UEU-co logo


    Print   Close Window
Note: Large images and tables on this page may necessitate printing in landscape mode.

Copyright © The McGraw-Hill Companies.  All rights reserved.

CURRENT Diagnosis & Treatment in Cardiology > Chapter 4. Unstable Angina/Non-ST Elevation Myocardial Infarction >

Essentials of Diagnosis

  • New or worsening symptoms (angina, pulmonary edema) or signs (electrocardiographic [ECG] changes) of myocardial ischemia.
  • Absence or mild elevation of cardiac enzymes (creatine kinase and its MB fraction or troponin I or T) without prolonged ST segment elevation on ECG.
  • Unstable angina and non-ST elevation myocardial infarction are closely related in pathogenesis and clinical presentation and are therefore discussed as one entity in this chapter.

General Considerations


Unstable angina and non-ST elevation myocardial infarction (USA/NSTEMI) are a part of the wide spectrum of acute coronary syndrome. They are closely related in pathogenesis but with different severity in presentation. Compared with ST elevation myocardial infarction (STEMI), the incidence of USA/NSTEMI has been increasing. In the current era, USA/NSTEMI is the admitting diagnosis for about 40–50% of all admissions to cardiac care units.

Clinical Spectrum

Atherosclerotic coronary artery disease comprises a spectrum of conditions that ranges from a totally asymptomatic state at one end to sudden cardiac death at the other (Table 4–1). It is clear that coronary artery disease, the primary cause of mortality and morbidity in much of the industrialized world, takes its toll through such acute complications (unstable coronary syndromes) as unstable angina, myocardial infarction, acute congestive heart failure, and sudden cardiac death. Also known as acute ischemic syndromes, these are the first clinical expressions of atherosclerotic coronary artery disease in 40–60% of patients with coronary artery disease.

Table 4–1. Clinical Spectrum of Atherosclerotic Coronary Artery Disease.


Subclinical symptoms or asymptomatic


Stable angina


Unstable angina1


Acute myocardial infarction1


Acute pulmonary edema1


Sudden death1

1Acute unstable ischemic syndromes.


Angina pectoris is the symptomatic equivalent of transient myocardial ischemia, which results from a temporary imbalance in the myocardial oxygen demand and supply. Most episodes of myocardial ischemia are generally believed to result from an absolute reduction in regional myocardial blood flow below basal levels, with the subendocardium carrying a greater burden of flow deficit relative to the epicardium, whether triggered by a primary reduction in coronary blood flow or an increase in oxygen demand. As shown in Figure 4–1, the various acute coronary syndromes share a more-or-less common pathophysiologic substrate. The differences in clinical presentation result largely from the differences in the magnitude of coronary occlusion, the duration of the occlusion, the modifying influence of local and systemic blood flow, and the adequacy of coronary collaterals.

Figure 4–1.

Schematic summarizing the current view of the key pathophysiologic events in acute coronary syndromes.

In patients with unstable angina, most episodes of resting ischemia occur without antecedent changes in myocardial oxygen demand but are triggered by primary and episodic reductions in coronary blood flow. Worsening of ischemic symptoms in patients with stable coronary artery disease may be triggered by such obvious extrinsic factors such as severe anemia, thyrotoxicosis, acute tachyarrhythmias, hypotension, and drugs capable of increasing myocardial oxygen demand or coronary steal; in most cases, however, no obvious external trigger can be identified. In these patients—who constitute the majority—the evolution of unstable angina and its clinical complications is the outcome of a complex interplay involving coronary atherosclerotic plaque and resultant stenosis, platelet-fibrin thrombus formation, and abnormal vascular tone.

Unstable Plaque

Several studies have shown that the atherosclerotic plaque responsible for acute unstable coronary syndromes is characterized by a fissure or rupture in its fibrous cap, most frequently at the shoulder region (junction of the normal part of the arterial wall and the plaque-bearing segment). These plaques tend to have relatively thin acellular fibrous caps infiltrated with foam cells or macrophages and eccentric pools of soft and necrotic lipid core. Many clinical and angiographic studies suggest that plaque fissure leading to unstable angina or acute MI may occur not only at sites of severe atherosclerotic stenosis, but even more commonly at minimal coronary stenoses. Serial angiographic observations have shown that development from stable to unstable angina is associated with progression of atherosclerotic disease in 60–75% of patients. This may reflect ongoing episodes of mural thrombosis and incorporation into the underlying plaque. These and other studies have shown that coronary lesions initially occluding less than 75% of the coronary artery area are likely to progress and lead to unstable angina or myocardial infarction; lesions occluding more than 75% are likely to lead to total occlusion. The latter are less likely to lead to myocardial infarction, probably because of the possibility of collateral blood vessel development in more severely stenotic arteries. Furthermore, outward positive remodeling (Glagov effect) of coronary artery segments containing large atherosclerotic plaques may minimize luminal compromise and yet enhance vulnerability for plaque disruption.

Although the precise mechanisms are not known, several hypotheses explain the propensity of plaques to rupture. These include circumferential hemodynamic stresses related to arterial pulse and pressure, intraplaque hemorrhage from small intimal fissures, vasoconstriction, and the twisting and bending of arteries. Other possibilities are inflammatory processes that involve elaboration of matrix-degrading enzymes (collagenase, elastase, stromelysin, cathepsins) released by foam cells or macrophages and other mesenchymal cells in the plaques in response to undefined stimuli (including, but not limited to, oxidized low-density lipoprotein [LDL]). An excess of matrix-degrading enzymatic activity may contribute to loss of collagen in the protective fibrous cap of the plaque, predisposing it to disruption. Similarly reduced synthesis of collagen, resulting from increased death of matrix-synthesizing smooth muscle cells by apoptosis (programmed cell death), may also contribute to plaque disruption. Intracellular pathogens, such as Chlamydophila pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and immune activation have recently been shown to cause inflammatory responses in atherosclerotic plaques and are implicated as potential triggers for plaque rupture.

