular rupture within the first 10 days (1% to 5%), papillary muscle infarction (rare), ventricular aneurysm (rare), reinfarction (5%), and mural thrombosis (rare) with a risk of peripheral embolization. Overall mortality in the first year is 35%, followed by 5% to 10% per year.
 

PATHOPHYSIOLOGY OF CAD

Coronary artery disease is a spectrum of ischemia- related syndromes encompassing a range of diseases from angina to ST-elevation MI. Ischemia can be caused by reduced coronary blood flow, increased myocardial demand, or hypoxia due to diminished oxygen transport. At the core of the disease process is atherosclerotic plaque and platelet aggregation.

Angina is characterized by pain or discomfort due to ischemia without frank infarction. It has three patterns: stable, Prinzmetal's, and unstable. Angina typically reflects fixed plaque and is characterized by chest pain with exertion that is relieved by rest; increased oxygen demand is the most common underlying cause. Prinzmetal's angina indicates coronary artery spasm and resulting ischemia. Unstable angina is defined as anginal symptoms at rest, increasingly frequent anginal symptoms, and new-onset angina.

Unstable angina and MI are usually caused by plaque rupture, platelet plugging, and thrombus formation. Myocardial infarction represents the death of cardiac muscle cells; it may be transmural or subendocardial. A transmural infarct involves the full thickness of the myocardial wall and is usually caused by acute plaque disruption with superimposed occlusive thrombosis. A subendocardial infarct is in an area of normally diminished perfusion—the inner one-third to one-half of the ventricular wall. These infarcts are typically a result of global atherosclerosis that leads to global borderline perfusion. The critical point is reached by increased oxygen demand, vasospasm, or hypotension without superimposed thrombosis. The myocardial injury is therefore multifocal.

Platelet aggregation and activation are central mechanisms in the pathophysiology of ACS. Platelets are activated when vessel wall endothelium is damaged, exposing collagen in the arterial subendothelial matrix. This causes platelet deregulation and a change in conformation in the endothelial cell. More platelets are attracted to the site by chemoattractant agents. Various agents are involved in platelet activation. These include thromboxane A₂, collagen, and adenosine diphosphate (ADP). By binding to surface receptors on neighboring platelets, ADP amplifies the cyclical process of platelet activation and degranulation.

Ultimately, glycoprotein IIb/IIIa receptors are activated, which then bind fibrinogen and von Willebrand factor, promoting platelet crosslinking and subsequent thrombus formation. Cyclo-oxygenase activation in platelets results in thromboxane A₂ release, which further activates neighboring platelets. Coagulation pathway products convert prothrombin to thrombin, which converts fibrinogen to fibrin and further stabilizes the clot. There are a number of medications used to treat UA/NSTEMI that target each of these steps, which we will discuss.

Treatment of CAD depends on the patient's condition and where it falls along the ACS spectrum and the risk for adverse events. While patients with STEMI need to be immediately reperfused, patients with UA/NSTEMI are treated according to the risk for adverse events. In this article, we will focus on the diagnosis and treatment of UA/NSTEMI.
 

DIAGNOSTIC CONSIDERATIONS

Diagnosis of ACS requires an accurate and thorough patient history, physical examination, laboratory values, and ECG interpretation. Patients with ACS may present in a variety of ways. The most common chief complaint is chest discomfort. This may be described as burning, tightness, squeezing, or heaviness, and may be dull, sharp, or stabbing in character. It may radiate to the jaw, neck, left shoulder, or arm. The pain is transmitted via visceral pathways and thus is difficult to localize.

Chest pain in ACS is typically sudden in onset and becomes more intense over time. Depending on the patient's place on the spectrum of the disease, the pain may resolve with rest and worsen with exertion or require medical intervention for resolution. Patients with AMI typically have symptoms for at least 30 minutes. Associated symptoms include nausea, vomiting, diaphoresis, palpitations, or shortness of breath.

Traditional risk factors for CAD include hypertension, diabetes mellitus, hyperlipidemia, elevated blood homocysteine levels, hypoestrogenemia in women, positive family history (when onset is before age 50), age, male gender, and cigarette smoking.

