UNSTABLE ANGINA

General Considerations
A. BACKGROUND AND HISTORICAL PERSPECTIVE

Nearly 40 years ago, the term intermediate coronary syndrome was used to describe what is now known as the syndrome of unstable angina, which has also been given numerous other labels: preinfarction angina, status anginosus, crescendo angina, impending myocardial infarction (MI), coronary failure, acute coronary insufficiency, spasmodic angina, and atypical angina—all of which terms attest to the heterogeneity of its clinical presentation. In the current era, unstable angina is the admitting diagnosis for about 40–50% of all admissions to cardiac intensive care units.
B. 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 30–40% of patients with coronary artery disease.

Table 4–1. Clinical spectrum of atherosclerotic coronary artery disease.

C. PATHOPHYSIOLOGY

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.
1. 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 (fatty gruel or pultaceous debris). Many clinical and angiographic studies suggest that plaque fissure leading to unstable angina or acute myocardial infarction 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) released by foam cells or macrophages and other mesenchymal cells 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 Chlamydia 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.
2. Dynamic obstruction—
a. Thrombosis— Plaque fissure or rupture initiates the process of mural—and eventually luminal—thrombosis by exposing platelets to the thrombogenic components of plaque (collagen, lipid gruel, and tissue factor, etc). 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% of acute coronary syndromes seen during autopsy, however, neither plaque fissure nor rupture can be found underlying thrombosis (plaque erosion). The mechanism of coronary thrombosis is unclear in these cases, but it might include severe stenosis and an enhanced prothrombic tendency of circulating blood.
b. Vasoconstriction— 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;98:2219.
Ross R: Atherosclerosis—An inflammatory disease. N Engl J Med 1999;340:115.
Shah PK: Plaque disruption and thrombosis, potential role of inflammation and infection. Cardiol Clin 1999;17:271.
Clinical Findings
A. 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 min; 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.

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.
B. 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.
C. 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 in the presence of risk factors for or in the case of known coronary artery disease. 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, from 5% to 10% of patients with a compelling clinical history (especially middle-aged women) turn out to have angiographically normal coronary arteries. In general, the more profound the changes, the greater the likelihood of an ischemic origin for the pain and the worse the prognosis.
1. ECG and Holter monitoring— Electrocardiographic 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. It is therefore not surprising that 40–50% of patients admitted with a clinical diagnosis of unstable angina have no electrocardiographic 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 in a patient with a compelling clinical history and an appropriate risk-factor profile should never be used to disregard the diagnosis of unstable angina.
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 subjects without such changes. Frequent and severe ECG changes on Holter monitoring, in general, indicate an increased risk of adverse clinical outcome.
2. Angiography— 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. The minority 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 the majority of patients (even those with Prinzmetal’s 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.
3. 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 electrocardiographic, 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 electrocardio- graphic 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.
P>4. 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 non-ST elevation myocardial infarction, 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 MI. 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.
Morrow DA, Rafai N, Antman EM 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. J Am Coll Cardiol 1998;31:1460.
Morrow DA, Rafai N, Antman EM et al: Serum amyloid A predicts early mortality in acute coronary syndromes: A TIMI 11A substudy. J Am Coll Cardiol 2000;35:358.
Toss H, Lindahl B, Siegbahn A et al: Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation 1997;96:4204.
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.
A. 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—which represents the severe end of the continuum of acute ischemic syndromes.
B. 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 x-ray film 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), magnetic resonance imaging (MRI), computed tomography (CT) scanning, or aortography.
C. 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 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.
D. 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 vein thrombosis, and possibly pulmonary angiography, is necessary to exclude the diagnosis.
E. 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.
F. 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 amphetamine) may also produce clinical syndromes of chest pain, sometimes related to drug-induced acute coronary syndrome precipitated by the vasoconstrictor and prothrombic effects of drugs.
Management
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.

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 20–30 µg/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 others. 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 subjects 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 h 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 endpoints (eg, the arterial blood pressure).
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 myocardial infarction.
b. Antiplatelet and anticoagulant therapy— Coronary thrombosis had 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 decade, however, when several placebo-controlled randomized trials were completed.
1. Aspirin— 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. Low doses of aspirin (75–81 mg/day) are preferable because the gastrointestinal side effects are clearly lessened with lower doses. 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.
2. Ticlopidine and Clopidogrel— These two 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. 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 gastro- intestinal side effects.
3. 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—a 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. Low-molecular-weight heparin has certain pharmacologically superior features to UFH: longer half-life, weaker binding to plasma protein, higher bioavailability with subcutaneous injection, more predictable dose response, less incidence of heparin-induced thrombocytopenia. Dalteparin has been shown to be superior to placebo and equivalent to UFH for acute, short-term treatment of USA/NSTEMI in reducing composite end-points in FRISC and FRIC trials, respectively. In FRISC II trial, dalteparin also lowered the risk of death or MI 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, MI, or recurrent angina over UFH. This reduction is mainly due to a decrease of recurrent angina. Taken together, acute treatment with LMWH is as effective or marginally superior to UFH in USA/NSTEMI patients receiving aspirin,. However because LMWH is easier to use and does not require PTT monitoring, it is being increasingly preferred over UFH.
4. Glycoprotein IIb/IIIa receptor inhibitor— Activation of glycoprotein IIb/IIIa (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. Current available intravenous IIb/IIIa receptor inhibitors are abciximab, a monoclonal antibody against 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, MI, 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 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 IIb/IIIa inhibitors.
The efficacy of intravenous 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, MI, 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 ASA and heparin, is beneficial in high-risk patients with UA/NSTEMI undergoing PCI,
c. Thrombolytic drugs— A number of trials have examined the role of thrombolytic therapy in unstable angina. 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. It may well be that antiplatelet-anticoagulant therapy is so effective in itself that any additional benefits are difficult to demonstrate and adding thrombolytic therapy would reduce the risk-to-benefit ratio of the therapy. At this time, therefore, the routine use of thrombolytic therapy in unstable angina cannot be recommended.
d. Beta-blockers— Beta-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 b-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 b-blockers offer any additional benefit in unstable angina in patients who are already receiving nitrates and antiplatelet-anticoagulant therapy. At present, the use of b-blockers in patients with unstable angina should be considered an adjunctive therapy.
e. Calcium blockers— Calcium 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 blockers have been used in its management. In general, although calcium 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 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 blockers. The protective effects of the heart rate-slowing calcium blocker diltiazem have been reported in patients with a non-Q wave myocardial infarction and preserved ventricular function. As in the case of b-blockers, the additive benefits of calcium 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.