Dynamic Obstruction


Plaque fissure or rupture initiates the process of mural—and eventually luminal—thrombosis by exposing platelets to the thrombogenic components of plaque (eg, collagen, lipid gruel, and tissue factor). This leads to platelet attachment, aggregation, platelet thrombus formation, and the exposure of tissue factor, an abundant procoagulant in the plaque, which interacts with clotting factor VII. The ensuing cascade of events results in the formation of thrombin, which contributes to further platelet aggregation, fibrin formation, and vasoconstriction; it may also play a role as a smooth muscle cell mitogen and chemoattractant for inflammatory cells. The magnitude of the thrombotic response may be further modulated by such local rheologic factors as the shear rate, as well as the status of local and circulating coagulability, platelet aggregability, and fibrinolysis. The superimposition of thrombus on a fissured atherosclerotic plaque can abruptly worsen the local coronary stenosis and lead to a sudden decrease in blood flow. In about 20–40% of acute coronary syndromes seen during autopsy, however, neither plaque fissure nor rupture can be found underlying thrombosis (plaque erosion).


It has become increasingly clear that atherosclerosis is generally associated with a reduced vasodilator response, an increased vasoconstrictor response, or a paradoxical vasoconstrictor response to a variety of stimuli: flow changes, exercise, vasoactive substances (eg, acetylcholine, platelet aggregates, thrombin). This abnormal vasomotor response has been observed well before the development of full-blown atherosclerosis; it has also been seen in patients with risk factors for coronary artery disease but no overt atherosclerosis. The response has generally been attributed to endothelial dysfunction with enhanced inactivation or a reduction in the release of nitric oxide or related nitroso-vasodilators (eg, the relaxation factor produced by the normal endothelium). Some studies have also suggested other causes, such as enhanced sensitivity of the vascular smooth muscle, abnormal platelet function, and an increased release of endothelin (a vasoconstrictor peptide).

Braunwald E. Unstable angina, an etiologic approach to management. Circulation. 1998 Nov 24;98(21):2219–22. [PMID: 98226306]

Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115–26. [PMID: 9887164]

Shah PK. Mechanisms of plaque vulnerability and rupture. J Am Coll Cardiol. 2003 Feb 19;41(4 Suppl S):15S–22S. [PMID: 12644336]

Clinical Findings

Symptoms and Signs

Unstable angina is a clinical syndrome characterized by symptoms of ischemia, which may include classic retrosternal chest pain or such pain surrogates as a burning sensation, feeling of indigestion, or dyspnea (Table 4–2). Anginal symptoms may also be felt primarily or as radiation in the neck, jaw, teeth, arms, back, or epigastrium. In some patients, particularly the elderly, dyspnea, fatigue, diaphoresis, light-headedness, a feeling of indigestion and the desire to burp or defecate, or nausea and emesis may accompany other symptoms—or may be the only symptoms. The pain of unstable angina typically lasts 15–30 minutes; it can last longer in some patients. The clinical presentation of unstable angina can take any one of several forms.

Table 4–2. Clinical Presentation of Unstable Angina.

New onset of ischemic symptoms


At rest only


During exertion only


At rest and exertion

Intensification of previous ischemic symptoms


Increased frequency, severity, duration


Change in pattern (eg, symptoms at rest)

Recurrence of ischemic symptoms within 4–6 weeks after an acute myocardial infarction



Recurrence of ischemia within 4–6 weeks following bypass surgery or coronary catheterization


Recurrent acute pulmonary edema


Prinzmetal (variant) angina

There may be an onset of ischemic symptoms in a patient who had been previously free of angina, with or without a history of coronary artery disease. If symptoms are effort-induced, they are often rapidly progressive, with more frequent, easily provoked, and prolonged episodes. Rest pain may follow a period of crescendo effort angina—or exist from the beginning.

Symptoms may intensify or change in a patient with antecedent angina. Pain may be provoked by less effort and be more frequent and prolonged than before. The response to nitrates may decrease and their consumption increase. The appearance of new pain at rest or with minimal exertion is particularly ominous. On the other hand, recurrent long-standing ischemic symptoms at rest do not necessarily constitute an acute ischemic syndrome. Ischemic symptoms may recur shortly after (usually within 4 weeks) an acute myocardial infarction, coronary artery bypass surgery, or catheter-based coronary artery intervention. In some patients, an acute unstable coronary syndrome may manifest itself as acute pulmonary edema or sudden cardiac death.

Physical Examination

No physical finding is specific for unstable angina, and when the patient is free of pain the examination may be entirely normal. During episodes of ischemia, a dyskinetic left ventricular apical impulse, a third or fourth heart sound, or a transient murmur of ischemic mitral regurgitation may be detected. Similarly, during episodes of prolonged or severe ischemia there may be transient evidence of left ventricular failure, such as pulmonary congestion or edema, diaphoresis, or hypotension. Arrhythmias and conduction disturbances may occur during episodes of myocardial ischemia.

The findings from physical examination, especially as they relate to signs of heart failure, provide important prognostic information. An analysis of data from four randomized clinical trials (GUSTO IIb, PURSUIT, PARAGON A and B) revealed that Killip classification, a commonly used classification based on physical examination of patients at presentation of STEMI, is a strong independent predictor for short- and long-term mortality, with higher Killip class associated with higher mortality rate. This is also recently confirmed using data from the Canadian ACS Registries.

Diagnostic Studies

Unstable angina is a common reason for admission to the hospital, and the diagnosis, in general, rests entirely on clinical grounds. In a patient with typical effort-induced chest discomfort that is new or rapidly progressive, the diagnosis is relatively straightforward, particularly (but not necessarily) when there are associated ECG changes. Often, however, the symptoms are less clear-cut. The pain may be atypical in terms of its location, radiation, character, and so on, or the patient may have had a single, prolonged episode of pain—which may or may not have resolved by the time of presentation. The physician should strongly suspect unstable angina, particularly when coronary artery disease or its risk factors are present. When in doubt, it is safer to err on the side of caution and consider the diagnosis to be unstable angina until proven otherwise. Even though dynamic ST-T changes on the ECG make the diagnosis more certain, between 5% and 10% of patients with a compelling clinical history (especially middle-aged women) have no critical coronary stenosis on coronary angiography. In rare instances, especially in women, spontaneous coronary artery dissection, unrelated to coronary atherosclerosis, may be the basis for an acute coronary syndrome. In general, the more profound the changes in ECG, the greater the likelihood of an ischemic origin for the pain and the worse the prognosis.