For patients with UA/NSTEMI, the physical examination is typically normal and thus not helpful in distinguishing either condition from other causes of chest pain. Findings of heart dysfunction that are helpful include a soft S₁, a paradoxically split S₂, an S₃ or S₄ (or both), a palpable precordial systolic bulge, and bibasilar rales. A thorough vascular exam is useful; evidence of vascular disease increases the risk of concurrent CAD.

An ECG is often used to screen patients for ACS when they present with chest pain. Findings consistent with UA/NSTEMI include ST-segment depression of 1 mm or more or T-wave inversion in two contiguous limb or precordial leads. About one-third of patients with these changes will have non-Q-wave MI. It is important to obtain serial ECGs, particularly with and without pain to check for dynamic changes.

A chest x-ray should be obtained to evaluate for other potential causes of chest pain such as pneumothorax, pneumonia, or a widened mediastinum that suggests an aortic dissection. Other findings may include cardiomegaly or signs of left ventricular dysfunction such as pulmonary venous hypertension, Kerley B lines, and pleural effusions.

Laboratory evaluation determines if cardiac biomarkers were released into the blood during myocardial ischemia. The most common are the proteins troponin I and T, the enzyme creatine kinase (CK) and its myocardial subunit (CK-MB), and myoglobin. The cardiac troponins I and T are very specific for myocardial tissue. Elevated levels of these proteins are seen at 4 to 6 hours after infarction and peak at 12 hours. Levels remain elevated for 3 to 10 days. Creatine kinase and CK-MB are detectable four to six hours after acute infarction and peak values are seen at 12 to 18 hours. Values normalize at 24 to 36 hours. Because CK and CK-MB are also found in skeletal muscle, levels may be elevated after vigorous exercise, rhabdomyolysis, skeletal muscle trauma, dermatomyositis or polymyositis, renal failure, and cardiac contusion. Myoglobin is a non-specific marker for muscle injury and is detectable in the serum two to four hours after infarction.

A single measurement of cardiac markers has a low sensitivity (30% to 40%) in ruling out AMI. Therefore, serial measurements should be taken at intervals of three to six hours. In general, sensitivity increases over time. Specificity remains constant over time at approximately 90%.
 

RISK STRATIFICATION

Various methods of risk stratification have been developed for patients with UA/NSTEMI. The TIMI Risk Score is one of the most widely accepted. The score predicts the risk of death or reinfarction and the need for urgent target-vessel revascularization (see box). As the patient's score increases from 0-1 to 6-7, the risk of death or reinfarction or the need for revascularization within 14 days rises from 4.7% to 40.9%.

Boersema analyzed the baseline characteristics of patients in the emergency department in relation to risk of death and death plus MI at 30 days. That analysis, known as the Boersema Score, found that the most important factors associated with death were age, pulse rate, systolic blood pressure, ST-segment depression, signs of pump failure, and increased levels of biomarkers.

Although risk stratification systems such as the TIMI and Boersema scores are helpful, their use in the clinical setting may be impractical. Objective data, such as an ECG with ST-segment depression, elevated troponin I levels, and angina refractory to medications, are more routinely used to identify high-risk patients.
 

TREATMENT GUIDELINES

All patients being evaluated for ACS should have a large-bore IV line inserted and should be placed on a cardiac monitor. Hypertension and tachycardia should be controlled. Patients should be treated with oxygen, morphine, beta blockers, nitrates, and aspirin.

Further therapy depends on risk stratification and where on the spectrum of ACS the patient falls (see algorithm below). Current therapeutic interventions include antiplatelet and antithrombin agents. For patients with UA/NSTEMI, current guidelines from the American Heart Association (AHA) and the American College of Cardiology (ACC) recommend aspirin (or clopidogrel if aspirin is contraindicated), heparin, and a glycoprotein IIb/IIIa inhibitor. When possible, high-risk patients should be managed with diagnostic coronary angiography followed by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery as indicated.

We will now take a closer look at some of the key interventions.

