The recognition of the proximate role of coronary thrombosis secondary to plaque rupture or erosion as the underlining cause of ST-segment elevation acute myocardial infarction (AMI) opened the door to the development of pharmacologic and mechanical interventions that have saved countless lives from a disease process that previously had few options and carried a high mortality rate. Thrombolytic agents were the first to provide substantial and sustained improvements in the morbidity and mortality of AMI. Summarized in this chapter are the key trials of thrombolytic agents and adjuncts to fibrinolysis along with recommendations for their application in AMI.

The discovery that hemolytic streptococci produce a thrombolytic substance is attributed to a 1933 report by Dr. William Smith Tillett.¹ However, it would be another 50 years before streptokinase was systemically evaluated in the treatment of AMI. Although sporadic use of streptokinase in AMI was reported during that interval, concerns regarding antigenicity, hemodynamic effects, efficacy, dosing, timing, and even method of delivery restricted acceptance. In 1986, the landmark Gruppo Italiano per la Sperimentazione della Streptochinasi nell’ Infarto Miocardico (GISSI) study was published demonstrating a marked improvement in AMI survival with treatment.² The GISSI study evaluated 11,806 patients presenting with an AMI within 12 hours of symptom onset. Patients were randomized to treatment with streptokinase or placebo, with both groups otherwise receiving standard of care. There was a significant reduction in 30-day and 1-year mortality compared with placebo (10.7% vs 13.0% and 17.2% vs 19.0%, respectively). It was observed that the more rapidly a patient received streptokinase from symptom onset, the greater the mortality benefit. The results were confirmed by the Second International Study of Infarct Survival Collaborative Group (ISIS-2) trial (see below),³ resulting in the acceptance of streptokinase as first-line treatment of AMI.

With the therapeutic benefits of streptokinase well established, pharmaceutical research and development turned to identifying agents with greater specificity for fibrin and with fewer side effects. There are currently four US Food and Drug Administration (FDA)-approved thrombolytic agents for the use in the United States: streptokinase, alteplase, reteplase, and tenecteplase (Table 17-1). The three fibrin-specific agents are discussed in the following sections.

Alteplase

Alteplase (tPA) is a recombinant tissue plasminogen activator. It promotes fibrinolysis by converting plasminogen to plasmin. The efficacy and safety of tPA were evaluated and compared with streptokinase in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO)-I trial published in 1993.⁴ The investigators randomized 41,021 patients presenting with an AMI into 1 of 4 treatment regimens: (1) streptokinase 1.5 million units over a 60-minute period, with subcutaneous heparin at 12,500 units twice daily, beginning 4 hours after the start of thrombolytic therapy; (2) streptokinase 1.5 million units over a 60-minute period, with an intravenous heparin bolus dose of 5000 units and infusion of 1000 units per hour adjusted for an activated partial thromboplastin time between 60 and 85 seconds; (3) accelerated tPA in a bolus dose of 15 mg, followed by a 0.75 mg/kg of body weight infusion over 30 minutes (not to exceed 50 mg), followed by 0.5 mg/kg over the subsequent 60 minutes (not to exceed 35 mg), with the same intravenous heparin regimen as arm 2; and (4) the combination of intravenous tPA as a 1.0 mg/kg infusion over 60 minutes (not to exceed 90 mg, with 10% given in a bolus dose) and streptokinase (1.0 million units over 60 minutes) given simultaneously but through separate intravenous catheters, along with intravenous heparin. The results demonstrated a statistically significant reduction in mortality at 24 hours and at 30 days with accelerated tPA and intravenous heparin compared with streptokinase (10 lives saved per 1000 patients treated). However, there was an increased risk of hemorrhagic stroke in the accelerated tPA arm compared with streptokinase (2 hemorrhagic strokes per 1000 patients treated). Despite the increased risk of intracranial bleeding, tPA was easier to use, lacked the antigenicity of streptokinase, and had an overall mortality benefit. As a result, tPA rapidly became the preferred agent for the treatment of AMI.

Reteplase

Reteplase (rPA) is a deletion mutant of recombinant plasminogen activator. The key differences are that it lacks the kringle-1, finger, and growth factor portions of wild-type tPA. These differences result in the same specificity for fibrin but decreased affinity, with a longer half-life, making it suitable for bolus administration.⁵ The pilot evaluations of rPA compared with tPA were the Reteplase Angiographic Phase II Interventional Dose-Finding Study (RAPID)-I and RAPID-II.^6,7 These studies demonstrated a slight increase in the rate of artery patency by coronary angiography at 90 minutes without an increase in the risk of bleeding. However, the key registration trial, GUSTO-III, demonstrated essentially no differences in mortality or bleeding between rPA and tPA.⁸ The primary advantage of rPA is thus easier administration (as a double bolus) compared with the bolus plus infusion regimen of tPA.

Tenecteplase

Tenecteplase (TNK) is a genetically altered variant of tPA with three amino acid substitutions. The result is a more fibrin-specific lytic, with a longer half-life and greater resistance to plasminogen activator inhibitor 1 (PAI-1).⁹ This allows TNK to be administered as a single bolus. The key registration trial of TNK was the Assessment of the Safety and Efficacy of a New Thrombolytic Study (ASSENT)-2 head-to-head comparison with tPA. As with GUSTO-III, the results of the study demonstrated no difference in 30-day mortality or intracranial hemorrhage. Of note, there were statistically significantly fewer nonintracranial bleeding events and a lower need for transfusions; these observations were attributed to the increased fibrin specificity of TNK. Given the ease of administration, equivalent efficacy, and slightly improved bleeding profile, TNK now enjoys the largest share of the thrombolytic market for AMI in the United States.

