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New Developments in the Treatment of Unstable Angina

Course Authors

Brian M. Go, M.D., and H. Vernon Anderson, M.D.

Release Date: 09/12/1998

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Understand the clinical definition of unstable angina and the underlying pathophysiology

  • Identify ways of risk stratification in unstable angina and their utility

  • Recognize standard and new medical therapy for unstable angina and the role of cardiac catheterization.

 

Unstable angina used to be associated with an acute, in hospital, mortality of approximately 35% thirty years ago. Many advances have occurred in the interim both in terms of diagnosis as well as treatment. Dr. Vernon Anderson, an Associate Professor and interventional cardiologist at the Hermann Heart Center and the University of Texas Medical School at Houston, is a world renowned expert in this important area. He and his colleague, Dr. Brian Go, have assembled the most up-to-date information on the diagnosis and treatment of unstable angina for this issue of Cardiovascular Cyberounds®. Please welcome Drs. Go and Anderson to Cyberounds®!

-- Richard W. Smalling, M.D., Ph.D., Cardiovascular Moderator

Introduction

Unstable angina (UA) is one of the most frequently cited diagnoses for hospital admissions in the United States and the numbers are increasing.(1),(2) UA, along with its associated condition, non-Q-wave myocardial infarction (NQMI), are together, unfortunately, associated with significant short term morbidity and mortality.(3) Although there have been significant improvements in our understanding of the basic biology of UA, these two entities still lack the comprehensiveness of clinical diagnosis, prognostic indicators and therapy that have revolutionized acute myocardial infarction with ST-segment elevation.(4) Fortunately, in recent years, there has been a resurgence in attention to UA and NQMI. Along with new ways of detecting myocardial injury, improved treatments have been developed and the optimal role for invasive therapy is being sought.(5)

Definition of Unstable Angina

Within the continuum of clinical coronary syndromes, UA exists between stable angina and acute myocardial infarction.(6) The hallmark of infarction is, of course, the presence of ST-segment elevations on an electrocardiogram (ECG). Traditionally, UA has been defined as angina of increasing frequency and/or severity, angina of new onset (less than two months) and angina occurring at rest or with minimal activity.(6) The ECG tracings, usually, are completely normal or show only nonspecific changes, for example, ST-segment depressions or T-wave flattening or inversion.

With the advent of serum markers that can be detected with increased sensitivity when there is only slight myocardial injury, the ability to find "NQMI" in patients with anginal syndromes but no characteristic ST-segment elevations on the ECG has also increased. In addition to the older, established enzyme marker CK-MB, we now have troponin-T, troponin-I, and myoglobin. Patients with angina and normal CK-MB who previously would have been defined as having only UA are now being reconsidered because of increases in troponins or CK-MB isoforms.(7)

Elevation in troponin values has been shown to have adverse prognostic significance and higher clinical event rates.(8),(9),(10),(11),(12) This underscores the importance of identifying those patients who have evidence of injury (NQMI) within the larger group of patients with UA. And yet from a treatment perspective, the distinction between UA and NQMI may not be of such great importance. Biologically they both share similar underlying pathophysiology and, as we now understand, require common therapies initially.

Pathophysiology of Unstable Angina

The pathophysiology of UA is variable, multi-factorial and dynamic.(13),(14) Variability is reflected in the heterogeneous clinical course of patients with this diagnosis. While the majority often stabilizes on medications, many others continue to experience episodes of chest pain and may progress to a myocardial infarction and even death.

The basic process underlying UA involves destabilization of an atherosclerotic plaque, mostly caused by a small erosion or fissuring. This destabilization leads to platelet accumulation and activation of the coagulation system with formation of thrombus. Elements in the atherosclerotic vessel wall, along with released vasoactive components, help activate more platelets and accelerate this thrombus formation. The cascade is then further amplified by substances released by the platelets themselves, the inability of damaged endothelium to vasodilate fully and smooth muscle hyperreactivity. This creates an imbalance between oxygen demand of the myocardium and its supply through the artery, as blood flow across the unstable lesion alternates between periods of obstruction and recanalization. The contribution of each of these individual reactive components can vary from one person to another.(15),(16),(17)

There is increasing evidence that inflammation may play a key role in UA. Locally, increased activity of neutrophils, monocytes, lymphocytes and C-reactive protein have all been identified in the culprit vessel wall. These increases in inflammatory components do not appear to be solely a reaction to ischemia. The exact stimulus for the inflammation is unknown but may be infectious in origin.(18) For example, an association between coronary heart disease and Chlamydia pneumonia has been proposed. In the future, it is possible that patients with UA may even benefit from treatment with an antibiotic.(18)

