Use of Concomitant Glycoprotein IIb/IIIa Inhibitors with Catheter-directed Peripheral Arterial Thrombolysis

Abstract

THROMBOSIS of a peripheral artery or bypass graft can result in severely compromised nutrient blood flow to the limb. If left untreated, gangrene can develop and amputation may be necessary. When peripheral arterial thrombosis is diagnosed, percutaneous delivery of thrombolytic agents offers the opportunity to restore circulation and expose any underlying culprit lesion responsible for the occlusion. All clinically available thrombolytic agents are plasminogen activators; they convert plasminogen to its active form plasmin. Fibrin-bound plasmin then cleaves the insoluble fibrin polymer, forming smaller, soluble fibrin degradation products. If all goes as planned, antegrade arterial blood flow is restored and limb perfusion is returned to normal. Thrombolytic agents were first discovered in the early 1930s, when Tillett and Garner (1) noted fibrinolytic properties of a product of the bacterium streptococcus. Of necessity, however, clinical use of this “streptococcal fibrinolysin” awaited the formulation of a suitably pure form of the agent. After investigation in animal models of vascular thrombosis (2) and after testing intrapleural administration of the newly renamed agent streptokinase in patients with loculated hemothoraces (3), Tillett and colleagues (4) infused the agent into the veins of a small number of volunteers; this seminal work was published in 1955. Just 1 year later, Cliffton and Grunnet (5) published a report on the administration of a streptokinase and plasminogen mixture to dissolve pathologic occlusive thrombi in peripheral vessels. Interestingly, some of Cliffton’s patients were treated through a primitive catheter-directed intraarterial approach (5,6). Unfortunately, innovation in the development of thrombolytic strategies slowed dramatically thereafter. Novel approaches to intraarterial thrombolytic therapy awaited the development of adequate guide wire and catheter technical armamentaria and the emergence of a cadre of interventionalists skillful in the use of percutaneous techniques. Although quantum leaps would not be realized for years to come, a group led by Dotter (7) popularized catheter-directed thrombolytic infusion in the 1970s with use of low-dose streptokinase in an effort to limit distant bleeding complications. A decade later, McNamara and Fischer (8) published excellent results with catheter-directed urokinase (UK) administered in very high doses for just a few hours, then in decreasing doses in a stepwise fashion over a period as long as 2 days. By the decade of the 1990s, UK was the most commonly employed peripheral thrombolytic agent. The Rochester (9), STILE (10), and TOPAS (11,12) randomized clinical trials established the utility of catheter-directed thrombolysis in comparison with primary operative therapy. Virtually all thrombolytic cases in the United States were performed with use of UK, an agent that became the workhorse of the peripheral interventionalist. Then, with little warning, the US Food and Drug Administration raised concerns about the manufacture of UK, and its manufacturer, Abbott Laboratories, voluntarily withdrew UK from the marketplace in early 1999 (13). Although the controversy over UK was at first greeted with gloom by interventional radiologists and vascular surgeons, the absence of this familiar agent prompted investigation into alternative thrombolytic agents and treatment strategies. Alteplase, reteplase, and tenecteplase were studied (14). Many practitioners became relatively comfortable with the alternate agents, although anecdotal impressions surfaced suggesting that these alternative agents may be associated with an increased risk of hemorrhage. So while clinicians were comfortable adding full systemic heparinization to a regimen of intraarterial UK, heparin was kept to minimal, almost homeopathic doses with the other agents (15). In this renewed era of investigation stimulated by the loss of UK from the marketplace, clinicians sought alternate treatment strategies to enhance the efficacy of thrombolytic therapy. These investigations arose after realFrom the Department of Vascular Surgery, Desk S40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. Received March 10, 2004; accepted March 10. Address correspondence to K.O.; E-mail: ourielk@ccf.org