Diagnostic Imaging
November 2003

INTERVENTION

Revolution storms along in thrombolytic agents

Alteplase took over, but its 15 minutes of fame may end now that urokinase is back on the market

Imagine the following motion picture script: For years, interventional radiologists search for an optimal thrombolytic agent. They need a drug that is potent and safe to perform up to 120 tasks, from clearing a stent to treating a patient with acute stroke. Then, urokinase shows up.

For 20 years, urokinase dominated the picture, but its fall and return played out just like the movies. The FDA pulled the plug on the drug in 1999, citing flawed manufacturing practices, but cleared it again for marketing in 2002. Unlike the movies, however, there is no such thing as a still frame in clinical practice. During those three years, the set had changed.

"When urokinase went off the market, we went through a learning curve to work out how to use tissue plasminogen activator (tPA)," said Dr. G. David Dixon, an interventional radiologist at St. Luke's Hospital in Kansas City, MO.

By the time urokinase had been removed from interventional radiologists' shelves, the drug's safety record had been well established. In contrast, the first sizable study to suggest that alteplase was just as safe and efficient as urokinase-the STILE trial-had been published only a few years earlier (Ann Surg 1994;220:251-268). Alteplase is known as tPA or rt-PA and manufactured by Genentech under the trade name Activase.

The short duration of tPA's use did not discourage physicians from using it at the time. They learned to use it successfully both at academic centers and in private practices, and they continue to turn to this agent, Dixon said.

No real alternative was available at the time the rug was pulled out from under urokinase. Clinicians were reluctant to experiment with reteplase (rPA, manufactured by Centocor as Retavase) and streptokinase (manufactured by Hoechst Marion Roussel and Pharmacia & Upjohn as Streptase and Kabikinase, respectively). Although clinicians considered tPA adequate to take urokinase's place, it was not an easy change.

"We had to figure out what the appropriate dose for tPA in the same setting was. And that took some time," said Dr. Kieran Murphy, director of interventional neuroradiology at Johns Hopkins University.

Safety was a huge concern among specialists wrestling with dose control, Murphy said. JHU physicians knew, for instance, exactly what 100,000 units of urokinase could do. What effects could a 1-mg dose of tPA have? Calculating the right dose for a particular application, such as acute stroke or peripheral thrombosis, was far more complex than just drawing equivalence charts per application based on urokinase.

"It took us a while and a little research to figure out that 20 mg of tPA was equivalent to about, roughly, a million units of urokinase," Murphy said. "That meant going to the peer-reviewed literature, seeing what was used in Europe, and working up the appropriate doses."

Alteplase use did not become established without much questioning and skepticism. Even in Canada, where a protocol using tPA for acute ischemic stroke within three hours of symptom onset was approved in 1999, the controversy regarding its safety raged on. The drug's bleeding complication rate was the major concern for many clinicians on both sides of the border. Some patients would bleed profusely at the catheter's puncture site and also in their gums or nose.

Intracranial hemorrhage was the most feared complication, however, and the grounds for concern were well documented. Some data on patients treated for myocardial infarction with tPA indicated that at least 1% had suffered intracranial hemorrhage. Many interventionalists took a cautious approach when they started using the drug. No one really knew whether they would get better results or face similar-or even worse-complications, said Dr. Dominic 'Nick' C. Yee, an interventional radiologist for In-vision Imaging in Inglewood, CO.

In their 2000 review of the existing clinical literature, Stanford University interventionalists cited the benefits of using alteplase, compared with surgery, for treatment of peripheral arterial occlusive disease. They noted that the risk of adverse bleeding seemed related to both overall dose and duration of infusion (J Vasc Intervent Radiol 2000;11:149-161).

When physicians realized that the doses they were using for certain applications, such as peripheral arterial thrombolysis, were too high, they immediately responded. They found that tPA was still as effective as urokinase, even at lower doses, Yee said.

"In the literature, the dosing was anywhere between 3 to 5 mg/hour of tPA. We rapidly went down to 1 mg/hour," Yee said. "Most people felt very comfortable with doing 0.25 and even 0.5 mg/hour, and they found it was still effective. It's probably not as quick as a much higher dose, but it's still faster than urokinase."

Dr. Michael F. Mastromatteo, a clinical instructor of interventional radiology at Beth Israel Deaconess Medical Center, found other advantages to alteplase.