With our current diagnostic tools, one cannot confidently determine which coronary lesions will progress slowly or rapidly. The degree of vessel obstruction does not differ between stable and unstable angina and the progression from stable to unstable angina is not associated with increased stenosis. Additionally, the degree of stenosis does not predict response to medical therapy.(19),(20),(21),(22)

In patients with UA, angiographic evidence suggests that the type of coronary lesion, not the severity of the lesion, could determine the clinical course.(23) Angiographically, coronary lesions of patients with UA often have evidence of hazy, irregular borders and thrombi, compared to lesions in patients with stable angina. It has also been proposed that unstable plaques may possess elevated temperatures, perhaps due to the inflammatory process. This has raised the possibility of identification of activated plaques by thermal detection.(24) Whether traditional angiography or these more sophisticated methods will be useful in the future remains an active area of research.

Initial Risk Assessment and Use of the Electrocardiogram

The major deciding factor for initiation of therapy in patients with ischemic chest pain is based on analysis of the ST-segment on the ECG. If there is ST-segment elevation indicative of acute myocardial infarction, then reperfusion therapy is indicated immediately by either thrombolytic therapy or coronary angioplasty.(25) Otherwise, patients are treated with observation, monitoring and an intensive medical regimen. Serial ECG's and blood chemistry tests for markers of myocardial injury are obtained at regular intervals, generally every 6-to-8 hours, for 24 hours.

Although more than 80% of patients with UA stabilize comfortably on intensive medical therapy,(26) there is no standard way to predict which of these patients are at increased risk of myocardial infarction or cardiac death. Early risk stratification in UA and NQMI is problematic, partly due to the wide variability in disease progression and lack of bedside prognostic tools.(27) Braunwald's classification (see Table 1) of UA has shown prognostic utility in some studies(28),(29) but can be cumbersome to employ because of the many subclassifications.

Table 1. Classification of Unstable Angina.

  Clinical Settings
Severity A. Develops from extracardiac condition that worsens myocardial ischemia B. Develops without extracardiac condition C. Develops < 2 weeks after acute MI
I. New onset exertional angina, no rest angina IA IB IC
II. Angina at rest > 48 hrs. & < 30 days IIA IIIB IIC
III. Angina at rest < 48 hrs IIIA IIIB IIIC

Modified from Braunwald(28)

Rizik et al. have proposed a simpler classification system (Table 2) that also appears to have prognostic utility.(30)

Table 2. Classification of Unstable Angina.

Table Headline

Class IA: Worsening of chronic angina with ECG changes.

Class IB: Worsening of chronic angina without ECG changes.

Class II: New-onset exertional angina.

Class III: New-onset rest angina.

Class IV: Prolonged rest angina (>20mins) with ECG changes.

Modified from Rizak D et al.

Both classification systems consider ECG changes paramount. There is an increased mortality risk in patients with T-wave abnormalities versus a normal ECG(31) and even more so in those with ST-segment depression versus nonspecific ECG changes.(32)

Despite providing some valuable information, the resting ECG is only of modest utility in initial risk assessment.(33) The ECG is only a snapshot in time and, if the patient is not having angina during the tracing, it may not reflect the dynamic nature of the unstable coronary lesion. Continuous multilead ECG monitoring has been proposed as a better technique of monitoring and identifying patients at increased risk for adverse events.(27) Additionally, as discussed next, new biochemical markers of myocardial injury have added significantly to the ability to assess risk.(8),(9),(10),(11),(12)

New Markers for Myocardial Necrosis

Compared to the CK-MB, the troponins (troponin-T and troponin-I) have been shown to be more sensitive for detection of minor myocardial damage.(34),(35) The initial time course for detection of myocardial injury using troponins is similar to the assessment using CK-MB, that is, the first 24 hours, but any elevations in troponin levels may continue for up to 11 days.(36) Independent of either ECG or CK-MB findings, elevation in troponin levels in patients with UA carries a worse prognosis.(8),(9),(10),(11),(12)