Supplemental oxygen. Although oxygen is routinely given to patients with suspected ACS, no long-term benefit has been shown. It is important that patients receive only two to four liters of oxygen via nasal cannula; higher levels may cause constriction of blood vessels and worsen ischemia. The benefit of oxygen in high-risk patients with UA/NSTEMI has not been proven.

Morphine. The effectiveness of morphine has yet to be evaluated in clinical trials. Its analgesic and anxiolytic effects may be beneficial; it may also decrease afterload through venodilation. Morphine may be used when nitrates do not relieve pain and while other medications are being initiated.

Beta blockers. Beta blockers have antiarrhythmic, anti-ischemic, and antihypertensive properties. They decrease myocardial oxygen demand by decreasing heart rate, systemic arterial pressure, and myocardial contractility. Therapy with intravenous (IV) metoprolol or esmolol should be initiated in the emergency department. Metoprolol is administered by IV push in three doses of 5 mg each. This should be followed by oral metoprolol, 25 to 50 mg immediately, then every 6 to 8 hours. Esmolol is a very short-acting agent that is administered as an IV bolus of 500 mcg/kg, followed by a continuous infusion of 50 to 200 mcg/kg/min.

Use of these agents should be avoided in patients with evidence of large or multiple old infarctions, bronchospastic disease, and bradyarrhythmias. Adverse effects include bradycardia, CHF, and atrioventricular blockade. Patients with airway disease may have asthma exacerbations.

For patients with AMI, beta blockers reduce chest pain, wall stress, infarct size, incidence of cardiovascular complications, and mortality rate (in patients not treated with fibrinolytics). Beta blockers have been shown to prolong life in patients with CAD after MI. Fewer studies have been done on patients with UA/NSTEMI.

Currently, the AHA/ACC guidelines recommend early treatment with beta blockers in all patients with UA/NSTEMI, unless contraindicated.

Nitrates. Nitroglycerin is denitrated in smooth muscle cells, releasing nitric oxide and ultimately relaxing smooth muscle cells in arteries, arterioles, and veins. Smooth muscle cell relaxation leads to peripheral venodilation, reducing preload and in turn decreasing cardiac output and heart size. Afterload reduction via arteriolar dilation may also contribute to these effects, but it is thought that the veins are most sensitive to nitrates. Overall, cardiac work and myocardial oxygen consumption are decreased. Nitroglycerin also has a direct vasodilator effect on the coronary vascular bed, increasing myocardial blood flow.

Rapid treatment with a sublingual nitroglycerin tablet or spray or nitroglycerin ointment usually is sufficient in patients with UA/NSTEMI. In cases of refractory angina, an IV infusion of nitroglycerin is recommended. Doses are titrated to pain relief, with careful monitoring of blood pressure. Nitroglycerin's adverse effects include hypotension, which may lead to reflex tachycardia and worsening ischemia.

Patients with right ventricular infarction are volume-dependent. Because nitrates reduce preload, they commonly cause hypotension, which is associated with an increase in infarct size in this population. One-third of patients with inferior infarctions have right ventricular involvement, so caution must be used in administering nitrates to these patients.

Several clinical trials have shown benefits in administering nitroglycerin to AMI patients not treated with thrombolytics. These trials found a reduction in infarct size, decreased rate of cardiovascular complications, and improved regional function. In these trials, nitroglycerin was titrated to blood pressure control, not symptom relief. In normotensive patients, mean arterial pressure decreased 10%; in hypertensive patients, it decreased 30%. Only small studies have evaluated the use of nitrates in UA/NSTEMI. Practice is based largely on clinical experience.

Currently, the AHA/ACC guidelines recommend IV nitroglycerin for the first 24 to 48 hours for patients with AMI and recurrent ischemia, CHF, or hypertension. Guidelines from the Agency for Health Care Policy and Research recommend one sublingual nitroglycerin tablet every five minutes up to three times for patients with UA/NSTEMI, followed by IV nitroglycerin for patients who are not responsive to the initial therapy. This should be given concomitantly with beta blockers.
 