ECG and Holter Monitoring

ECG abnormalities are common in patients with unstable angina. In view of the episodic nature of ischemia, however, the changes may not be present if the ECG is recorded during an ischemia-free period or the ischemia involves the myocardial territories (eg, the circumflex coronary artery territory) that do not show well on the standard 12-lead ECG. Therefore, it is not surprising that 40–50% of patients admitted with a clinical diagnosis of unstable angina have no ECG abnormalities on initial presentation. The ECG abnormalities tend to be in the form of transient ST-segment depression or elevation and, less frequently, T wave inversion, flattening, peaking or pseudo-normalization (ie, the T wave becomes transiently upright from a baseline state of inversion). It must be emphasized, however, that a normal or unremarkable ECG should never be used to disregard the diagnosis of unstable angina in a patient with a compelling clinical history and an appropriate risk-factor profile.

Continuous Holter ambulatory ECG recording reveals a much higher prevalence of transient ST-T wave abnormalities, of which 70–80% are not accompanied by symptoms (silent ischemia). These episodes, which may be associated with transient ventricular dysfunction and reduced myocardial perfusion, are much more prevalent in patients with ST-T changes on their admission tracings (up to 80%) than in persons without such changes. Frequent and severe ECG changes on Holter monitoring, in general, indicate an increased risk of adverse clinical outcome.


More than 90–95% of patients with a clinical syndrome of unstable angina have angiographically detectable atherosclerotic coronary artery disease of varying severity and extent. The prevalence of single-, two-, and three-vessel disease is roughly equal, especially in patients older than 55 and those with a past history of stable angina. In relatively younger patients and in those with no prior history of stable angina, the frequency of single-vessel disease is relatively higher (50–60%). Left mainstem disease is found in 10–15% of patients with unstable angina. A subset of patients (5–10%) with angiographically normal or near normal coronary arteries may have noncardiac symptoms masquerading as unstable angina, the clinical syndrome X (ischemic symptoms with angiographically normal arteries and possible microvascular dysfunction), or the rare primary vasospastic syndrome of Prinzmetal (variant) angina. It should be recognized, however, that most patients (even those with Prinzmetal angina) tend to have a significant atherosclerotic lesion on which the spasm is superimposed. In general, the extent (number of vessels involved, location of lesions) and severity (the percentage of diameter-narrowing, the minimal luminal diameter, or the length of the lesion) of coronary artery disease and the prevalence of collateral circulation, as judged by traditional angiographic criteria, do not differ between patients with unstable angina and those with stable coronary artery disease. The morphologic features of the culprit lesions do tend to differ, however. The culprit lesion in patients with unstable angina tends to be more eccentric and irregular, with overhanging margins and filling defects or lucencies. These findings (on autopsy or in vivo angioscopy) represent a fissured plaque, with or without a superimposed thrombus. Such unstable features in the culprit lesion are detected more frequently when angiography is performed early in the clinical course.

Noninvasive Tests

Any form of provocative testing (exercise or pharmacologic stress) is clearly contraindicated in the acute phase of the disease because of the inherent risk of provoking a serious complication. Several studies of patients who had been pain-free and clinically stable for more than 3–5 days, however, have shown that such testing, using ECG, scintigraphic, or echocardiographic evaluation may be safe. Provocative testing is used primarily to stratify patients into low- and high-risk subsets. Aggressive diagnostic and therapeutic interventions can then be selectively applied to the high-risk patients; the low-risk patients are treated more conservatively. In general, these studies have shown that patients who have good exercise duration and ventricular function, without significant inducible ischemia or ECG changes on admission, are at a very low risk and can be managed conservatively. On the other hand, patients with ECG changes on admission, a history of prior myocardial infarction, evidence of inducible ischemia, and ventricular dysfunction tend to be at a higher risk for adverse cardiac events and therefore in greater need of further and more invasive evaluation.

Other Laboratory Findings

Blood levels of myocardial enzymes are, by definition, not elevated in unstable angina; if they are elevated without evolution of Q waves, the diagnosis is generally a non–Q wave myocardial infarction (or NSTEMI). This distinction is somewhat arbitrary, however.

There is evidence of elevated blood levels of biochemical inflammation markers (eg, C-reactive protein [CRP], serum amyloid A, fibrinogen) in patients presenting with USA/NSTEMI. An elevated blood level of CRP or serum amyloid A on admission is associated with a higher risk for early mortality, even in patients in whom classic myocardial damage marker (cardiac-specific troponins) is negative. Increased blood level of fibrinogen is also associated with increased rate of death or myocardial infarction. The presence of such markers may be useful in risk stratification for clinical outcomes; however, their current roles in diagnosing USA/NSTEMI have not been established. It is also unclear whether treatment strategies based on these biochemical markers would alter clinical outcomes.

Khot UN et al. Prognostic importance of physical examination for heart failure in non-ST-elevation acute coronary syndromes: the enduring value of Killip classification. JAMA. 2003 Oct 22;290(16):2174–81. [PMID: 14570953]

Morrow DA et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: A TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1998 Jun;31(7):1460–5. [PMID: 9626820]

Morrow DA et al. Serum amyloid A predicts early mortality in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol. 2000 Feb;35(2):358–62. [PMID: 10676681]

Segev A et al. Prognostic significance of admission heart failure in patients with non-ST-elevation acute coronary syndromes (from the Canadian Acute Coronary Syndrome Registries). Am J Cardiol. 2006 Aug 15;98(4):470–3. [PMID: 16893699]

Toss H et al. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation. 1997 Dec 16;96(12):4204–10. [PMID: 9416883]

Differential Diagnosis

Conditions that simulate or masquerade as unstable angina include acute myocardial infarction, acute aortic dissection, acute pericarditis, pulmonary embolism, esophageal spasm, hiatal hernia, chest wall pain, and so on. Careful attention to the history, risk factors, and objective findings of ischemia (transient ST-T changes and mild elevations of troponins in particular) remain the cornerstones for the diagnosis.

Acute Myocardial Infarction

Although myocardial infarction often produces more prolonged pain, the clinical presentation can be indistinguishable from that of unstable angina. As stated earlier, this distinction should be considered somewhat arbitrary because abnormal myocardial technetium-99m pyrophosphate uptake, mild creatine kinase elevations detected on very frequent blood sampling, and increases in troponin-T and I levels (released from necrotic myocytes) are observed in some patients with otherwise classic symptoms of unstable angina.

Acute Aortic Dissection

The pain of aortic dissection is usually prolonged and severe. It frequently begins in or radiates to the back and tends to be relatively unrelenting and often tearing in nature; transient ST-T changes are rare. An abnormal chest radiograph showing a widened mediastinum, accompanied by asymmetry in arterial pulses and blood pressure, can provide clues to the diagnosis of aortic dissection, which can be verified by bedside echocardiography (transesophageal, with or without transthoracic echocardiography), MRI, CT scanning, or aortography.

