Managing Unstable Angina in High-Risk Patients (Part I)

Author(s): 

Derek P. Chew, MBBS and David J. Moliterno, MD

Platelets are now widely acknowledged as pivotal in the development of arterial thrombosis and its resultant acute ischemic coronary syndromes (ACS), including unstable angina (UA), non-Q wave myocardial infarction (NQWMI), ST-segment elevation acute myocardial infarction (AMI) and the acute ischemic complications of percutaneous coronary intervention (PCI).1 Injury to the endothelium of a coronary artery generally results in platelet adhesion, followed by platelet activation and aggregation. Platelet aggregation, in turn, causes thrombus formation. The extent of occlusion of the coronary artery by a thrombus generally determines the clinical presentation of ACS — whether as UA, NQWMI or Q-wave MI.2

Recognition of the compositional and pathophysiological differences between arterial and venous thrombi has contributed to recent advances in the management of ACS. Arterial thrombi are composed primarily of platelets with little fibrin and few erythrocytes (“white” thrombi), whereas venous thrombi are composed primarily of erythrocytes in a fibrin mesh (“red” thrombi). However, the distinction between these two types of thrombi is not absolute since the composition of thrombi is in a constant state of flux that is determined by the stage of thrombus formation. Thrombi that occur in coronary arteries of patients with stent thrombosis and UA are primarily “white” thrombi, whereas the more complete occlusions found in patients with AMI are more likely to be composed of “red” thrombi. This difference in the composition of thrombi may offer a partial explanation as to why fibrinolytic agents are effective as first-line treatment in patients with AMI but of no benefit in patients with UA or NQWMI.3

Platelet activation is mediated by multiple agonists and can occur via several different pathways. However, regardless of the agonist that stimulates platelet activation, a key component leading to formation of platelet-rich thrombi is the expression and activation of glycoprotein (GP) IIb/IIIa on the surface, enabling the binding of fibrinogen and other adhesive proteins to platelet receptor glycoprotein IIb/IIIa on multiple platelets.1,2,4,5 Consequently, research has focused on discovering antagonists of this receptor that could completely inhibit platelet aggregation and thereby reduce the morbidity and mortality associated with ACS.2

Risk Stratification in ACS
Patients with ACS are heterogeneous with respect to the severity and prognosis of their underlying disease. Early risk stratification allows for more appropriate decisions for admission and therapeutic triage of patients, and is essential in the selection of the most beneficial and cost-effective approach for the individual patient.6 Patient prognosis can be correlated with the Braunwald classification of UA, and an association between the severity of pain (Class III or C) and in-hospital event rates has been observed. The electrocardiogram (ECG) remains the gold standard for early diagnosis of AMI. However, in patients with UA, ECG results can be inconclusive. In patients presenting acutely with chest pain, approximately 40% will have a normal ECG, 26% will have inverted T-waves, and approximately 20% will have ST-segment depression.7

In recognition of the sweeping changes that have occurred in the practice of coronary angiography and intervention since the 1994 publication of the Agency for Health Care Policy and Research (AHCPR) guidelines, the American College of Cardiology (ACC) and American Heart Association (AHA) have recently revised guidelines for the care of ACS. With the increased utilization of coronary stenting and improvements in adjunctive pharmacology over the past 5 years, the relationship between specific AHA/ACC lesion morphology classifications and clinical outcomes has been obscured; the current task force committee has therefore recommended a change from the prior classification of lesion morphology toward a “low-risk, high-risk” patient-based classification.8

Multivariate analyses have shown age, history of significant documented coronary stenosis, significant ST-segment deviation, rest angina and elevation in serum cardiac-specific markers to be important risk predictors among patients presenting with non-ST segment elevation ACS. Serum cardiac troponin T and I levels are directly related to adverse patient outcomes and can provide prognostic information that is distinct from and additive to findings of elevated creatinine kinase-MB (CK-MB) (Figure 1).9 Furthermore, they are more sensitive than CK-MB.7 The development of rapid assays for the detection of serum markers of myocardial necrosis, such as troponin T and I, represents an exciting and useful advance. The presence of either elevated troponin T or I has been shown to be predictive of adverse clinical outcomes (death, MI, or need for revascularization).10 A direct, quantitative relationship between serum troponin level and the risk of subsequent ischemic events has been demonstrated10 in large, randomized, controlled clinical trials, including Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-IIa,11 GUSTO-III,12 Thrombolysis in Myocardial Infarction (TIMI)11a13 and Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC)-II studies.14 C-reactive protein levels, a nonspecific marker of inflammation, also provide additional information for risk stratification of patients with UA and NQWMI.8,10 In addition, other potentially useful markers such as brain (B-Type) natriuretic peptide are emerging.15