"TPA continues to work even after the last dose you give, whereas urokinase has a relatively short half-life," he said.

The sudden practice shift forced upon radiologists, however, had consequences for both clinicians and patients. A number of interventionalists, fearing litigation arising from the procedure's uncertain complication rate, limited the number of cases they took on. Others dropped thrombolysis altogether.

"It was a detriment when urokinase got pulled off the market," said Dr. Randy Stickney, an interventional radiologist for Tulsa X-Ray Laboratory in Oklahoma. "It hurt us. We probably did not take on some cases that we used to take on, because we had more confidence in urokinase."

With urokinase back on the market, interventional radiologists are wondering what shape the field of thrombolysis will take in a few years. For some, it is only a matter of time before Abbokinase-Abbot Laboratories' trade name for urokinase-regains the position it once had. Abbott is trying to raise awareness among clinicians about its return, according to Tareta Adams, public affairs manager for the hospital products division. The company remains confident in the product's long-term prospects.

"Physician feedback and sales trends confirm that physicians still want this product," Adams said.

Some interventional radiologists confirm that assertion.

"I'd like to get it back on my shelf," said Dr. Mary E. Jensen, director of interventional neuroradiology at the University of Virginia.

Jensen had used Abbokinase for intracranial thrombolysis. Alteplase's clot-dissolving capabilities, on the other hand, never impressed her, and she had to deal with its hemorrhagic complications. Physicians like her could potentially switch back to urokinase. Justifying its cost to their respective hospital's pharmacies remains an issue, however.

"I have no apprehensions or concerns about urokinase whatsoever. It is an extremely good thrombolytic agent that was very successful in our hands in a variety of circumstances," said Dr. David Hunter, director of interventional radiology at the University of Minnesota. "The drug is, however, very expensive and relatively slow."

Hunter thinks urokinase could eventually find its own niche in thrombolysis, but its cost will limit that niche. The issue of cost remains a marginal one at this stage, however. Even though urokinase once dominated thrombolysis, the field has changed dramatically. Only three years later, competing against similar or new drugs is less important than finding a place where new techniques are being embraced. A number of studies presented in April at the 28th annual meeting of the Society of Interventional Radiology in Salt Lake City confirm this trend. The trials reviewed new thrombolytics, combined therapies, and the use of mechanical devices for thrombolysis.

The APART-Phase II trial in Germany assessed the role of abciximab (ReoPro), a glycoprotein IIb/IIIa platelet inhibitor as an adjunct to reteplase in patients with peripheral artery occlusion. The researchers found that the combined abciximab-reteplase treatment was safe and efficient, and it helped reduce the number of leg amputations. Their findings validated results from the PROMPT trial, which found that a GP IIb/IIIa inhibitor used in combination with urokinase was safe and more efficacious than urokinase alone.

In another study, Louisiana investigators evaluated tenecteplase (TNK) in peripheral thrombolysis. They found that treatment with TNK was not only safe and feasible, but also faster and less likely to have bleeding complications than tPA.

Another team of researchers in Germany presented its findings on the use of a transcatheter ultrasound thrombolysis system (Acolysis, manufactured by Vascular Solutions), which they tested alone or in combination with either thrombolytics or balloon angioplasty in patients with peripheral arterial occlusions. They found that blood flow restoration was successful in 92.9% percent of patients treated with transcatheter ultrasound therapy alone.

"Even the new thrombolytic agents will prove to be relatively similar in their efficacy and safety patterns when used with appropriate regimens," Hunter said. "The use of adjunctive agents such as ReoPro, anti-inflammatory agents, other antiplatelet agents, and mechanical devices will definitely change the picture of how thrombolytic drugs are used."

Others believe that training physicians to perform these techniques is far more important than the preference for a particular thrombolytic or procedure.

"We need to figure out ways of delivering the drugs intelligently to allow more physicians to be able to perform these procedures," Murphy said. "Otherwise, there will always be only a couple hundred people in the country who can do it."

Only 3% of acute stroke patients are treated, according to Murphy. He thinks physicians need to come up with ways of treating people for acute stroke with thrombolytics that cross economic boundaries.

"Otherwise, we are only making healthcare better for a tiny, tiny percentage of people in the planet," Murphy said.