Acute Pericarditis

Acute pericarditis may be difficult to differentiate from unstable angina. A history of a febrile or respiratory illness suggests the former. The pain of pericarditis is classically pleuritic in nature and worsens with breathing, coughing, deglutition, truncal movement, and supine posture. A pericardial friction rub is diagnostic, but it is often evanescent, and frequent auscultation may be needed. Prolonged, diffuse ST elevation that is not accompanied by reciprocal ST depression or myocardial necrosis is typical of pericarditis. Leukocytosis and an elevated erythrocyte sedimentation rate are common in pericarditis but not in unstable angina. Echocardiography may detect pericardial effusion in patients with pericarditis; diffuse ventricular hypokinesis may imply associated myocarditis. Regional dysfunction, especially if transient, is more likely to reflect myocardial ischemia.

Acute Pulmonary Embolism

Chest pain in acute pulmonary embolism is also pleuritic in nature and almost always accompanied by dyspnea. Arterial hypoxemia is common, and the ECG may show sinus tachycardia with a rightward axis shift. Precordial ST-T wave abnormalities may simulate patterns of anterior myocardial ischemia or infarction. A high index of suspicion, combined with a noninvasive assessment of pulmonary ventilation-perfusion mismatch, evidence of lower extremity deep venous thrombosis, CT angiography, and possibly pulmonary angiography, is necessary to exclude the diagnosis.

Gastrointestinal Causes of Pain

Various gastrointestinal pathologies can mimic unstable angina. These include esophageal spasm, peptic ulcer, hiatal hernia, cholecystitis, and acute pancreatitis. A history compatible with those conditions, the response to specific therapy, and appropriate biochemical tests and imaging procedures should help clarify the situation. It should be noted that these abdominal conditions may produce ECG changes that simulate acute myocardial ischemia.

Other Causes of Chest Pain

Many patients present with noncardiac chest pain that mimics unstable angina, and sometimes no specific diagnosis can be reached. The pain may be musculoskeletal or there may be nonspecific changes on the ECG that increase the diagnostic confusion. In these patients, a definite diagnosis often cannot be reached despite careful clinical observation. When the pain has abated and the patient is stable, a provocative test for myocardial ischemia may help rule out ischemic heart disease. Although coronary angiography may provide evidence of atherosclerotic coronary artery disease, anatomic evidence does not necessarily prove an ischemic cause for the symptoms. In some patients, acute myocarditis may also produce chest pain syndromes simulating unstable angina and acute myocardial infarction. Recreational drug use (cocaine and methamphetamine) may also produce clinical syndromes of chest pain, sometimes related to drug-induced acute coronary syndrome precipitated by the vasoconstrictor and prothrombic effects of these drugs.


In treating unstable angina, the initial objective is to stratify patients for their short-term morbidity and mortality risks based on their clinical presentations (Figure 4–2). Following risk stratification, management objectives include eliminating episodes of ischemia and preventing acute myocardial infarction and death.

Figure 4–2.

Algorithm in risk stratification and management of USA/NSTEMI.

1All patients should receive risk factor modification (lipid lowering, smoking cessation, blood pressure/diabetes mellitus control, dietary counseling, exercise program, weight control). 2High risk features include accelerating ischemic symptoms in preceding 48 h, rest pain > 20 min, presence of clinical congestive heart failure, advanced age (> 75 years), new bundle-branch clock or rest angina with transient ST-segment changes > 0.5 mm, sustained ventricular tachycardia or marked elevation of cardiac enzyme. (ACC/AHA guidelines for unstable angina. J Am Coll Cardiol. 2000;36:970.) 3Intermediate risk features include history of prior MI/PVD/CABG/CVA/aspirin use, resolved prolonged rest angina (> 20 min), rest angina (< 20 min) relieved with rest or sublingual nitroglycerin, age > 70 years, T-wave inversion > 2 mm, presence of pathologic Q wave, slightly elevated cardiac enzyme. (ACC/AHA guidelines for unstable angina. J Am Coll Cardiol. 2000;36:970.) 4Low-risk features do not have the clinical features included in items 2 and 3 but have new-onset Canadian Cardiovascular Society (CCS) class III or IV angina in the past 2 weeks without prolonged (> 20 min) rest angina, normal or unchanged ECG, normal cardiac enzyme. (ACC/AHA guidelines for unstable angina. J Am Coll Cardiol. 2000;36:970.) CABG, coronary artery bypass grafting; CVA, cerebrovascular accident; ECG, electrocardiogram; LMWH, low-molecular-weight heparin; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

Initial Management

During this early in-hospital phase, therapy is primarily aimed at stabilizing the patient by stabilizing the culprit coronary lesion and thus preventing a recurrence of myocardial ischemia at rest and progression to myocardial infarction.

General Measures

Patients whose history is compatible with a diagnosis of unstable angina should be promptly hospitalized—ideally, in an intensive or intermediate care unit. General supportive care includes bed rest with continuous monitoring of cardiac rate and rhythm and frequent evaluation of vital signs; relief of anxiety with appropriate reassurance and, if necessary, anxiolytic medication; treatment of associated precipitating or aggravating factors such as hypoxia, hypertension, dysrhythmias, heart failure, acute blood loss, and thyrotoxicosis. A 12-lead ECG should be repeated if it is initially unrevealing or if any significant change has occurred in symptoms or clinical stability. Serial cardiac enzyme evaluation should be performed to rule out an acute myocardial infarction.

Specific Drug Therapy


Nitrates are generally considered one of the cornerstones of therapy (Tables 4–3 and 4–4). They tend to relieve and prevent ischemia by improving subendocardial blood flow in the ischemic zone through their vasodilator actions, predominantly on the large epicardial vessels, including the stenotic segments and the coronary collaterals. Unlike acetylcholine and other endothelium-dependent vasodilators, nitrates produce their effects by directly stimulating cyclic guanosine monophosphate (GMP) in the vascular smooth muscle without requiring an intact or functional endothelium; hence their effects are generally well preserved in atherosclerosis. Reduction of left ventricular preload and afterload by peripheral vasodilator actions may contribute to the reduction of myocardial ischemia. Although nitrates may reduce the number of both symptomatic and asymptomatic episodes of myocardial ischemia in unstable angina, no effect has yet been demonstrated on the incidence of progression to myocardial infarction or death.

