Management of Acute Coronary Syndromes with Emphasis on New Information for the Treatment of ST-Segment Elevation Acute Myocardi

Author(s): 

A. Michael Lincoff, MD

Acute coronary syndromes, which include unstable angina (UA), non-Q wave myocardial infarction (NQWMI) and ST-segment elevation acute myocardial infarction (AMI), represent the most common diagnoses for admission of patients with cardiovascular disease. In 1999, these disorders were responsible for approximately 1.5 million hospital admissions in the United States.1 The predominant risk factors for heart disease are smoking, abnormal cholesterol levels (total cholesterol, high-density lipoprotein, and low-density lipoprotein), physical inactivity, excess weight, diabetes mellitus, hypertension, advanced age and male sex.2

Both atherosclerotic plaque and the resultant thrombus created by the procoagulant response to vessel injury create luminal obstruction. Depending on the extent and duration, vessel obstruction or occlusion can be expressed in the broad range of symptoms associated with acute coronary syndromes (ACS). In UA and NQWMI, the distinguishing pathogenic lesion is most frequently a platelet-rich, non-occlusive thrombus overlaying an acutely fissured plaque. In AMI, the overlying thrombus is more often completely occlusive.3

The benefit of any reperfusion strategy is dependent not only upon the early, complete, and sustained restoration of infarct-related artery flow, but also on effective reestablishment of perfusion to the myocardium. However, epicardial vessel patency and microvascular perfusion are not always closely partnered.4 This failure of reperfusion is thought to be the consequence of distal embolization of platelets and inflammatory cells resulting from lysis of the occlusive epicardial thrombus, as well as ischemia and reperfusion injury associated with inflammatory cell infiltration and tissue edema. Therefore, while bolus administration of fibrinolytic agents may reduce the time to treatment and medication errors, the problems of fibrinolytic resistance associated with the platelet-rich thrombus, distal embolization of platelet-leukocyte aggregates, and ischemia-reperfusion induced microvascular dysfunction may not be overcome by improvements in fibrinolytic and antithrombin (e.g., heparin, low-molecular-weight heparin, bivalirudin) therapies alone.

Several aspects of fibrinolytic therapy are known to compromise its efficacy. First, it is known from phase II angiographic studies that even newer fibrinolytic regimens are unable to provide complete restoration of normal epicardial flow [Thrombolysis in Myocardial Infarction (TIMI) 3] in 30–50% of patients.5 Furthermore, among patients achieving TIMI 3 flow, myocardial contrast echocardiography (MCE) documents abnormal perfusion in 16–30% of patients.4,6,7 These persistent defects are associated with reduced myocardial recovery, reduced ejection fraction and increased clinical events.6,8 One factor contributing to abnormal microvascular perfusion is distal embolization of atherothrombotic debris from the upstream epicardial lesion, as evidenced by post mortem studies of MI tissue, and local responses to cellular ischemia, including endothelial cell swelling and leukocyte accumulation associated with ischemia and reperfusion injury.

Because the glycoprotein (GP) IIb/IIIa receptor is the final common pathway for platelet aggregation, several agents that specifically antagonize fibrinogen binding by the GP IIb/IIIa receptor have been developed in an effort to improve the efficacy of treatment options in the management of ACS and reduce acute complications associated with percutaneous coronary interventions.3 Unlike aspirin, platelet GP IIb/IIIa blockers prevent the binding of fibrinogen to the GP IIb/IIIa receptor, and thus inhibit platelet aggregation regardless of the agonist pathway responsible for initiating activation and aggregation.3

These considerations provide the rationale for combining fibrinolytic therapy with potent platelet receptor inhibition by GP IIb/IIIa receptor antagonists. Thrombus is a conglomerate mesh of thrombin, fibrin and activated platelets.9 Although fibrinolytic therapy is able to digest this fibrin mesh, its actions may also be proaggregatory. Clot-bound thrombin molecules released into the fluid phase further activate the coagulant pathway (predisposing to rethrombosis) and recruit circulating platelets (by increasing platelet activation and adhesion molecule expression), thus perpetuating the formation of platelet-rich thrombi. Aggregated platelets are an abundant source of plasminogen activator inhibitor (PAI)-1 and platelet factor 4 (a natural antiheparin), further compromising the efficacy of fibrinolytic therapy.10

By blocking the final common pathway of platelet aggregation, GP IIb/IIIa receptor inhibition contributes to the disaggregation of platelet thrombus, reduces the impact of local platelet activation and may limit the platelet-leukocyte interactions in the distal microcirculation. Thus, by targeting each component of arterial thrombosis — fibrin, thrombin formation, and platelet aggregation — a combined pharmacologic reperfusion strategy may prove synergistic, enabling faster restoration of epicardial blood flow, reduced recurrent thrombosis, reduced distal embolization and reduced inflammatory cell aggregation, as well as providing a microenvironment that is more conducive to early percutaneous coronary intervention (PCI).

Interest is growing among cardiovascular interventionalists in achieving rapid and complete reperfusion in AMI by combining fibrinolytic monotherapy with rapid angioplasty or a fibrinolytic and a GP IIb/IIIa inhibitor followed by angioplasty. In the Strategies for Patency Enhancement in the Emergency Department (SPEED) trial, patients receiving combined reduced-dose reteplase (a fibrinolytic agent) and abciximab followed by PCI achieved an 86% rate of 90-minute TIMI 3 flow, with a trend toward improved clinical outcome.11 The TIMI-14 trials have provided further insights into the potential benefits of combined pharmacotherapy.9,12 Most recently, the results of the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-V trial suggest that combined fibrinolytic and platelet GP IIb/IIIa inhibitor therapy can provide better outcomes and reduced ischemic complications in AMI patients, thus establishing a new pharmacologic paradigm of care in AMI management.13


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