Reperfusion Therapies for Acute ST Elevation Myocardial Infarction

Historical Perspective

Thrombosis was implicated as the cause of acute myocardial infarction (MI) almost a century ago. However, the pathophysiology remained obscure and, as recently as 44 years ago, many investigators believed that thrombosis was a secondary event. Chazov and Rentrop demonstrated that recanalization was achievable pharmacologically with favorable clinical consequences. Thus the concept of reperfusion therapy for acute ST elevation myocardial infarction (STEMI) was born by demonstrating that ischemic injury could be attenuated by restoration of myocardial perfusion.

Underlying this concept was a hypothesis formulated by Dr. Eugene Braunwald: MI evolves dynamically, the magnitude of irreversible injury sustained is related to the duration of ischemia, and the clinical consequences of infarction are a reflection of the extent of irreversible injury sustained. It was postulated that reduction of myocardial oxygen requirements, enhancement of myocardial perfusion, or both when implemented within the first few hours after the onset of myocardial ischemia would reduce the magnitude of irreversible injury sustained by the myocardium and improve prognosis. Thus reperfusion—first with pharmacologic agents and later with primary percutaneous coronary intervention (primary PCI)—was consistent with Braunwald's hypothesis, resulting in marked improvements in prognosis. Prior to the reperfusion era, hospital mortality from acute STEMI approached 25% ; with reperfusion therapy, the current STEMI mortality rates in the United States are less than 5%.

Coronary Thrombosis and the Pathogenesis of Acute Myocardial Infarction

Although Herrick attributed fatal acute MI to a thrombotically occluded coronary artery in 1912, autopsy studies in the late 1970s did not demonstrate coronary thrombosis in patients who had died of acute MI. Thus coronary thrombosis was considered a consequence, rather than the underlying cause, of acute MI. In 1980, DeWood and colleagues reported the results of coronary angiography performed early after the onset of acute transmural MI: within 4 hours of symptom onset, 87% of infarct-obstructed arteries were completely occluded. However, 12 to 24 hours after onset, the prevalence of coronary occlusion was only 65%. When patients with subtotal occlusion of the obstructed artery were included, the prevalence of angiographically demonstrable coronary thrombosis in the first 4 hours was 98%. Over the past decade, further understanding of the pathology underlying acute coronary occlusion has come from autopsy studies, angiography, and intracoronary imaging: underlying culprit soft lipid plaques, thin cap fibroatheromas, bulky plaques with characteristic erosion, and/or calcified nodules have all been found to predispose to plaque rupture and coronary occlusion ( Fig. 11.1 ). Efforts to reduce mortality have focused on both prevention of plaque rupture and rapid restoration of blood flow in thrombotically occluded coronary arteries.

This chapter addresses the developments in reperfusion therapy for STEMI responsible for a profound improvement in survival ( Fig. 11.2 ).

Thrombolytic Agents: The First Pathway to Coronary Reperfusion

Coronary blood flow depends upon a complex balance between thrombosis, thrombolysis, and counterregulation by inhibition of both processes. From recent intravascular ultrasound and optical coherence tomography studies, we now know that underlying plaques prone to thrombosis are characterized by thin cap fibroatheromas (TCFA), lipid-rich cores, erosion of the intima, and calcified nodules : the rupture of an underlying atherosclerotic plaque leads to thrombosis due to the procoagulant effects of exposed collagen, von Willebrand factor, and tissue factor in the vessel wall. Activation of platelets accompanying the vascular injury accelerates ongoing thrombosis. Thrombin and fibrin generated by the coagulation cascade may undergo concomitant or subsequent lysis resulting from activation of the fibrinolytic system and conversion of the zymogen plasminogen to the active serine protease, plasmin, by the circulating plasminogen activators, tissue-type plasminogen activator (tPA) or urokinase plasminogen activator (uPA). Any strategy designed to reduce myocardial damage must enhance the rapidity and extent of recanalization and promote sustained patency.

