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.
Table 17-1Comparison of the Available Thrombolytics ||Download (.pdf) Table 17-1 Comparison of the Available Thrombolytics
| ||Streptokinase ||Alteplase (tPA) ||Reteplase (rPA) ||Tenecteplase (TNK) |
|Molecular weight (kDa) ||47 ||70 ||39 ||70 |
|Dosage ||1.5 million units infused over 30-60 min ||15-mg bolus, then 0.75 mg/kg 30-min infusion (max, 50 mg), then 0.5 mg/kg 60-min infusion (max, 35 mg) ||Double bolus 10 IU 30 min apart ||Single bolus 0.5 mg/kg |
|Half-life (min) ||20 ||4 ||15 ||17-25 |
|Fibrin specificity ||– ||++ ||+ ||+++ |
|Fibrinogen depletion ||++++ ||++ ||+++ ||+ |
|Antigenicity ||++ ||– ||– ||– |
|90-min coronary patency ||+ ||++ ||+++ ||+++ |
|ICH risks ||+ ||++ ||++ ||++ |