Table 4–3. Effects of Medical Therapy in Unstable Angina.

Therapy Recurrent Ischemia Progression to Acute Myocardial Infarction Mortality
Nitrates ? ?
Calcium channel blockers ?*
-Blockers ? ?
Aspirin/clopidogrel ?
Thrombolytics ? ? ?

, reduction in frequency; ?, benefit not clearly established; *, increased risk with nifedipine, decreased risk with diltiazem in non–Q wave infarction in two studies.

LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.

Table 4–4. Mechanisms of Action and Adverse Effects of Drug Therapy in Unstable Angina.

Agent Myocardial Blood Flow Myocardial Oxygen Demand Vasoconstriction Platelet Fibrin Thrombus Adverse Effects
Nitrates ? Hypotension, reflex tachycardia, rarely bradycardia, headaches, increased intracranial and intraocular pressure, methemoglobinemia, alcohol intoxication, tolerance, decreased heparin effect not established.
Calcium channel blockers Hypotension, excessive bradyarrhythmias (verapamil, dilitiazem), increased heart rate (nifedipine), worsening heart failure, worsening ischemia from coronary steal (nifedipine).
-Blockers ? ? Excessive bradyarrhythmias, worsening heart failure, increased bronchospasm.
Aspirin * ? ? Gastritis or ulceration, bleeding, allergy.
Heparin * ? ? Bleeding, thrombocytopenia, rarely increased thrombotic risk, osteoporosis, increased K+.

, increase; , decrease; ?, not established; *, increase or maintenance of coronary flow is due to prevention of thrombotic occlusion rather than to any direct vasodilator action.

In the very acute phase, it is preferable to use intravenous nitroglycerin to ensure adequate bioavailability, a rapid onset and cessation of action, and easy dose titratability. Oral, sublingual, transdermal, and transmucosal preparations are better suited for subacute and chronic use. To minimize the chances of abrupt hypotension, nitroglycerin infusion should be started at 10 mcg/min and the infusion rate titrated according to symptoms and blood pressure. The goal is to use the lowest dose that will relieve ischemic symptoms without incurring side effects. The side effects of nitrates include hypotension, which should be meticulously avoided; reflex tachycardia associated with hypotension; occasional profound bradycardia, presumably related to vagal stimulation; headaches; and facial flushing. Rare side effects include methemoglobinemia, alcohol intoxication, and an increase in intraocular and intracranial pressure. Some studies have shown a nitroglycerin-induced decrease in the anticoagulant effect of heparin; these results have not been confirmed by other studies. More recent studies suggest that nitroglycerin may reduce the circulating levels of exogenously administered tissue plasminogen activator, possibly reducing its thrombolytic efficacy. Because the magnitude of reduced arterial pressure that a patient can tolerate without developing signs of organ hypoperfusion varies, it is difficult to define an absolute cut-off point. A reasonable approach in normotensive patients without heart failure is to maintain the arterial systolic blood pressure no lower than 100–110 mm Hg; in hypertensive patients, reduction below 120–130 mm Hg may be unwise.

Continuous and prolonged administration of intravenous nitroglycerin for more than 24 hours may lead to the attenuation of both its peripheral and coronary dilator actions. This effect is due to the development of tolerance in some patients, presumably from depletion of sulfhydryl groups. Some studies show that this attenuation diminishes when sulfhydryl donors such as N-acetylcysteine are administered. At the present time, however, there is no easy and practical way to avoid or overcome this problem other than escalating the dose to maintain reduction in measurable end points (eg, the arterial blood pressure).

With the increasing use of phosphodiesterase-5 inhibitors (such as sildenafil) for erectile dysfunction among patients with coronary artery disease or the recreational use of such medication, it is important to obtain a history of whether the patient has taken such medication 24 hours prior to presentation of USA/NSTEMI. Nitrate-mediated vasodilation in the presence of phosphodiesterase-5 inhibition can lead to prolonged hypotension or even death.

Antiplatelet and Anticoagulant Therapy

Coronary thrombosis has long been suspected as a culprit in the pathophysiology of unstable angina, and several observational studies published in the 1950s and 1960s reported on the beneficial effects of anticoagulation. The protective effects of aspirin (including the fact that taking a single aspirin had the same benefit as taking more than one) in coronary-prone patients were also described in the 1950s. The unequivocal benefits of antiplatelet and anticoagulant therapy in unstable angina were established only in the past 2 decades, however, when several placebo-controlled randomized trials were completed.


Aspirin has been shown to reduce the risk of developing myocardial infarction by about 50% in at least four randomized trials. The protective effect of aspirin in unstable angina has been comparable, in the dosage range of 75–1200 mg/day. However, because of the potential for gastrointestinal side effects, low doses of aspirin (75–81 mg/day) are preferable. A lower dose should be preceded by a loading dose of 160–325 mg on the first day in order to initiate the antiplatelet effect more rapidly.

Ticlopidine and Clopidogrel

These two thienopyridine drugs are adenosine diphosphate (ADP) antagonists that are approved for antiplatelet therapy. They have been shown to be comparable to aspirin in reducing the risk of developing acute myocardial infarction in unstable angina. Both drugs have delayed onset of full antiplatelet effect, hence they are not suitable in acute cases. Because they are more expensive than aspirin and carry a 1% risk of agranulocytosis and, rarely, thrombotic thrombocytopenia purpura, ticlopidine and clopidogrel should be used only when a patient cannot tolerate aspirin due to hypersensitivity or major gastrointestinal side effects.

Due to a better safety profile and faster onset of action, clopidogrel is the preferred thienopyridine. Extrapolation based on the CURE trial suggested that the combination of aspirin and clopidogrel appears to modestly reduce the combined incidence of cardiovascular death, myocardial infarction, or stroke in USA/NSTEMI patients who are not undergoing revascularization procedures. However, this small additional benefit is at the expense of increased major or minor bleeding and cost. The optimal duration of such combination therapy has not been established either.

Unfractionated Heparin and Low-Molecular-Weight Heparin

The protective effect of intravenous unfractionated heparin (UFH) in treating unstable angina has been demonstrated in randomized trials. During short-term use, the risk of myocardial infarction in unstable angina is reduced by about 90%, and ischemic episodes are reduced by about 70%.

