Fibrinolytic Therapy with tPA Failed Because it was Based on a Flawed Concept Introduction

J Cardiol, Cardiovasc Ther, Victor Gurewich
2018 J Cardiol & Cardiovasc Ther   unpublished
The science historian Thomas Kuhn observed that science tends not to progress as a linear accumulation of new knowledge, but rather undergoes periodic revolutions which he called paradigm shifts [1]. He found that a paradigm shift was required before new findings that challenge a long-accepted concept or established practice are adopted by the scientific community. This observation is particularly relevant to fibrinolysis where a therapeutic regimen based on the premise that tPA was alone
more » ... tPA was alone responsible for fibrinolysis has resulted in this therapy becoming prematurely discredited and replaced. Primary percutaneous coronary intervention (PCI) is now the treatment of choice for AMI, and other endovascular procedures are being used increasingly in ischemic stroke as well. However, a technically demanding hospital procedure inevitably delays myocardial or brain reperfusion on which the salvage of function and reduction of mortality depend. In non-human primates, the duration of coronary occlusion is the main determinant of myocardial infarct size [2]. In human AMI, when coronary reperfusion takes place within two hours of the event, infarct size measured 2% by scan whereas the figure jumped to 12% one-hour later. After four hours, little further cardiac damage occurred showing that it was already at maximum [3]. Similarly, in a study of primary PCI, it was pre-procedural patency (TIMI-3) and not post PCI patency that was the independent predictor of one year survival [4]. In another study, the 6 month mortality in higher risk AMI patients increased from 5% to 13% when reperfusion was delayed from less than two to four or more hours [5]. These findings underscore the importance of prompt reperfusion, preferably within two hours of the event. For most patients, this is readily achievable only with fibrinolytic therapy that can be administered intravenously before catheterization could be done. Unfortunately, current fibrinolytic therapy with tPA is neither sufficiently effective nor safe enough to make this a realistic option. Even when tPA was used as an adjunctive treatment, so-called facilitated PCI, tPA had to be abandoned because it significantly increased the bleeding and rethrombosis complication rate from the procedure [6]. Therefore, a better, safer fibrinolytic regimen is required to make early reperfusion in AMI or ischemic stroke feasible. Abstract Fibrinolytic therapy has become synonymous with tPA based on the belief that tPA alone was responsible for natural fibrinolysis. Although this assumption was belied from the outset by disappointing clinical results, it persisted, eventually causing fibrinolysis to be discredited and replaced by an endovascular procedure. Since time to reperfusion is the critical determinant of outcome, which in acute myocardial infarction (AMI) means within two hours, a time-consuming hospital procedure is ill-suited as first line treatment. For this purpose, fibrinolysis is better suited. The assumption that tPA is responsible for fibrinolysis is contradicted by published findings. Instead, tPA initiates fibrinolysis which is continued by urokinase plasminogen activator (uPA) which has the dominant effect. tPA and uPA gene deletion and clot lysis studies showed the activators to have complementary functions, requiring both for a full effect at fibrin-specific doses. They are also synergistic in combination thereby requiring much lower doses. A clinical proof of concept study in 101AMI patients was published. Each received a mini IV bolus of tPA followed by a 90 minute infusion of pro-uPA, the native form of uPA. A near doubling of the 24h TIMI-3 infarct artery patency rate compared to tPA was obtained. In further contrast to tPA, there were no reocclusions and the mortality was only 1%. A sequential combination of both activators, mimicking natural fibrinolysis, holds promise to significantly improve the efficacy and safety of therapeutic fibrinolysis.