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(Circulation. 1997;95:793-795.)
© 1997 American Heart Association, Inc.

Articles

Confusion in Reperfusion

Problems in the Clinical Development of Antithrombotic Drugs

Francesca Catella-Lawson, MD; Garret A. FitzGerald, MD

the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia.

Key Words: Editorials • thrombolysis • platelet aggregation inhibitors

	Introduction

 
A paradoxical effect of the administration of thrombolytic drugs, such as recombinant tissue plasminogen activator (rTPA) and streptokinase, is marked platelet activation in vivo.^{1 2} Multiple experiments in animal models attest to the functional importance of this observation.^{3 4} However, perhaps the most convincing evidence is that the effects of aspirin, which inhibits thromboxane (Tx) A₂–dependent platelet activation, and streptokinase are roughly additive in reducing 30-day mortality in patients presenting with myocardial infarction.⁵ The data supporting the concomitant use of heparin with therapeutic thrombolysis in this disease are somewhat less convincing.^{6 7} However, this may reflect such variables as the timing and route of heparin administration.⁸ Comparable efficacy of unfractionated and low-molecular-weight heparins has recently been established in the treatment of unstable angina.⁹ However, irrespective of the quality of the evidence, heparins are commonly administered to patients with myocardial infarction in combination with thrombolytic drugs and aspirin.

Given the multiple pathways by which platelets may be activated, it seems surprising that a drug such as aspirin should exhibit clinical efficacy in the prevention of thrombosis. Perhaps this reflects its role in blocking formation of TxA₂, an amplification signal for other platelet agonists.¹⁰ However, the quest for a more potent but well-tolerated platelet inhibitor continues. This has proven to be no easy task, as exemplified most recently by the outcome of the CAPRIE trial of clopidogrel.¹¹ This drug, a thienopyridine, like ticlopidine, predominantly inhibits platelet activation induced by ADP, although the precise molecular basis of action of these compounds remains to be . . . [Full Text of this Article]

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