Myoglobin, a protein found in striated muscle, quickly rises following myocardial damage and is rapidly cleared by the kidneys. Unlike troponins and CK-MB, which rise a little more slowly and are detectable over 6-to-12 hours, elevations in myoglobin are seen very early and peak within four hours of injury, returning to normal levels within 8-10 hours. Though very sensitive, the lack of specificity for myocardial origin and the short detectable duration will likely limit myoglobin's role in UA.(37),(38),(39),(40)

Standard Medical Therapy for Unstable Angina

The goals of therapy, in patients with UA, center on optimizing the balance between myocardial oxygen demand and delivery and stabilization of the thrombus-laden plaque. The standard therapy for UA consists of anti-ischemic drugs, including: aspirin, intravenous heparin, nitroglycerin, beta-blockers and calcium antagonists.(5)

Aspirin is useful in all acute coronary syndromes, including UA. Aspirin's main benefit (inhibiting platelet aggregation) is derived from its irreversible inhibition of platelet cyclo-oxygenase activity, thereby blocking thromboxane A2 production.(41) Aspirin therapy in patients with UA greatly decreases the incidence of myocardial infarction and death.(42),(43),(44),(45)

Intravenous heparin> inhibits further thrombus formation by potentiating antithrombin III activity. In combination with aspirin, numerous studies demonstrate heparin as efficacious in the treatment of UA.(46),(47)

Nitroglycerin is given intravenously in patients considered as high risk and in those patients with recurrent chest pain. Nitroglycerin dilates coronary arteries and arterioles, decreases blood pressure, improves oxygen delivery to the myocardium and thereby improves left ventricular function. Patients can be changed to an oral or topical form, once chest pain episodes subside and stabilization is achieved.

Beta-blockers lower the workload of the heart by decreasing blood pressure, heart rate and cardiac contractility. As a class, they have been found to help prevent progression of UA to myocardial infarction and death. Additionally, in patients with elevated sympathetic tone, beta-blockers, along with anxiolytics and a calm environment, can act to decrease sympathetic activity and, thus, control tachycardia and hypertension. Calcium antagonists may be added to therapy or used instead of beta-blockers in patients in whom contraindications exist.

Antiplatelet Agents (GP IIb/IIIa receptor inhibitors, Ticlopidine, Clopidogrel)

A. GP IIb/IIIa receptor inhibitors

The final common pathway to aggregation of platelets and formation of thrombus is the cross-linking of glycoprotein IIb/IIIa receptors on platelet membranes. Specific plasma proteins, such as fibrinogen and von Willebrand's factor, provide the linkage. An emerging new class of drugs, IIb/IIIa receptor inhibitors, hinder the binding of these receptors.(48) IIb/IIIa inhibitors, all given intravenously, include eptifibatide (Integrilin®), tirofiban (Aggrastat®), and abciximab (ReoPro®).(49)

The initial trials involving IIb/IIIa receptor inhibitors demonstrated a decrease in adverse clinical events, vessel restenosis (the reaccumulation, or re-formation, of atherosclerotic plaque material at a site that has been treated with an intervention) and death when they are given with aspirin and heparin.(50),(51) An increased incidence of major bleeding in patients receiving abciximab was found to be avoidable by utilizing lower doses of heparin.(51)

The optimal use of intravenous IIb/IIIa receptor inhibitors in patients with UA appears to be in conjunction with an antithrombin drug, such as heparin. Without the concomitant use of heparin, the IIb/IIIa inhibitors were less effective. But in combination with heparin, IIb/IIIa inhibitors reduced the incidence of myocardial infarction and death at 48 hours and 30 days.(52),(53),(54) In order to avoid bleeding the heparin dose must not be excessive. Weight-adjusting the heparin dose helps in this regard.

An oral form of IIb/IIIa inhibitors may offer the possibility of chronic administration and extended effects. Initial studies are evaluating the role of oral IIb/IIIa inhibitors after coronary stent placement(55) and in patients with acute coronary syndromes.(56),(57) Future large scale studies will help define the role for oral IIb/IIIa inhibitors in coronary interventions and in the treatment of UA.(58)

B. Ticlopidine

Ticlopidine (Ticlid®), given orally, inhibits the aggregation of platelets by acting on transduction of the ADP signal. Like aspirin, ticlopidine , given as 250 mg twice a day, has been shown to decrease the incidence of myocardial infarction and death in patients with UA.(59) Unlike aspirin, however, beneficial effects of ticlopidine may not be apparent for at least a week, mostly because of its pharmokinetic profile. In combination with aspirin, ticlopidine helps prevent subacute thrombosis after coronary stent deployment. Though ticlopidine is usually discontinued one month after coronary stent placement, hematologic monitoring during that time may be required to detect neutropenia.(60),(61),(62)

