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When urokinase was gone: commentary on another year of thrombolysis without urokinase.

A shortage of urokinase developed in the United States in 1999 as a result of a U.S. Food and Drug Administration (FDA) intervention. Although not banned by the FDA, the manufacturers stopped production and marketing of urokinase in the United States. This was the result of concerns raised by a routine, 1998 inspection of Abbott Laboratories, the only provider of recombinant urokinase (Abbokinase; Abbott Laboratories, Abbott Park, IL) in the United States, and BioWhittaker, the only source of the human neonatal kidney cells used by Abbott (1,2). Consequently, new approaches to peripheral vascular thrombolysis were developed, most notably using recombinant tissue plasminogen activator (rt-PA) (Alteplase; Genentech, South San Francisco, CA) based regimens. Most practitioners quickly exhausted their urokinase supplies and altered their practice of pharmacologic peripheral vascular thrombolysis (3). Shortly after the withdrawal of urokinase from the U.S. market, we conducted a pilot e-mail survey of the practice of peripheral vascular thrombolysis (3). The findings of this survey suggested that there were substantial problems in making the transition from the use of urokinase to rt-PA, although expert opinion at the time stated that the two agents should have similar efficacy and safety (4) and the FDA encouraged “physicians to consider the appropriateness of other treatment options” while listing the alternative agents (1). Most respondents to the pilot survey reported a reduction in efficacy and an increase in hemorrhagic complications. This was reflected in several reports and numerous anecdotes of an increased risk of bleeding complications, leading to a need to reduce the dose of rt-PA and the level of heparin anticoagulation (5–7). Some of these initial problems seem to have been related to incorrect dosing and the use of full anticoagulation with heparin, which had been the usual practice when using urokinase (6). Over time, the recommended dose of rt-PA for peripheral vascular thrombolysis was reduced. The use of heparin infusion was either discontinued or continued at a subtherapeutic level (5–8). Others recommended the use of r-PA (reteplase; Centocor, Malvern, PA), which was reported to cause fewer bleeding complications (8). To assess the effects of the withdrawal of urokinase on the practice of peripheral vascular thrombolysis after this initial period of adjustment, we conducted a larger survey just more than 1 year after the cessation of production and marketing of urokinase in the United States. This provides some insight into the way in which the practice of pharmacologic thrombolysis has changed and the effect of these changes on outcomes.