Combination therapy: management of acute myocardial infarction in the new millennium.

This is an overview of current and investigational options available to Emergency Physicians for the management of acute myocardial infarction (AMI). New fibrinolytic agents with differing fibrin specificity and longer half-lives have demonstrated substantial improvements over older agents, allowing the optimization of dosage regimens, permitting us to investigate prehospital administration, and permitting us to see the importance of adjunctive medical therapies. Fibrinolytic therapy has unquestionably improved the treatment of acute myocardial infarction, reducing mortality by 50% when administered in the first hour following onset of symptoms and by 30% when administered within 12 h of symptom onset (1–5). Clearly, faster reperfusion reduces mortality, and a major responsibility for reducing the time to reperfusion falls on the emergency medical team from ambulance response to management of disease in the Emergency Department (ED). Survival depends on efficient left ventricular functioning, and left ventricular functioning is dependent on having a patent artery and perfusion in the microvasculature. The more muscle that is preserved, the higher the ejection fraction. Myocardial necrosis is reduced with prompt reperfusion following successful thrombolysis; therefore, ventricular function also is preserved, and survival is improved (6–8). Administering t-PA in the accelerated (90-min) dosing regimen produces a mean of 72% and 85% infarct vessel patency (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60and 90-min angiography, respectively (9–12). However, patency with a fibrinolytic will be achieved rapidly in only a number of patients, regardless of dosing. There are some patients who will not develop TIMI 2 or 3 flow with fibrinolytic agents alone, and of those who achieve patency, approximately half will experience recurrent ischemia or reocclusion in the ensuing hours to days (13–15). Thus, despite progress in fibrinolytic strategies and high acute patency rates, optimal (prompt, complete, and sustained) myocardial reperfusion (TIMI-3 flow) occurs in only about one-fourth of all treated patients (14). In our quest to achieve quicker reperfusion, an initial step was to increase the amount of lytic agent since thrombolysis is dose dependent. This was accompanied by an unacceptable increase in the incidence of bleeding and intracranial hemorrhage (ICH) as seen with the 150-mg dose of t-PA, and more recently in TIMI 10B with higher doses of TNK t-PA. Similarly, increasing heparin had an adverse effect on mortality and bleeding if the activated partial thromboplastin time (aPTT) were not kept in a 50to 70-s window of time, as seen in GUSTO I. In addition, following cessation of heparin therapy, the rebound effect results in hypercoaguability. Of all antiplatelet agents, it appears that those in the newest class, inhibitors of the platelet surface receptor glycoprotein (GP) IIb/IIIa, present a low potential for excessive bleeding and ICH. In pooled data from clinical trials of the GPIIb/IIIa inhibitors, the rate of excess major bleeding in the first 30,000 patients was 1.3%. However, a substantial amount of that bleeding was seen in the earliest trials when unfractionated heparin was given at full dose, and vascular sheaths were left in place longer. When the amount of heparin was reduced, the amount of bleeding events was comparable to placebo. The incidence of ICH with IIb/IIIa inhibitors is virtually identical to placebo (GPIIb/IIIa inhibitors 0.10% vs. placebo 0.09%). These agents occupy the GPIIb/IIIa receptor to prevent the binding of fibrinogen and clot formation. The GPIIb/IIIa receptor is the final common pathway receptor involved in platelet aggregation and, therefore, agPlease note the changes made to this article since its first printing: on page 33S, right column, line 17, “TIMI 11B” is now “TIMI 10B.” On page 34S, left column, line 31, the sentence should read “In TIMI-14, the 32% rate of TIMI-3 patency provided by abciximab was shown to be equal to the patency provided by streptokinase.” On page 35S, left column, the last sentence now reads “[A]lthough early benefits of lamifiban therapy were seen in this study, the 30-day primary composite end point was similar between the patients randomized to lamifiban and the patients who received placebo.” Finally, on page 36S, the legends to Figures 2 and 3 have been transposed. Therefore, the legend to Figure 2 now reads “TIMI 3 flow in TIMI-14” and Figure 3 now reads “SPEED: TIMI 3 flow at 60–90 min.” The Journal of Emergency Medicine, Vol. 19, Supplement, 33S-38S, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/00 $–see front matter