C. Clopidogrel

Another agent that works through ADP transduction to inhibit platelet aggregation is clopidogrel (Plavix®). Clopidogrel is structurally similar to ticlopidine. Given at 75 mg orally once a day, clopidogrel was deemed efficacious compared to aspirin in secondary prevention in patients with a history of stroke, myocardial infarction or peripheral vascular disease. There was no increase in side effects over aspirin, including no excess neutropenia.(63) Both clopidogrel and ticlopidine can be used in patients who have an intolerance to aspirin.(5) Combination therapy that includes aspirin and in addition either ticlopidine or clopidogrel has not been fully evaluated but, theoretically, may offer significant advantages.

Antithrombins (Low-Molecular-Weight Heparin)

Low-molecular-weight heparin (LMWH) differs from standard heparin in that the polysaccharide chain binding to the antithrombin III complex is shorter and of lower molecular weight. This is achieved by fractionation. Several proposed benefits of LMWH over standard unfractionated heparin include:

  1. greater inhibition of Factor Xa, which may provide improved activity against existing thrombus;
  2. the level of anticoagulation is more predictable and the bioavailability greater, enabling subcutaneous delivery and eliminating the need for routine anticoagulation monitoring; and
  3. a considerably lower incidence of heparin-induced thrombocytopenia.(64)

In patients with UA, LMWH is beneficial when added to aspirin(65) and is comparable to unfractionated heparin, without causing an increase in major bleeding.(66) Existing LMWH's include dalteparin (Fragmin®), nadroparin (Fraxiparin®), and enoxaparin (Lovenox®).

These agents differ in the degree of inhibition of factor Xa.(67) Enoxaparin has the highest degree of anti-Xa activity and, in one study, was demonstrated more efficacious than unfractionated heparin in reducing the risk of recurrent angina, myocardial infarction and death in patients with UA or NQMI over a 30 day period.(68) In this study, Enoxaparin was given at 1 mg per kilogram of body weight subcutaneously every 12 hours for a minimum of two days and maximum of eight days. Importantly, the optimal duration of antithrombin therapy in hospitalized patients and potentially in outpatients has yet to be determined.(69)

Early Invasive Therapy and the Role of Revascularization

For UA patients, a debate exists as to when to perform coronary angiography and revascularization. Two large trials evaluating two management strategies have been the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial and the Veteran Affairs non-Q-wave Infarction Strategies in Hospital (VANQWISH). These trials compared an early invasive strategy involving cardiac catheterization and revascularization, if appropriate, against a more conservative strategy of medications alone without early catheterization. In the conservative strategy other noninvasive tests were used for risk stratification and catheterization was only done later if these tests indicated a higher liklihood of adverse prognosis. These trials did not clearly establish an advantage to either strategy.(70),(71) Because of high crossover rates, however, the number of revascularizations between the groups in both these studies were very close.(5)

UA management ultimately centers on individualization of therapy and the concept of plaque stabilization or passivation. If ischemia cannot be controlled on medical therapy, then coronary angiography with intent of revascularization is warranted. An intra-aortic balloon counterpulsation device may be placed in the catheterization laboratory to assist with stabilization, if necessary.(72) Patients controlled on medical therapy who would reasonably require cardiac catheterization prior to hospital discharge include those deemed to have increased risk or those with compromised left ventricular function.

Patients with UA who have normal left ventricular function, no elevation in troponins, lower levels of presenting angina, minimal changes on presenting ECG and age under 70 years old, are in a lower risk category.(73) In these patients with low risk clinically, a noninvasive stress test can be performed, if desired, to provide further risk stratification.

Contention remains regarding when to perform routine revascularization in patients admitted with UA. The proposed benefit of plaque passivation with medical therapy, prior to any revascularization, must be weighed against the risk of plaque progression, adverse clinical events and a possible prolonged hospital stay.(74),(75)

Summary

Recent developments and insights have added to the arsenal used in the management of UA. New therapeutic options focus on promising antiplatelet and antithrombin agents. The markers for myocardial injury, which are used in UA and the prognostic significance of these markers, are being investigated and defined. Debate remains regarding the timing of intervention in UA treatment as medical therapy changes and stent deployment increases. Ongoing large-scale studies will offer clarification in the applicability and role of these new modalities.
Footnotes

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