The available thrombolytic agents are plasminogen activators. These agents function as proteases that directly or indirectly hydrolyze a single peptide bond (Arg ⁵⁶¹ Val ⁵⁶² ) on the inactive substrate molecule, plasminogen, to form the active serine protease enzyme, plasmin. Plasmin is responsible for the degradation of fibrin and diverse other proteins, with consequent dissolution of intravascular thrombi. First-generation agents (nonfibrin selective) include streptokinase and urokinase. Second- and subsequent-generation (fibrin-selective) agents include tPA, rPA, and molecular variants of tPA such as tenecteplase (TNK tPA). Agents that are relatively fibrin specific, such as tPA, produce less depletion of fibrinogen, less plasminemia, and less depletion of α ₂ -antiplasmin than that seen with nonfibrin-specific agents, such as streptokinase. The pathophysiology and development of fibrinolytic agents has been extensively reviewed by the original investigators.

Magnitude and Timing

Fibrinolysis was initially evaluated using an invasive, intracoronary infusion methodology. Rentrop and colleagues, using intracoronary SK, demonstrated improved cardiac function and alleviation of chest pain accompanying recanalization compared with intracoronary nitroglycerin alone or conventional therapy. The Western Washington randomized trial substantiated the efficacy of intracoronary SK in lysing coronary thrombi, with favorable effects on mortality. However, constraints on the availability of immediate cardiac catheterization, time delays, increased costs, and risk limited enthusiasm for intracoronary administration as primary therapy for patients with acute MI.

Early patency trials employed angiographic endpoints to delineate patency 90 minutes after the administration of a thrombolytic agent. Patients with Thrombolysis in Myocardial Infarction (TIMI) 2 (slow) or TIMI 3 (normal) flow grades were considered together in delineating overall patency incidence. Even when no thrombolytic agent is given, patency rates range from 9% to 29% in the 0- to 90-minute interval. Considerable “catch up” occurs (i.e., patency attributable to endogenous fibrinolysis), as judged from results of arteriography performed later. The magnitude of restoration of flow appears to be a major determinant of benefit. Patients with delayed transit of contrast in the infarct-related artery (TIMI grade 2 flow) may not be exhibiting optimal or adequate recanalization. The Second Thrombolytic Trial of Eminase in Acute Myocardial Infarction (TEAM-2) study analyzed data with respect to flow in patients treated with nonfibrin-specific plasminogen activators. When TIMI flow grades were considered with respect to enzymatic and electrocardiographic markers of infarct size, no statistically significant difference was seen for TIMI flow grades 0, 1, or 2. However, better outcomes were seen with TIMI grade 3 flow. The GUSTO-I angiographic study confirmed this association between magnitude of flow restoration and outcomes. Lack of patency (TIMI grade 0 or 1) was associated with the highest mortality rate (8.9%). Traditionally defined patency (TIMI grades 2 and 3) was associated with a lower mortality rate (5.7%, P = .004). The mortality for patients with TIMI grade 2 flow was 7.4% and numerically lower (4.4%) for those with TIMI grade 3 flow ( P = .08). The GUSTO-I angiographic trial directly compared SK and tPA. Front-loaded tPA was associated with complete reperfusion at 90 minutes (TIMI grade 3) in 54% of patients. With SK, complete reperfusion occurred in fewer than 32% of patients. Patency trials have consistently shown more rapid and complete reperfusion with clot-selective agents.

Fibrinolysis efficacy is not only related to magnitude of reperfusion but also to timing of administration. Fresh clots lyse much more rapidly than older ones in which fibrin cross-linking has proceeded. Intervention within 30 to 60 minutes is likely to be particularly beneficial because more myocardium will remain viable and therefore amenable to salvage and because clot lysis will be much more rapid and complete. Accordingly, the rapidity with which patients are treated should be maximized. Current American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend the earliest possible application of therapy (within 30 minutes of emergency department arrival) with fibrinolysis for patients with STEMI (Class 1A recommendation).