Two studies have compared the relative benefits of intravenous heparin with those of aspirin alone or combined with heparin. Although both agents offer protection against the development of acute myocardial infarction in unstable angina, the studies show that heparin may be somewhat more effective in reducing both the risk of infarct development and the number of ischemic episodes. Aspirin and heparin together may not be superior to heparin alone, but aspirin does offer protection against rebound reactivation of acute ischemic syndromes shortly after short-term heparin therapy ends—an argument for their combined use in unstable angina. Because combined therapy may increase the risk of bleeding, only low-dose aspirin should be used.

Recently, low-molecular-weight heparin (LMWH) was tested to examine its role as an alternative anticoagulation therapy to UFH in patients with USA/NSTEMI. LMWH has certain pharmacologically superior features to UFH: longer half-life, weaker binding to plasma protein, higher bioavailability with subcutaneous injection, more predictable dose response, and less incidence of heparin-induced thrombocytopenia. Dalteparin has been shown to be superior to placebo and equivalent to UFH for immediate, short-term treatment of USA/NSTEMI in reducing composite end points in the FRISC and FRIC trials, respectively. In the FRISC II trial, dalteparin also lowered the risk of death or myocardial infarction in patients receiving invasive procedures, especially in high-risk patients. In ESSENCE and thrombolysis in myocardial infarction (TIMI) 11B trials, enoxaparin (modestly but significantly) reduced the combined incidence of death, myocardial infarction, or recurrent angina over UFH. This reduction is mainly due to a decrease in recurrent angina. But in the SYNERGY trial, enoxaparin was not superior to UFH in reducing mortality or non-fatal myocardial infarction in high-risk patients undergoing early invasive therapy. Taken together, acute treatment with LMWH is likely as effective as UFH in USA/NSTEMI patients receiving aspirin. However, because LMWH is easier to use and does not require partial thromboplastin time monitoring, it is being increasingly preferred over UFH.

Direct Thrombin Inhibitors

Medications in this class include hirudin, bivalirudin, argatroban, efegatran, and inogatran. Compared with heparin, direct thrombin inhibitors, as a class, appear to offer a small reduction in death or myocardial infarction in patients with USA/NSTEMI. However, hirudin is associated with an excess of major bleeding compared with heparin whereas argatroban, efegatran, and inogatran are associated with an increased risk of death or myocardial infarction.

Bivalirudin was recently tested in the ACUITY trial. Bivalirudin was shown to be noninferior to heparin in composite ischemia end points (death, myocardial infarction, or unplanned revascularization) in USA/NSTEMI patients with moderate- or high-risk features undergoing invasive therapy when it was used in conjuction with a glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor. Taken together, direct thrombin inhibitors have not been routinely used in the medical management of USA/NSTEMI; however, they are alternative antithrombotics for patients with heparin-induced thrombocytopenia.

Glycoprotein IIb/IIIa Receptor Inhibitor

Activation of GP IIb/IIIa receptors leads to interaction of receptors with ligands such as fibrinogen followed by platelet aggregation. Several GP IIb/IIIa receptor antagonists have been developed to inhibit this agonist-induced platelet aggregation and tested in clinical trials. Currently available intravenous IIb/IIIa receptor inhibitors are abciximab, a monoclonal antibody against the receptor; nonpeptidic inhibitors, lamifiban and tirofiban; and a peptidic inhibitor, eptifibatide.

Four major randomized clinical trials (PRISM, PRISM-PLUS, PURSUIT, and PARAGON) evaluated the efficacy of intravenous GP IIb/IIIa receptor inhibitors in reducing clinical events (death, myocardial infarction, or refractory angina) in patients with USA/NSTEMI. Different inhibitors were tested in the trials (tirofiban in PRISM and PRISM-PLUS, eptifibatide in PURSUIT, and lamifiban in PARAGON). Although patient population, experimental designs, angiographic strategies, and end point measurement in these trials were different, these trials showed consistent, though small, reduction of short-term composite event rates in the management of the acute phase of USA/NSTEMI. However, the efficacy of these GP IIb/IIIa inhibitors in reducing short-term mortality is not as consistent if only death is considered as the clinical end point. Subgroup analysis of these trials indicated that patients with high-risk features would benefit more from the use of GP IIb/IIIa inhibitors.

The efficacy of intravenous abciximab on clinical outcome in patients with USA/NSTEMI without early intervention was tested in GUSTO-IV ACS trial. There was no survival benefit in patients receiving abciximab when compared with placebo at 30 days or at 1 year.

The efficacy of intravenous GP IIb/IIIa inhibitors in reducing clinical events in patients with USA/NSTEMI undergoing percutaneous coronary intervention (PCI) was also tested—abciximab in EPILOG and CAPTURE, tirofiban in RESTORE. These trials consistently showed a reduction of short-term clinical events (composite end point of death, myocardial infarction, urgent or repeat revascularization). The major benefit appears to be in nonfatal adverse events rather than mortality.

At the present time there is no clinical role for oral GP IIb/IIIa antagonists such as xemilofiban, orbofiban, and sibrafiban because of lack of proven clinical benefit and increased risk of bleeding.

Thus, overall data suggest that intravenous GP IIb/IIIa inhibitor used judiciously, along with aspirin and heparin, is beneficial in high-risk patients with USA/NSTEMI undergoing PCI. Table 4–5 summarizes the use of various antiplatelet, antithrombotic, and GP IIb/IIIa inhibitors in different USA/NSTEMI settings.

Table 4–5. Use of Antiplatelet, Antithrombotic, and Gp IIb/IIIa Inhibitors in Different Subsets of Patients with USA/NSTEMI Based on AHA/ACC Guideline Recommendation.

  Aspirin Clopidogrel UFH or LMWH GP IIb/IIIa inhibitors
Low risk 1
Moderate risk 1
High risk 1
No plan for early invasive therapy ✓3
Revascularization with PCI ✓6,7
Revascularization with CABG No6

1See Figure 4–2 for risk classification.

2Use in patients who are unable to take aspirin due to hypersensitivity or major gastrointestinal intolerance.

3Optimal duration of use has not been established; guideline recommends use for at least 1 month and for up to 9 months.

4Class IIa indication.

5Only tirofiban or eptifibatide (not abciximab) is indicated for this use.

6Hold clopidogrel until coronary anatomy is defined by angiography and the decision whether to use PCI or CABG is made.

7In the current “drug eluting stent” era, the use of such stent and optimal duration of treatment with clopidogrel after drug eluting stent has been under great debate due to the complication of late stent thrombosis.

8Administered prior to PCI.

