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CLINICAL STUDIES

Overcoming thrombolytic resistance

Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction

^a Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

Manuscript received January 4, 1999; revised manuscript received May 27, 1999, accepted June 30, 1999.

Reprint requests and correspondence: Dr. Christopher P. Cannon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115
ccannon{at}rics.bwh.harvard.edu

OBJECTIVES

We sought to review the emerging data and the clinical rationale for combining glycoprotein (GP) IIb/IIIa inhibitors with thrombolytic therapy for acute myocardial infarction (AMI).

BACKGROUND

Although thrombolytic therapy has been a major advance in the treatment of acute ST segment elevation MI, new single-bolus thrombolytic agents have been unable to break the "thrombolytic ceiling" in infarct-related artery (IRA) patency.

METHODS

Recent literature on GPIIb/IIIa inhibitors in acute coronary syndromes was reviewed.

RESULTS

A new approach toward improving current thrombolytic–antithrombotic regimens focuses on "targeted therapy" for each component of the occlusive coronary thrombus: fibrin, thrombin and platelets. For the fibrin component, front-loading and/or bolus dosing of plasminogen activators (PAs) has identified the currently available doses of tissue-type plasminogen activator (t-PA) and recombinant tissue-type plasminogen activator (r-PA). For the thrombin component, several recent trials have shown that lower doses of heparin improve the safety profile of the thrombolytic-antithrombotic regimen. For the platelet component, aspirin has been shown to be effective, but the GPIIb/IIIa inhibitors offer the potential for more effective platelet inhibition and improved clinical efficacy. The benefits of GPIIb/IIIa inhibition in reducing death, MI or urgent revascularization in the setting of percutaneous coronary intervention are well established. Emerging experimental and clinical data now suggest that combining GPIIb/IIIa inhibition with reduced-dose thrombolytic therapy may improve early IRA patency without increasing bleeding risk.

CONCLUSIONS

Given the strong clinical and physiologic rationale, clinical investigation in acute ST segment elevation MI is currently focused on combining the potent GPIIb/IIIa receptor inhibitors with reduced-dose fibrinolytic agents in acute MI, with the goal of overcoming "thrombolytic resistance."

Abbreviations and Acronyms   AMI = acute myocardial infarction   GP = glycoprotein   GUSTO = Global Utilization of Streptokinase and TPA for Occluded arteries   ICH = intracranial hemorrhage   IRA = infarct-related artery   MI = myocardial infarction   PAI-1 = plasminogen activator inhibitor-1   PCI = percutaneous coronary intervention   r-PA = recombinant plasminogen activator   TIMI = Thrombolysis In Myocardial Infarction   TNK-tpa = TNK–tissue-type plasminogen activator   t-PA = tissue-type plasminogen activator   TxA2 = thromboxane A2

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