Introduction Robert Roberts, MD

T he benefit of intravenous thrombolytic therapy in acute myocardial infarction (MI) has been firmly established by national and international clinical

trials. Thrombolysis induced within the early hours of the onset of infarction is associated with limitations of infarct size, improved ventricular function, and a low hospital morbidity. However, soon after the initial trials, it be- came clear that lysis induced by thrombolytic therapy was followed by a significant incidence of reinfarction (lo%), just as was observed with the putative spontaneous lysis that occurs with non-Q-wave infarction. The need for adjunctive therapy was appreciated and a significant reduction in reinfarction was observed with aspirin.

Recent studies suggest that heparin may reduce the reocclusion rate after thrombolysis in patients receiving recombinant tissue-type plasminogen activator (rt-PA). Ongoing research has also identified potential adjunctive strategies for future study that may shorten the time to thrombolysis and prevent reocclusion. Among these agents are thrombin, platelet and small peptide inhibi- tors, factor VIIa complex, monoclonal antibodies to platelet glycoprotein IIb/IIIa, and activated protein C. In addition, some studies have suggested that /3 blockers, calcium antagonists, angiotensin-converting enzyme in- hibitors, and nitrates also may be useful adjuncts to thrombolytic therapy.

When thrombolytic therapy was first introduced, it was administered through the intracoronary route, and it became standard practice to administer heparin, proba- bly to avoid catheter-related problems. It then became evident that intravenous administration was an effective alternative that would also minimize complications. In the absence of data from a prospective clinical trial, phy- sicians continue to administer heparin with the conviction that it prevents reocclusion and, based on clinical data and rational empiricism, aspirin was added in the hope of preventing platelet aggregation and rethrombosis. The results of the Second International Study of Infarct Sur- vival (ISIS-2) indicated improved survival in patients

From the Department of Cardiology, Baylor College of Medicine, Houston, Texas.

Address for reprints: Robert Roberts, MD, Baylor College of Mcdi- tine, 6535 Fannin, MS F-905, Houston, Texas 77030.

who received aspirin in conjunction with a thrombolytic agent. The results of several trials showing significant benefit in patients with ischemic cardiac disease, includ- ing unstable angina, further solidified the recommenda- tion that aspirin be a part of routine postthrombolytic therapy. The most recent study by Theroux et al of pa- tients with unstable angina shows marked reduction in the incidence of reinfarction with aspirin and a similar benefit with heparin and is relevant because a significant proportion of patients with unstable angina exhibit coro- nary thrombi. In the recent American College of Cardiol- ogy/American Heart Association (ACC/AHA) guide- lines on the early management of patients with acute MI, it is recommended that aspirin be administered (160 mg immediately and continued on a daily basis indefinitely) in patients receiving thrombolytic therapy.

The role of heparin as an adjunctive treatment during and after thrombolytic therapy for acute MI remains highly controversial. Interest in this topic intensified after the publication of the Second Gruppo Italian0 per lo Studio della Soprawivenza nell’Infarto Miocardico study, which reported that the addition of heparin to

Robert Robertrr, MD

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 25, 1991 1A

A SYMPOSIUM: ADJUNCTWE THERAPIES IN THROMROLYSIS

thrombolytic agents (streptokinase and t-PA) did not induce a further reduction in mortality. These findings prompted the statement, in a recent review by Yusuf et al, that “at present, adjunctive heparin therapy is not indi- cated in patients with acute MI who have been treated with thrombolytic therapy.” In contrast, the recently published ACC/AHA guidelines strongly recommend the use of heparin in combination with or immediately after thrombolytic therapy.

The paucity of data regarding the comparative effica- cy of adjunctive heparin versus adjunctive aspirin led to the Heparin-Aspirin Reperfusion Trial (HART). HART, a multicenter study involving 3 university hospi- tals, compared heparin with aspirin in 205 patients with acute MI who received t-PA. At 18 hours, 82% patency was observed in the heparin-treated patients, compared to 52% in the group that received t-PA plus aspirin, a difference that was statistically significant. These data suggested that the high early patency rates associated with t-PA can be sustained only with early concomitant systemic heparinization and not with aspirin as adjunc- tive therapy. These data are supported by a pilot study (Bleich et al) in which patients were randomized to t-PA plus heparin or t-PA alone. As in HART, sustained pa- tency rates were significantly higher in the patients treat- ed with a combined regimen of t-PA plus heparin. Recent evidence from the European Cooperative Study Group Trial (ECSG-6) also confirms the value of intravenous heparin as an adjunct to thrombolytic therapy with t-PA.

These studies, in conjunction with the Australian Na- tional Heart Foundation Study, confirm the necessity of heparin as adjunctive therapy when using t-PA in pa- tients with acute MI. In addition, the results suggest that heparin is only necessary for the initial 24 to 48 hours,

after which aspirin alone appears adequate. Aspirin in- hibits platelet aggregation by inhibiting the synthesis of thromboxane and thus its beneficial results are expected. In contrast, the beneficial effect of heparin is more difti- cult to understand because heparin has no effect on plate- lets per se. Because the studies suggest that heparin is more effective during the first 24 to 48 hours after initia- tion of thrombolytic therapy, when thrombin levels are increased, it is reasonable to postulate that heparin exerts its antiplatelet action by neutralizing thrombin, a sub- stance known to induce platelet aggregation. The ACC/ AHA guidelines strongly recommend the use of heparin in combination with or immediately after thrombolytic therapy.

The role of fi blockers and calcium antagonists as adjunctive agents remains to be resolved. These agents are often used during acute MI in the absence of reperfu- sion therapy, but little data are available as to whether either or both of these agents are beneficial after throm- bolytic therapy. The results of the Second Thrombolysis in Myocardial Infarction (TIMI-2) study suggested that /3 blockers may be beneficial in preventing myocardial ischemia after thrombolysis. In ISIS-2 there was a sug- gestion that fl blockers may prevent myocardial rupture; however, this was not confirmed in the TIMI- study. The ACC/AHA guidelines note that use of a calcium antagonist may be preferable to a /3 blocker after reperfu- sion because of the enhanced vasomotor activity pro- duced by recanalization.

The papers included in this supplement entitled “Ad- junctive Therapies in Thrombolysis” will further explore the role of heparin, aspirin, /3 blockers, calcium antago- nists, and other new investigative approaches for anti- platelet and anticoagulant activity.

PA THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67