CABG, coronary artery bypass grafting; GP, glycoprotein; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin; USA/NSTEMI, unstable angina/non-ST elevation myocardial infarction.

Thrombolytic Drugs

A number of trials have examined the role of thrombolytic therapy in USA/NSTEMI. Despite improved angiographic appearance of the culprit vessel following thrombolytic therapy, no clear-cut benefit over and above antiplatelet and anticoagulant therapy alone has been demonstrated. The precise reasons for this are unclear, especially because there is general agreement about the important pathophysiologic contribution of thrombus to unstable angina. At this time, therefore, the routine use of thrombolytic therapy in unstable angina cannot be recommended.


-Blockers are commonly used in managing ischemic heart disease because they have been shown to reduce the frequency of both symptomatic and asymptomatic ischemic episodes in stable as well as unstable angina. The protective effects of -blockers in ischemic heart disease are generally attributed to their negative chronotropic and inotropic effects, which reduce the imbalance of myocardial oxygen demand and supply. Their ability to reduce the risk of infarct development is less clear, but they do decrease reinfarction and mortality rates in postinfarction patients. The mechanism of their protective effect against reinfarction remains unexplained, although it has been speculated that they reduce the risk of plaque rupture by reducing mechanical stress on the vulnerable plaque. It is also unclear whether -blockers offer any additional benefit in unstable angina in patients who are already receiving nitrates and antiplatelet-anticoagulant therapy. At present, the use of -blockers in patients with unstable angina should be considered an adjunctive therapy.

Calcium Channel Blockers

Calcium channel blockers are also frequently used in managing ischemic heart disease. Their beneficial effects in myocardial ischemia are generally attributed to their ability to improve myocardial blood flow by reducing coronary vascular tone and dilation of large epicardial vessels and coronary stenoses through an endothelium-independent action. They also reduce myocardial workload through their negative chronotropic and inotropic and peripheral vasodilator effects. Because exaggerated vasoconstriction may play a role in unstable angina, calcium channel blockers have been used in its management. In general, although calcium channel blockers have been shown to reduce the frequency of ischemic episodes in unstable angina, their protective effect against the development of acute myocardial infarction has not been definitively demonstrated. In fact, the use of such calcium channel blockers as nifedipine tends to increase the risk of ischemic complications in unstable angina. Such adverse effects may well be due to reflex tachycardia or coronary steal caused by the arteriole-dilating actions of some calcium channel blockers. The protective effects of the heart rate-slowing calcium channel blocker diltiazem have been reported in patients with a non-Q wave myocardial infarction and preserved ventricular function. As in the case of -blockers, the additive benefits of calcium channel blockers in patients with unstable angina who are receiving nitrates and antithrombotic therapy have not been defined, and their use should also be considered an adjunct to such drugs.

A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. N Engl J Med. 1998 May 21;338(21):1498–505. [PMID: 9599104]

Anderson JL et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction); American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association of Cardiovascular and Pulmonary Rehabilitation; Society for Academic Emergency Medicine. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007 Aug 14;50(7):e1–e157. [PMID: 17692738]

Bertrand ME et al. Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation: recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 2000 Sep;21(17):1406–32. [PMID: 10952834]

Chew DP et al. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation. 2001 Jan 16;103(2):201–6. [PMID: 11208677]

Cohen M et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997 Aug 14;337(7):447–52. [PMID: 9250846]

Direct Thrombin Inhibitor Trialists’ Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet. 2002 Jan 26;359(9303):294–302. [PMID: 11830196]

Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. The RESTORE Investigators. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation. 1997 Sep 2;96(5):1445–53. [PMID: 9315530]

Goodman SG et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events. J Am Coll Cardiol. 2000 Sep;36(3):693–8. [PMID: 10987586]

Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med. 1998 Aug 13;339(7):436–43. [PMID: 9705684]

Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med. 1998 May 21;338(21):1488–97. [PMID: 9599103]

International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina. The PARAGON Investigators. Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network. Circulation. 1998 Jun 23;97(24):2386–95. [PMID: 9641689]

Long-term low molecular mass heparin in unstable coronary artery disease: FRISC II prospective randomized multicenter study. FRagmin and Fast Revascularization during InStability in Coronary artery disease. Lancet. 1999 Aug 28;354(9180):701–7. [PMID: 10475180]

Low molecular weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet. 1996 Mar 2;347(9001):561–8. [PMID: 8596317]

Kaul S et al. Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin? J Am Coll Cardiol. 2000 Jun;35(7):1699–712. [PMID: 10841215]

Klein W et al. Comparison of low molecular weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation. 1997 Jul 1;96(1):61–8. [PMID: 9236418]

Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG investigators. N Engl J Med. 1997 Jun 12;336(24):1689–96. [PMID: 9182212]

Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet. 1997 May 17;349(9063):1429–35. [PMID: 9164316]

Stone GW et al; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006 Nov 23;355(21):2203–16. [PMID: 17124018]

Definitive Management

Catheter-Based Interventions

Endovascular interventions such as percutaneous coronary angioplasty, atherectomy, and laser-assisted angioplasty are commonly performed in patients with unstable angina to reduce the critical stenosis in the culprit artery or in multiple coronary arteries. Although these interventions accomplish an acute reduction in the severity of stenosis (80–93%), in patients with unstable angina they carry a somewhat higher risk of acute complications, including death (0–2%), abrupt closure (0–17%), acute myocardial infarction (0–13%), and the need for urgent coronary artery bypass surgery (0–12%), than in patients with stable angina. The risk is especially great when the procedure is performed soon after the onset of symptoms, in the absence of prior treatment with heparin, or in the presence of an angiographically visible intracoronary thrombus. The 3- to 6-month restenosis rate with these interventions is 17–44%.