ANTIPLATELET AGENTS

The choice of antiplatelet agents used in patients with UA/NSTEMI is directed by both the syndrome and management. In general, high-risk ACS patients should be treated with early invasive management, and lower-risk patients with conservative management in conjunction with invasive management if indicated.

Aspirin. Aspirin inhibits thromboxane synthesis by irreversibly inactivating the enzyme cyclo-oxygenase, reducing the synthesis of prostaglandins and thromboxane. Prostaglandins play a key role in inflammation, while thromboxane is central to platelet activation. Platelets are inactivated for the duration of aspirin therapy because they lack the mechanism to synthesize new protein. The effect of aspirin on smooth muscle cells is temporary; these cells can produce new protein.

Proper aspirin dosing is 160 to 325 mg orally. Doses of 160 mg or more cause immediate and nearly complete inhibition of thromboxane A2. Lesser doses may be effective for long-term prophylaxis but may not be as effective in the acute setting. Side effects of aspirin are dose-dependent and include gastrointestinal toxicity and increased risk of bleeding.

Aspirin should be given immediately to all patients with ACS who can tolerate the medication. The drug should be withheld from patients with aspirin allergy or active peptic ulcer disease.

Adenosine diphosphate receptor antagonists. Adenosine diphosphate receptor antagonists function by specifically and irreversibly blocking platelet activation and aggregation. Specifically, they prevent ADP-induced fibrinogen from binding to glycoprotein IIb/IIIa receptors.

Two ADP receptor antagonists currently used in the United States are ticlopidine and clopidogrel. Ticlopidine takes effect in 24 to 48 hours. In patients with UA/NSTEMI, it is effective in reducing vascular death and AMI at six months. Adverse effects include neutropenia.

Clopidogrel has a more rapid onset and is preferred in the acute setting; full and irreversible effects are reached within two hours. The drug is administered as a loading dose of 300 mg, followed by 75 mg daily. This medication has proved most beneficial in patients undergoing PCI. The most common adverse effects are gastrointestinal upset and rash. Use of clopidogrel is contraindicated in patients with active bleeding. Caution should be used in patients with a significant risk for bleeding complications.

In the CURE trial, 12,562 patients with UA/NSTEMI who were taking aspirin were randomized to receive clopidogrel (300-mg loading dose, followed by 75-mg daily doses) or placebo. The study showed that the combination of aspirin and clopidogrel improved outcomes in patients with UA/NSTEMI but increased the risk of adverse events such as bleeding.

Current AHA/ACC guidelines recommend that hospitalized patients for whom a noninterventional approach is planned should receive clopidogrel on admission and should continue on the medication for one to nine months. In patients who will undergo CABG surgery, clopidogrel should be withheld for at least five days or preferably one week. In patients who will undergo PCI within 24 to 36 hours, consideration should be given to withholding clopidogrel because the coronary anatomy has not yet been defined and thus the need for CABG surgery is not known.

Glycoprotein IIb/IIIa inhibitors. The common pathway for platelet aggregation and thrombus formation is the expression of glycoprotein IIb/IIIa and the crosslinking of its platelet receptors by fibrinogen molecules. Glycoprotein IIb/IIIa inhibitors function by occupying the platelet receptors, preventing fibrinogen from binding to platelets and blocking platelet-to-platelet linking and thus platelet aggregation.

Three glycoprotein IIb/IIIa inhibitors are available: abciximab, tirofiban, and eptifibatide. All require a 48- to 72-hour infusion to show a benefit. A number of large trials have evaluated glycoprotein IIb/IIIa inhibitors for use in patients with UA or non-Q-wave AMI. The main adverse effect is an increased risk of bleeding, as much as two to three times that seen with placebo in early trials.

In the PRISM study, 3,232 patients were randomized to treatment with IV tirofiban or heparin for 48 hours in addition to the aspirin they were already taking. The endpoints of death, AMI, or refractory ischemia at 48 hours was 32% lower in the tirofiban group. There was a reduction in the mortality rate up to 30 days.

