State of the Art

Evolving Strategies for Thrombolytic Therapy of Peripheral Vascular Occlusion

PHARMACOLOGY OF FIBRINOLYTIC AGENTS

The principal fibrinolytic agents currently in use or under investigation are outlined in Table 1 (1, 2, 3). Three of these drugs have been used extensively in the treatment of peripheral vascular occlusions; several others have been studied in a limited fashion. The goal of current thrombolytic drug design is to alter fibrin specificity, plasma half-life, and antigenicity to make safer and more effective agents.

Streptokinase (SK) (Streptase; AstraZeneca, Westborough, MA), the first widely used

THE ABBOKINASE STORY

Abbokinase has been produced by tissue culture techniques since 1978 (15). The drug is derived from kidney cells of Colombian premature neonates who have died of natural causes. After informed consent is obtained from the parents, kidney cells are harvested and processed by a tissue culture company in Colombia. Exhaustive screening for infectious agents follows. This process includes testing donor serum and one of the frozen ampules of extracted kidney cells for aerobic and anaerobic bacteria,

RT-PA IN PERIPHERAL ARTERIAL OCCLUSION

Table 2 outlines the results of the major published series involving regional rt-PA infusion therapy for thrombotic or embolic peripheral arterial or bypass graft occlusions (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). Several conclusions can be drawn from analysis of these studies:

• 1.

  rt-PA is effective in recanalizing acute and subacute PAO in approximately 70%–90% of cases. The wide range in success rates is partially caused by varying definitions for initial technical or clinical

RT-PA VERSUS OTHER FIBRINOLYTIC AGENTS IN PERIPHERAL ARTERIAL OCCLUSION

Table 3 outlines the principal studies that have directly compared rt-PA with SK or UK in treating acute PAO (29, 30, 31, 32, 33). Several conclusions can be drawn from these data:

• 1.

  rt-PA is at least as effective as UK and SK in opening acute or subacute native arterial or bypass graft occlusions.

• 2.

  rt-PA-based lysis is faster than UK-based lysis at the doses tested.

• 3.

  There is a tendency toward more bleeding with rt-PA, although these differences were not statistically significant in all series.

INITIAL BOLUS DELIVERY OF RT-PA

In current practice, many interventional radiologists treat acute PAO by initially saturating the thrombus with a large dose of fibrinolytic agent via pulse-spray, lacing, or bolus technique to accelerate lysis and rapidly restore some flow to the ischemic extremity. This approach has been proven to accelerate clot lysis, presumably by increasing the surface area for plasminogen activation and by mechanically fragmenting thrombus (36, 37). Lysis is then completed by slower delivery of the agent

HEMORRHAGIC EVENTS WITH RT-PA

The primary concern of interventional radiologists who use rt-PA for PAO is the possibility of severe bleeding complications, most notably intracranial hemorrhage. This fear is fueled by reports of unusually high complication rates (including intracranial hemorrhage) in some series of thrombolysis, by the experience of cardiologists in treating acute coronary thrombosis with rt-PA, and by anecdotal reports (43, 44). Although rt-PA is far more specific for fibrin-bound plasminogen than for free

RT-PA IN EXTREMITY VENOUS THROMBOSIS

Most trials of rt-PA thrombolysis for lower extremity deep venous thrombosis have involved systemic administration of the drug with or without comparison to another fibrinolytic agent (51, 52, 53, 54, 55). Several recent reports describe local rt-PA therapy for extremity venous thrombosis (56, 57, 58, 59, 60, 61, 62, 63). A recent trial comparing regional rt-PA infusion (20 mg over the course of 4 h daily for up to 7 days) with regional UK infusion (100,000 IU/h for up to 7 days) described

RT-PA IN CLOTTED HEMODIALYSIS GRAFTS

Few published reports have focused on the use of rt-PA in thrombosed hemodialysis grafts and dialysis catheters, and most involved the now largely abandoned method of local infusion (66, 67, 68). With use of the pulse-spray pharmacomechanical technique, our group treated 23 clotted dialysis grafts with rt-PA (0.5 mg/mL) with a mean dose of 7.1 ± 3.6 mg and an average lytic infusion time of 32 minutes (69). All grafts were successfully opened. A single major bleeding complication occurred in a

RETEPLASE IN PERIPHERAL VASCULAR OCCLUSIONS

Catheter-directed thrombolysis of peripheral arterial, axillosubclavian vein, and iliofemoral venous thrombosis has been performed with use of reteplase in doses ranging from 0.5 to 1.0 U/h given over 5–24 hours, sometimes with an initial bolus (eg, 2-5U) (Centocor, data on file, 1999). Reteplase has also been used to treat clotted hemodialysis grafts with use of pulse-spray and “lyse and wait” techniques. When heparin is administered, it is often at no more than half the normal dose. There

COST OF FIBRINOLYTIC AGENTS

The approximate hospital costs for single vials of Streptase (250,000 U), Abbokinase (250,000 IU), Activase (50 mg), and Retavase (20 U) are $150, $380, $1,100, and $2,150, respectively. Despite the relatively low cost of Streptase, most interventionalists in the United States do not consider it to be an effective and safe alternative to other thrombolytic agents for peripheral vascular occlusions. By available unit dose, Abbokinase (if available) is considerably less expensive than Activase.

PROTOCOL FOR RT-PA THROMBOLYSIS

Alteplase (50 mg) is reconstituted in sterile water for injection (USP) to a concentration of 1 mg/mL. Alteplase contains no antibacterial pre servatives. The drug should be prepared immediately before use and diluents that contain bacteriocidal agents should not be used. However, normal saline may be used for dilution of the reconstituted agent. The manufacturer states that Activase should be used within 8 hours of preparation. However, in vitro experiments indicate that 1 mg/mL solutions are

PROTOCOL FOR RETEPLASE THROMBOLYSIS

Reteplase is reconstituted with sterile water to a concentration of 1 U/mL; the solution contains no bacteriocidal agents. The drug can be diluted with normal saline to 0.02 U/mL and remains active (and physically and biologically stable) for at least 24 hours. The freshly reconstituted drug (10 U in 10 mL sterile water) may be frozen to −20°C for as long as 2 weeks and then thawed without significant loss of activity (Centocor, data on file, 1999). Half-milliliter aliquots (0.5 U) may be

CONCLUSION

The removal of UK from the U.S. marketplace has forced interventional radiologists to rethink the management of patients with peripheral vascular occlusive disease. The initial “shotgun” approach to the use of rt-PA and reteplase in noncoronary thrombolysis has evolved into more rational strategies for treatment based on existing published work and growing experience with these agents. Prospective clinical trials will be required to establish the safest and most effective protocols for use of