Several randomized clinical trials compared “early conservative” and “early invasive” strategies in treating patients with unstable angina. Earlier trials, such as TIMI IIIB and the Veterans Affairs non-Q wave infarction strategies in hospital (VANQWISH), did not show a beneficial role of early invasive strategy. In contrast, trials such as FRISC II, TACTICS-TIMI 18, and RITA-3 showed a reduction in nonfatal adverse events in USA/NSTEMI patients receiving early invasive treatment. Another recent trial (ICTUS) did not demonstrate superiority of early invasive strategy in reducing mortality compared with early conservative (selective invasive) strategy in high-risk USA/NSTEMI patients. Differences in patient characteristics, study designs, surgical mortality rates, and background antiischemic medications used may account for these conflicting results and thus it is difficult to reach a consensus recommendation when treating patients with USA/NSTEMI. A recent meta-analysis containing seven contemporary randomized trials suggested that early invasive therapy performed within 24 hours does not confer similar mortality benefit to the strategy to perform procedures more than 24 hours after randomization. Data from the CRUSADE registry also suggested that a delay of invasive procedure of 46 hours does not increase adverse events compared to a delay of 23 hours. Nevertheless, analysis from FRISC II, TACTICS-TIMI 18, and OPUS-TIMI 16 trials showed patients with high-risk features (such as older age, long-duration of ischemia, angina at rest, ST segment changes on ECG, positive cardiac enzymes, and high TIMI risk scores) benefit more from early invasive strategy with revascularization. Intentionally delaying invasive therapy should be cautioned against and not encouraged.

Coronary Artery Bypass Surgery

Randomized trials and observational series have shown that surgical myocardial revascularization in patients with unstable angina is relatively superior to medical therapy for controlling symptoms and improving effort tolerance and ventricular function.

At the present time, surgical revascularization can be considered an appropriate option for patients with unstable angina who do not stabilize with aggressive medical therapy or for whom angioplasty is unsuccessful or is followed by acute complications not amenable to additional catheter-based intervention. It is also applicable to patients who have severe multivessel or left mainstem coronary artery disease, particularly when left ventricular function is also impaired. Although multivessel angioplasty is performed in many centers, the bypass angioplasty revascularization investigation (BARI) trial showed coronary artery bypass grafting offered a lower repeat revascularization rate and a reduced instance of clinical angina compared with multivessel percutaneous transluminal coronary angioplasty. The BARI trial also revealed that coronary artery bypass grafting has a better long-term survival benefit compared with multivessel percutaneous transluminal coronary angioplasty, especially in diabetic patients.

Intra-Aortic Balloon Counterpulsation

Intra-aortic balloon counterpulsation is a useful adjunct in managing selected cases of unstable angina. It helps maintain or improve coronary artery blood flow and myocardial perfusion by augmenting diastolic aortic pressure; at the same time, systolic unloading contributes to a reduction in ventricular wall tension and myocardial oxygen demand and an improvement in ventricular function. These beneficial effects on myocardial oxygen supply and demand help stabilize patients with recurrent myocardial ischemia and those with serious intermittent or persistent hemodynamic or electrical instability. Cardiac catheterization and revascularization can then be carried out with relative safety.

Intra-aortic balloon counterpulsation (and the percutaneous method of insertion) carries a significant risk of vascular complications involving the lower extremities, especially in women, in patients older than 70 years, and in the presence of diabetes or aortoiliac disease. It should be viewed as a temporary stabilizing measure, pending definitive revascularization.

Bavry AA et al. Benefit of early invasive therapy in acute coronary syndromes; a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol. 2006 Oct 3;48(7):1319–25. [PMID: 17010789]

Boden WE et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med. 1998 Jun 18;338(25):1785–92. [PMID: 9632444]

Cantor WJ et al. Early cardiac catheterization is associated with lower mortality only among high-risk patients with ST- and non-ST-elevation acute coronary syndromes: observations from the OPUS-TIMI 16 trial. Am Heart J. 2005 Feb;149(2):275–83. [PMID: 15846265]

de Winter RJ et al; Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med. 2005 Sep 15;353(11):1095–104. [PMID: 16162880]

Fox KA et al; Randomized Intervention Trial of Unstable Angina Investigators. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet. 2002 Sep 7;360(9335):743–51. [PMID: 12241831]

Ryan JW et al; CRUSADE Investigators. Optimal timing of intervention in non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Registry. Circulation. 2005 Nov 15;112(20):3049–57. [PMID: 16275863]

Santa-Cruz RA et al. Aortic counterpulsation: a review of the hemodynamic effects and indications for use. Catheter Cardiovasc Interv. 2006 Jan;67(1):68–77. [PMID: 16342217]

Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol. 2000 Apr;35(5):1122–9. [PMID: 10758950]


With the advancement of treatment strategies, clinical event rates for refractory angina, myocardial infarction, and death have been reduced substantially. For example, in patients who were not treated with aspirin and heparin, the rate of refractory angina, myocardial infarction, and death was 23%, 12%, and 1.7%, respectively, within the first week of treatment and the rates became 10.7%, 1.6%, and 0%, respectively, if the patients were treated with aspirin and heparin. With the addition of a GP IIb/IIIa receptor inhibitor, the rate for refractory angina, myocardial infarction, or death was 10.6%, 8.3%, and 6.9%, respectively, at 6 months in the PRISM-PLUS trial. With the combination of early invasive strategy, GP IIb/IIIa inhibitor, heparin, and aspirin, the 6-month mortality rate decreased further to 3.3% in the TACTICS-TIMI 18 trial. Even with such decreases in the event rates, a substantial number of patients still continue to suffer from USA/NSTEMI and its complications due to the high prevalence of atherosclerosis. All patients should become acquainted with risk factor modification strategies, which include lipid lowering, smoking cessation, an exercise program, diabetes control, blood pressure control, dietary counseling, and weight control. Recently, the use of angiotensin-converting enzyme inhibitors has also been shown to reduce atherothrombotic events in patients with coronary artery disease especially in the presence of diabetes. With the advancement of therapies and risk factor modification, patients’ short- and long-term outcomes can be further improved. A simple mnemonic—ABCDE (Table 4–6) summarizes the long-term risk-reducing approach for patients with unstable coronary artery disease.

Table 4–6. ABCDE Approach for Long-Term Risk Reduction in Patients with USA/NSTEMI.

A:   Antiplatelet therapy (aspirin, clopidogrel)
Blood pressure control
Cholesterol-modifying medications (statins, fibrates, niacin)
Converting enzyme inhibitors
Cessation of smoking
D:   Dietary management (Mediterranean style diet, Ornish style low-fat diet)
E:   Exercise and weight control

USA/NSTEMI, unstable angina/non-ST elevation myocardial infarction.

Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000 Jan 22;355(9200):253–9. [PMID: 10675071]

Copyright © The McGraw-Hill Companies.  All rights reserved.
Privacy Notice. Any use is subject to the Terms of Use and Notice.

McGraw-Hill Education A Silverchair Information System The McGraw-Hill Companies

Leave a Reply

Time limit is exhausted. Please reload the CAPTCHA.


apply_now Pepperstone Group Limited