The PRISM-PLUS study evaluated patients with prolonged anginal pain or repetitive episodes of angina, at rest or during minimal exercise in the previous 12 hours, who also had new transient or persistent ST-T ischemic changes. The study included 1915 patients who were randomized to tirofiban, heparin, or both, for three days. Patients receiving the combination therapy had a reduction in the end points of death, AMI, or refractory ischemia at seven days. Their rate of AMI and death was lower for a six-month period. In contrast to the PRISM results, patients in this study who received tirofiban alone had an increased rate of cardiovascular events.

In the PURSUIT trial, 10,948 patients were randomized to receive a bolus dose of eptifibatide followed by infusion or placebo for up to three days. Eptifibatide showed a 10% relative reduction in death and AMI that was seen at four days and lasted to 30 days. The GUSTO IV-ACS trial evaluated a group of 7,800 patients with UA/NSTEMI who were admitted and did not undergo coronary intervention within 48 hours. All patients received aspirin and unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) and were randomized to receive abciximab bolus, abxicimab infusion, or placebo. At 30 days there was no difference in the rates of death and AMI.

The CAPTURE study evaluated 1,265 patients with refractory UA undergoing percutaneous transthoracic coronary angioplasty (PTCA). The patients were randomized to abciximab or placebo for 18 to 24 hours prior to PTCA and continuing until one hour afterward. The primary endpoints of death (from any cause), AMI, or urgent intervention for recurrent ischemia occurred in 11.3% of patients in the abciximab group, compared to 15.9% in the placebo group. Major bleeding occurred more often in the abciximab group (3.8% vs 1.9%). At six-month follow-ups, the rate of death, AMI, or repeat intervention was equal in the two groups.

A meta-analysis by Boersema and colleagues of six smaller randomized placebo-controlled trials evaluating the use of glycoprotein IIb/IIIa inhibitors in ACS found a slight reduction in the combination endpoints of death and AMI. However, there was no difference when the endpoints were evaluated individually. Overall, they recommended that glycoprotein IIb/IIIa inhibitors should be administered to patients undergoing PCI, since a modest benefit has been found in that group. The benefit in patients who do not undergo PCI is questionable.

Current AHA/ACC guidelines for patients with high-risk UA/NSTEMI recommend that a glycoprotein IIb/IIIa inhibitor should be administered, in addition to aspirin and heparin, to patients who will undergo catheterization and PCI.
 

ANTITHROMBIN THERAPY

Anticoagulants such as heparin reduce the formation of fibrin clots by inhibiting thrombin. Thrombin converts soluble fibrinogen to insoluble fibrin and activates coagulation factors V and VIII, which have positive feedback on coagulation through the prothrombinase complex. It also activates factor XIII, which promotes fibrin crosslinking and stabilizes thrombus formation.

Unfractionated heparin consists of a variety of molecules with molecular weights ranging from 2,000 to 20,000. The different-sized molecules exert different effects on the coagulation system. Heparin binds to and activates antithrombin III; this complex inactivates thrombin and factor X. Activated thrombin III inhibits the coagulation factors 1000 times faster than without heparin.

Heparin's activity is evaluated by monitoring activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT). Onset of activity is immediate. Heparin does not cross the placenta and must be used in pregnant women who need anticoagulation. The bioavailability of heparin is variable and must be closely monitored with laboratory tests and the dose adjusted accordingly. The most common adverse effect is increased bleeding. Regular heparin may cause moderate transient thrombocytopenia; in a few cases, this may be severe.

Low-molecular-weight heparin binds antithrombin III and inhibits factor X but has a lesser effect on thrombin. It is administered as a subcutaneous injection. Compared to UFH, LMWH does not require monitoring, has more predictable kinetics, is less protein-bound, and has a lower potential for inducing platelet activation. Low-molecular-weight heparin has greater bioavailability and a longer duration of action. It is also more convenient to administer, with dosing required only once or twice a day. It has been shown to be as effective as UFH in the treatment of patients with UA/NSTEMI.