While the seminal trials of fibrinolysis in AMI incorporated heparin anticoagulation, there still remained a significant risk of reinfarction and subsequent angina, heart failure, or death attributable to vessel reclosure within 30 days of randomization.¹⁰ As a result, investigators have evaluated a series of adjunct therapies to the thrombolytic agents to reduce the incidence of coronary artery rethrombosis and its consequences.

Low-Molecular-Weight Heparin

Low-molecular-weight heparin (LMWH) is an attractive alternative to unfractionated heparin (UFH) for several reasons. The action of LMWH is to inhibit the coagulation cascade at an earlier point in the cascade than heparin. LMWH also proportionally inhibits the activity of factor Xa versus factor IIa to a greater extent than UFH. Theoretically, this reduces thrombin generation and provides for a more even and reliable anticoagulant effect. Additionally, in the absence of renal dysfunction, there is little need for monitoring. In the Enoxaparin Versus Unfractionated Heparin With Fibrinolysis for ST-Elevation Myocardial Infarction–Thrombolysis in Myocardial Infarction (ExTRACT TIMI)-25 trial, the investigators compared enoxaparin and UFH as adjunctive therapy for fibrinolysis in AMI. The choice of thrombolytic agent (streptokinase, tPA, rPA, or TNK) was left to the discretion of the treating physician.¹¹ In the trial, 20,506 patients were randomized in a 1:1 fashion to either LMWH or UFH based on the thrombolytic they received. The results demonstrated a significant reduction in the primary end point of death or nonfatal myocardial infarction with LMWH compared with UFH (9.9% vs 12.0%; P < .001). Additionally, there was a significant reduction in the secondary end point of death, nonfatal reinfarction, or need for urgent revascularization (11.7% vs 14.5%; P < .0001). The benefits came at a cost of increased risk of major bleeding (2.1% vs 1.4%; P < .001) at 30 days. Of note, enoxaparin was continued to the end of the index hospitalization, whereas UFH was continued for 48 hours, suggesting a possible explanation for the observation of increased bleeding.

Fondaparinux

Fondaparinux is an anti-Xa inhibitor with a half-life of 16 to 24 hours. The seminal trial of fondaparinux in ST-segment elevation myocardial infarction was the Effects of Fondaparinux on Mortality and Reinfarction in Patients With Acute ST Elevation Myocardial Infarction–Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-6 trial. In OASIS-6, 12,092 patients presenting with an AMI were randomized to receive fondaparinux 2.5 mg daily for up to 8 days versus usual care (placebo or UFH). Of these patients, 2692 received thrombolytic therapy and fondaparinux, whereas 2744 received thrombolytic therapy with usual care.¹² Rate of death or reinfarction at 30 days was lower in those treated with fondaparinux versus UFH/placebo (9.7% vs 11.2%; P < .008), with a trend toward lower bleeding events. Of note, fondaparinux alone as an anticoagulant is not recommended in patients undergoing percutaneous coronary intervention (PCI) secondary to the observation of guide catheter thrombosis in OASIS-6.

Bivalirudin

Bivalirudin is a short-acting (half-life ~25 minutes) direct thrombin inhibitor that acts on both clot-bound and unbound thrombin.¹³ It is highly specific and does not result in platelet activation. It also partially inhibits platelets via blocking the binding of thrombin to the platelet protease activated receptor (PAR)-1. As an adjunct to thrombolytic therapy, bivalirudin was studied in the Hirulog Early Reperfusion Occlusion (HERO)-2 trial, which enrolled 17,073 patients presenting with an AMI to receive bivalirudin or UFH with standard-dose streptokinase.¹⁴ The trial demonstrated no significant difference in mortality at 30 days (10.8% vs 10.9%, respectively; P = .85). There was a statistically significant increase in mild to moderate bleeding but not severe or intracranial bleeding with bivalirudin treatment. Given the lack of mortality benefit and increased bleeding profile, bivalirudin is not recommended for routine use in the initial treatment of AMI after thrombolysis except in patients with a history of heparin-induced thrombocytopenia.

Platelet Glycoprotein IIb/IIIa Inhibitors

The platelet glycoprotein IIb/IIIa receptor inhibitors are a potent group of medications whose effect is directed at blocking platelet aggregation. The final common pathway of platelet activity is a conformational change in the glycoprotein IIb/IIIa receptor allowing for cross-linkage with other platelets via dimeric adhesion molecules. This process stabilizes thrombus and contributes to resistance to fibrinolysis and to artery reocclusion. A series of studies have been performed evaluating the efficacy of glycoprotein IIb/IIIa receptor blockade with thrombolytic therapy. Small dose-finding studies such as the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis–Acute Myocardial Infarction (IMPACT-AMI) trial of eptifibatide with tPA¹⁵ demonstrated improved patency rates when compared with placebo, prompting several large phase III studies. Among these, the GUSTO-V trial was a large multicenter, randomized, open-label trial that randomized 16,588 patients to standard-dose rPA or half-dose rPA plus full-dose abciximab. Both treatment arms also received UFH and aspirin. The study failed to produce a significant difference in the primary end point or mortality at 30 days. Although secondary end points including reinfarction, recurrent ischemia, and the need for “bailout” revascularization were significantly reduced, this was offset by an approximate doubling in nonintracranial bleeding and other measures of bleeding. Given the lack of mortality benefit and the increase in bleeding complications, routine use of glycoprotein IIb/IIIa inhibitors in combination with thrombolytic therapy is not recommended.

Aspirin