NEW ORLEANSAlteplase (Activase), a tissue plasminogen activator
(tPA) produced by recombinant DNA, appears to be a safe, feasible,
and economically attractive alternative to urokinase (Abbokinase) for
clearing occluded central venous access devices (CVADs), a study
among cancer patients shows.
CVAD occlusion occurs in up to 25% of all catheters placed, and
prevents infusion and/or withdrawal of materials, John Patrick
Timoney, PharmD, Memorial Sloan-Kettering Cancer Center, said at the
36th Annual Meeting of the American Society of Clinical Oncology (ASCO).
Occlusions can be caused by fibrin sheath formation, thrombosis, poor
positioning, or mechanical malfunction. The consequence can be need
for surgical removal, treatment delays, and loss of treatment
optionswith concomitant increased risk of morbidity, Dr.
Timoney said. Reports have estimated that 64% of CVAD occlusions are thrombotic.
Urokinase is currently the only thrombolytic agent FDA approved for
clearance of occluded catheters. In December 1998 and in January
1999, however, the FDA issued warnings regarding possible viral
contamination of urokinase.
Stimulated by those warnings, the Memorial Pharmacy and Therapeutics
Committee began to search for an alternative. This led to research
showing that cryopreserved and subsequently thawed dilutions of
alteplase were effective in ophthalmic applications. Streptokinase
was ruled out as an alternative, Dr. Timoney noted, because of its
potential for causing allergic reactions.
Dr. Timoney said that in one previously published small series,
alteplase successfully cleared catheters with radiologically
demonstrated thrombus where urokinase had failed, without adverse
events. In a larger randomized study, clots were resolved, with a
single dose, in 18% of 22 patients receiving urokinase and in 46% of
28 patients receiving alteplase.
There were concerns, Dr. Timoney said, over cost, vial size, and
stability. The agent is supplied (by Genentech) in 50 mg vials with
only 8-hour stability after reconstitution. That would have a
significant financial impact on an institution if you could not use
the entire vial, Dr. Timoney commented.
Frozen Alteplase Tested
Taking their cue from a report by Jaffe and coworkers of clinical
activity for up to a year for frozen alteplase, Dr. Timoney and his
colleagues froze 2.5 mL aliquots of alteplase in 5 mL vials at
20°C after aseptically reconstituting it from the 50 mg
vials with 50 mL of sterile water. An expiration date of 30 days was
determined based on published ophthalmologic effectiveness reports.
The 5 mL vials were thawed as needed.
With the aim of evaluating safety and efficacy, data were
prospectively monitored on 165 attempted clearances in 121 cancer
patients over a 4-month period. The alteplase dose was 1 mg/mL in a
volume sufficient to fill the catheter, which translated into a dose
of 2 mg for a standard 2 mL catheter.
Analysis showed that out of 165 attempts at catheter clearance, 133
were successful for an 80% success rate. The mean dwell time was 45
minutes (range, 1 to 250). There were no treatment-associated adverse events.
A cost analysis showed also that using all of the agent from the 50
mg vials makes alteplase about $30 cheaper per dose than urokinase.
We feel confident, Dr. Timoney concluded, that
cryopreservation does not alter the effectiveness of alteplase and
makes it an economically feasible alternative to urokinase for safe
and effective clearance of occluded CVADs.