In the ESSENCE trial, 3,171 patients with UA and non-Q-wave MI were randomized to treatment with aspirin and either IV UFH or subcutaneous LMWH. The group treated with LMWH had a 15% lower risk of death, AMI, or recurrent angina at 14 and 30 days. The greatest benefit was shown in patients with high TIMI risk scores. There was no increase in major bleeding complications.

The INTERACT trial compared the safety and efficacy of the LMWH enoxaparin to UFH in high-risk patients with non-ST-segment elevation ACS who were receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. The study evaluated 746 patients within 24 hours after onset of symptoms who received enoxaparin subcutaneously or UFH intravenously. All patients also received aspirin. The primary safety outcome—major non-CABG-related bleeding at 96 hours—was significantly lower in the enoxaparin group (1.8% vs 4.6%). Minor bleeding was more frequent in the enoxaparin group (30% versus 20.8%). Death or AMI was significantly lower in the enoxaparin group (5% versus 9%).

Current AHA/ACC guidelines recommend anticoagulation with subcutaneous LMWH or IV UFH in addition to aspirin, clopidogrel, or both. Enoxaparin is preferable to UFH unless CABG surgery is planned within 24 hours. In that case, UFH is preferred because it can be monitored, has a shorter half-life, and has been shown to have fewer bleeding complications.
 

CARDIAC CATHETERIZATION

There have been multiple trials evaluating the benefit of early angioplasty versus conservative treatment for patients with UA/NSTEMI and high-risk features. The most recent trials contradict the results of earlier studies and have shown benefit with early invasive therapy.

The FRISC II and TACTICS-TIMI 18 studies evaluated high-risk patients with UA/NSTEMI, comparing conservative management to early and aggressive intervention. Both showed a benefit with early intervention in this population. In the FRISC II trial, patients were medically managed for a mean of six days with beta blockers, aspirin, nitrates, and an LMWH prior to coronary intervention. The TACTICS-TIMI 18 study evaluated 2,220 patients with UA/NSTEMI who had ST-segment or T-wave changes, elevated levels of cardiac markers, a history of CAD, or all three findings. Patients were randomized to early intervention (catheterization within 48 hours of presentation) or conservative management (catheterization only if the patient had objective evidence of recurrent ischemia or an abnormal stress test). Patients were pretreated for an average of 22 hours with the glycoprotein IIb/IIIa inhibitor tirofiban.

The primary endpoint in the TACTICS-TIMI 18 study was a composite of death, nonfatal MI, and rehospitalization for ACS at six months. The primary endpoint was seen in 15.9% of patients in the early intervention arm and 19.4% of patients in the conservative arm. The rate of death or nonfatal MI at six months was also lower in the early intervention group (7.3% vs 9.5%). In patients without high-risk features, there was no benefit in the two treatment groups at six months. High-risk features were defined as a troponin T level above 0.01 ng/ml, ST-segment deviation, or a TIMI score above 4.

The most recent AHA/ACC guidelines recommend PCI for patients with recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemic therapy, an increased troponin level, or new or presumably new T-segment depression. Intervention is also recommended for recurrent angina/ischemia with symptoms of CHF, an S₃ gallop, pulmonary edema, worsening rales, or new or worsening mitral valve regurgitation. Other indications include high-risk findings on noninvasive stress testing, decreased left ventricular systolic function, hemodynamic instability, sustained ventricular tachycardia, PCI within the previous six months, or a history of CABG surgery.

Patients undergoing PCI should receive supplemental oxygen, morphine, nitrates, a beta blocker, aspirin, and heparin in the emergency department. The AHA/ACC also recommends concurrent treatment with a glycoprotein IIb/IIIa inhibitor.
 

EMERGING THERAPIES

Management of patients with UA/NSTEMI is constantly changing. New studies continually evaluate the benefit of emerging therapies, while clinicians find new uses for old interventions. The risk stratification process also is being refined to better determine which patients should receive the most aggressive therapy. Additionally, there is a new treatment concept that focuses on groups with the greatest benefit-to-harm ratio. Ultimately, patients with UA/NSTEMI and high-risk features should undergo early intervention.

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