On May 9 and 10, 1996, an international workshop on antithrombotic therapy for acute coronary syndromes was organized in Como, Italy, by the Divisione di Cardiologia of the Policlinico S. Matteo of the University of Pavia, Italy; The Cleveland Clinic Foundation of Cleveland, Ohio; and the Hemophilia and Thrombosis Centre Angelo Bianchi Bonomi of Milan, Italy. This workshop could not have come at a better time. Large multicenter trials on the use of direct antithrombins in acute coronary syndromes (GUSTO IIb and TIMI 9b) recently were completed, and the preliminary results of a series of other studies with a new class of antiplatelet agents (inhibitors of the final common pathway of platelet aggregation, the glycoprotein [GP] IIb/IIIa receptor) in patients undergoing coronary interventions had been released during the preceding months.
The rationale for the use of these new antithrombotic agents, the pivotal role of thrombin and platelets for thrombus formation on the surface of a rupturing plaque, was discussed in depth by hematologists during the first part of the meeting. The hypotheses derived from their experimental work are now well accepted by clinicians and have been designated the “thrombin” and “GPIIb/IIIa” hypotheses in acute coronary syndromes. Clinical validation of these hypotheses was the topic of the second part of the meeting.
The international multicenter trials GUSTO IIb and TIMI 9b have tested the thrombin hypothesis by comparing a direct antithrombin, hirudin, with standard heparin in studies of ±12 000 and of ±3000 patients, respectively, who had an acute coronary syndrome. The overall results of both trials were considered disappointing. Nevertheless, combined analysis of the results of both trials suggests a modest but significant reduction of 13% (P=.026) in the (re)infarction incidence with this agent at 30 days (corresponding to an absolute reduction of 9 events per 1000 patients treated) without a striking effect on mortality. Possible explanations for these modest results were discussed. A partial explanation, supported by coagulation data from the GUSTO IIb trial, is that although hirudin is a more potent inhibitor of thrombin activity compared with heparin, its effect on thrombin generation is the same or less than that of heparin. Therefore, as soon as the infusion is stopped, no further benefit can be expected from hirudin. The significant reduction in end points observed during the period of hirudin infusion in GUSTO IIb (first 24 to 48 hours), the absence of any additional effect afterward, and the very similar findings with the same agent in the HELVETICA trial in patients undergoing angioplasty support this idea and suggest that prolonged administration of a direct antithrombin is needed to “passivize” the ruptured coronary plaque and get the full benefit of direct thrombin inhibition.
As usual, when a nice hypothesis proves to be less promising in the clinical setting, another one emerges rapidly. In patients undergoing coronary interventions the impressive reduction in ischemic coronary events observed with c7E3, a monoclonal antibody directed against the GPIIb/IIIa receptor on the platelet membrane, was considered to be a strong support for the GPIIb/IIIa hypothesis. A meta-analysis presented at the meeting of different small studies on the use of GPIIb/IIIa antagonists in ±1200 patients with unstable angina suggested the possibility of a 40% to 50% reduction in the composite of death, (re)infarction, and refractory ischemia. Ongoing and planned prospective trials with these agents in patients who have unstable angina (PARAGON, PURSUIT, PRISM, and PRISM plus) and in patients who have ST-segment elevations receiving thrombolytic therapy (IMPACT-AMI, PARADIGM, PARAMOUNT, and GUSTO IV) were considered important. These trials eventually should indicate whether the GPIIb/IIIa hypothesis is more valid than the thrombin hypothesis. Other developments deemed attractive at the workshop were the combined use of GPIIb/IIIa inhibitors and direct antithrombins (preliminary work in animals supports this concept), inhibition of the extrinsic pathway at an upper level (eg, Xa, VIII, and tissue factor), and the combined use of agents that inhibit both thrombin generation and activity. The workshop concluded that more basic and clinical work is needed.
- Copyright © 1996 by American Heart Association