Alfimeprase Promising For Peripheral Arterial Occlusions

By Bruce Jancin

ROME -- The novel investigational thrombolytic agent alfimeprase might represent a big step forward in the treatment of noncoronary thrombotic occlusions, Dr. Stephen T. Kee said at the annual meeting of the Cardiovascular and Radiological Interventional Society of Europe.

Alfimeprase has received orphan drug status from both the Food and Drug Administration and the European Medicines Agency for treatment of peripheral arterial occlusion; results of phase III trials are due early next year.

Phase III trials of alfimeprase for central venous catheter occlusion are also ongoing, and Nuvelo Inc., the drug's developer, has scheduled clinical trials on deep venous thrombosis (DVT) to begin in the spring.

"I think this is an exciting drug. It potentially will once and for all get rid of the cerebral hemorrhage issue that surrounds us all when we try and treat these patients [using conventional thrombolytics]," said Dr. Kee, chief of interventional radiology at the University of California, Los Angeles, Medical Center.

That's because alfimeprase is rapidly inactivated by alpha2-macroglobin upon reaching the general circulation. Unlike tissue plasminogen activator (TPA) and other thrombolytics currently used to treat DVT and peripheral arterial occlusion, it can't act systemically, according to Dr. Kee.

Alfimeprase is derived from the venom of the southern copperhead snake. In addition to the lytic's probable safety advantage, it resolves clots in several hours.

This is far faster than current thrombolytics, which are typically administered via a multisidehole infusion catheter for 24-50 hours or longer under close monitoring in an ICU or step-down unit.

Dr. Kee usually approaches catheter-directed thrombolysis (CDT) for DVT through the ipsilateral popliteal vein. The rationale for CDT is that it removes the thrombus with minimal risk of systemic thrombolysis and hemorrhage.

The result is alleviation of painful leg edema along with preservation of venous valve function, prevention of pulmonary emboli, and avoidance of postthrombotic syndrome, he said.

Even when current thrombolytic agents for CDT are used, the associated risk of intracranial hemorrhage is lower than most physicians outside interventional radiology think, Dr. Kee said. In a pooled analysis of 19 studies, it was just 0.2%, and some of those studies used dosages higher than dosages that are now standard.

Today, TPA (Activase, Cathflo) is by far the most commonly used and most cost-effective agent, according to Dr. Kee. Reteplase and tenecteplase also are used in CDT. They are quite expensive because they come only in large vials suitable for treatment of acute MI. However, some hospital pharmacies will break down a 50-mg vial of tenecteplase, making it far more affordable.

Streptokinase and urokinase, both formerly popular in treating DVT, are now seldom used.

Who is a good candidate for CDT? Patients with acute iliofemoral DVT on ultrasound or ascending venography, because they have twice as great a risk of postthrombotic syndrome as do patients with only femoropopliteal DVT.

"When I'm talking to my patients, I make sure they understand that from the knee to the foot, you've got about six veins; from the knee to the hip, you've got three veins; and from the hip to the inferior vena cava, you've got one. And if that one vein has clot, you're in big trouble. A thrombosed iliac vein will rarely spontaneously recanalize," Dr. Kee said.

CDT in patients with clot in the inferior vena cava affecting both legs not only provides symptomatic relief and prevents pulmonary emboli but also preserves visceral organ function.

In femoropopliteal DVT, however, the threshold for intervention should be higher than at the other sites, because there is as yet no evidence that it prevents postthrombotic syndrome.

When asked to comment on this presentation, Dr. Anthony Comerota, director of the Jobst Vascular Center in Toledo, stated: "Those involved in the field are awaiting the analysis and release of the phase 3 trials in patients with acute peripheral arterial occlusions. I think this new class of drugs will have excellent potential for the rapid treatment of patients with extensive DVT.

"There are considerable data demonstrating the benefit of thrombus resolution in these patients. We know that venous patency is preserved along with valve function. What is needed is good level I data to establish a strategy of thrombus removal as standard of care for patients with extensive, symptomatic DVT," Dr. Comerota concluded.