Patients with non-ST elevation ACS should be risk-stratified to permit selective application of more aggressive catheter-based therapeutic strategies. Risk can be assessed at the bedside on the basis of presenting symptom complex (Braunwald class of angina), the 12-lead ECG, serum biochemical markers and physical examination. Patients should be considered at particularly high risk if they show signs of left ventricular decompensation, hypertension or ischemic mitral valve dysfunction during episodes of angina. Characterization of anginal symptoms by Braunwald classification can help define risk for subsequent in-hospital death, MI or survival to 30 days. Similarly, the presence and magnitude of electrocardiographic ST-segment depression on the 12-lead ECG has been correlated with in-hospital and 30-day death rates.10

Traditional Management Strategies for ACS
The primary goals of therapy in the treatment of ACS are stabilization of an evolving coronary arterial thrombosis, restoration of coronary artery patency, alleviation of chest pain symptoms and prevention of AMI and sudden death. The two primary management strategies to achieve these goals are treatment with medical management (conservative strategy) and interventional therapies such as PCI (aggressive strategy).

Pharmacologic therapies recommended for the ACS patient usually include oral aspirin and intravenous heparin.3 Thrombus formation has long been known to be inhibited to a degree by aspirin and several other therapeutic agents. Heparin and aspirin are therapeutically useful in a variety of acute ischemic coronary syndromes, but neither has all the characteristics considered desirable in an ideal antithrombotic agent.

Aspirin inhibits cyclooxygenase, thereby preventing the production of thromboxane A2, but leaves open all the other agonist pathways — notably thrombin and adenosine diphosphate (ADP) — that lead to platelet activation. Although all platelet activation agonists utilize this pathway, most of them can also activate the glycoprotein IIb/IIIa receptor even if the cyclooxygenase pathway is blocked. Consequently, although aspirin is cost-effective, it is not a potent platelet antagonist because it leaves numerous alternative routes available for platelet activation.3,16

Heparin is routinely used in the treatment of ACS to limit further stimulation of platelet aggregation by thrombin and stabilization of the thrombus by fibrin. However, its effectiveness is reduced by several factors, most notably its inability to inhibit clot-bound thrombin. Heparin indirectly inhibits thrombin-mediated thrombosis, and is therefore dependent on antithrombin levels. Also, heparin has been associated with higher rates of hemorrhagic stroke when administered at high doses in patients receiving thrombolytic therapy; it also may activate platelets or cause thrombocytopenia and ischemic or hemorrhagic complications.3,17–21

Other pharmacologic therapies used in the management of UA/NQWMI include intravenous nitroglycerin and beta-blockers. Nitroglycerin is often used to alleviate the pain associated with cardiac ischemia because it dilates the coronary arteries and reduces cardiac preload.22 Beta-blockers are often used in the management of UA to slow the heart rate and reduce myocardial oxygen demand.22,23 Lipid-lowering agents are known to reduce long-term mortality in patients with stable coronary disease or significant risk factors.24 Data from the GUSTO-IIb and Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trials were used to compare all-cause mortality among patients with acute coronary syndromes who were discharged on lipid-lowering agents (n = 3,653) with those who were not (n = 17,156).24 Lipid-lowering therapy was associated with a lower rate of death at 30 days (0.5% versus 1.0%, respectively; p = 0.001) and at 6 months (1.7% versus 3.5% respectively; p < 0.0001).24 After adjustment for the propensity to be prescribed lipid-lowering agents and other potential confounders, prescription of a lipid-lowering agent at discharge remained associated with a reduced risk of death at 6 months (p = 0.023). Prescription of a lipid-lowering drug at hospital discharge was thus independently associated with reduced short-term mortality among patients after an ACS.24 Table 1 describes available therapies for treating patients with unstable angina.17–20,22,23,25–55

Conservative and Invasive Management Strategies
Two different treatment strategies are employed in the management of patients with unstable angina and NQWMI.22 In the “early conservative” strategy, coronary angiography is reserved for those patients with evidence of recurrent ischemia (angina at rest or with minimal activity, dynamic ST-segment changes) or a strongly positive stress test despite maximal medical therapy.22 The conservative approach spares the use of invasive procedures along with their associated risks and costs.22 In the “early invasive” strategy, patients who do not have clinically obvious contraindications to coronary revascularization are recommended for coronary angiography and, if possible, angiographically directed revascularization.22 The invasive approach can identify those 10–15% of patients who have no significant coronary stenoses as well as the approximately 20% of patients with 3-vessel disease with left ventricular (LV) dysfunction or left main coronary artery disease. Early PCI also offers the potential of reducing the risk for subsequent hospitalization and the need for multiple drug regimens to manage angina.22


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