Alteplase as an Alternative to Urokinase for Catheter-Directed Therapy

An expert panel of vascular specialists has recommended alteplase (Activase®) as a safe, effective alternative to urokinase (Abbokinase®) (UK) for catheter-directed, thrombolytic therapy of acute limb ischemia and deep vein thrombosis (DVT), and for restoration of patency in hemodialysis grafts and clotted intravenous access devices. Although it was the standard of care for 20 years, in 1999 the FDA removed UK from the market. Reteplase and alteplase are the only two viable alternatives to UK for American vascular interventionalists. Because peer-reviewed studies have been published on alteplase for noncoronary applications, but not on reteplase, the panel focused on alteplase as an alternative to UK for the following noncoronary uses: peripheral arterial occlusive disease (PAOD), DVT, thrombosed hemodialysis access, and catheter clearance.

The Society of Cardiovascular and Interventional Radiology (SCVIR) convened a Multidisciplinary Advisory Panel on Catheter-Directed Thrombolytic Therapy in August of 1999, in order to develop preliminary recommendations regarding alternatives to UK. The Advisory Panel concluded that further studies are needed to define more clearly the role of alteplase in the treatment of regional thrombolysis; in particular, to determine the optimal dose, the lowest effective concentration of alteplase, and to identify coagulation parameters that predict bleeding complications.

This report summarizes the proceedings of the Advisory Panel meeting and provides preliminary guidelines for the clinical use of alteplase as an alternative to UK. An unrestricted educational grant from Genentech, Inc., supported the meeting of the panel. (For a more complete look at the recommendations, see Semba CP et al., JVIR 2000; 11:279-287.)

Alteplase: Clinical Experience

Although UK was the most widely used thrombolytic in the United States for two decades, physicians have accrued significant clinical experience with alteplase outside the coronary realm, most of which has been described in the scientific literature. Numerous clinical trials have reported on the safety and efficacy of the use of alteplase for PAOD, but few randomized prospective trials have directly compared alteplase with UK. There are still unresolved issues regarding the use of alteplase for PAOD, namely the optimal dose of alteplase and the optimal catheter technique for delivering the drug, as well as the role of heparin sodium (Tubex®) and the risk of adverse bleeding.

Clinical doses of alteplase for catheter-directed therapy vary widely. Studies to date have reported on weight-based doses in the range of 0.02 to 0.1 mg/kg/hour, and non-weight-based doses have ranged from 0.25 to 10 mg/hour. Although safety and efficacy have been shown with a range of dosing regimens, the lowest effective dose remains to be determined.

The Advisory Panel considered experience with alteplase from the National Audit of Thrombolysis for Acute Limb Ischemia (NATALI), a large database from Great Britain and Ireland. This experience, reported to the panel by Steven M. Thomas, MBBS, MRCP, included 697 patients treated between January of 1990 and May of 1998, the majority of whom received alteplase as a continuous infusion at a median rate of 1 mg/hour. A total dose of < 40 mg was given in 91.7 percent of cases. Major complications occurred in 11.9 percent of patients and minor complications in 18.6 percent. Risk factors for adverse bleeding complications were increasing age, female gender, thrombolysis of vascular grafts, concomitant use of aspirin, and increased severity of ischemia. No relationship was found between specific radiologic technique and risk of complications or adverse outcomes.

A large, randomized, prospective trial compared the efficacy of surgical revascularization versus thrombolysis with either UK or alteplase. The study, titled "Surgery versus Thrombolysis for Ischemia of the Lower Extremities" (STILE), included 393 patients. Results showed superior outcomes for chronic limb ischemia > 14 days treated with surgical revascularization initially, and improved outcomes were seen for initial thrombolysis in patients with acute limb ischemia (< 14 days). No significant differences in safety and efficacy were seen between alteplase and UK, suggesting that alteplase can replace UK for this indication.

A subsequent subanalysis of the STILE data revealed no difference in bleeding complications between the alteplase and UK groups with or without concomitant heparin. At 30 days, heparin decreased the composite endpoint of death, amputation, ongoing/recurrent ischemia, and major morbidity in the alteplase-treated patients (p = 0.01); and this benefit was sustained at one year (p = 0.06).

Other studies have not demonstrated a benefit with heparin during alteplase infusion, and some studies have found an increased risk of bleeding. The data regarding adjunctive heparin during alteplase infusion conflicts, and the Advisory Panel agreed that further study is needed.

Advisory Panel Recommendations

Dialysis Graft Thrombosis

Only a few small trials and case reports have been published on alteplase treatment of thrombosed dialysis grafts. No long-term data on patency or 30-day mortality rates are available, but the short-term data are promising, according to the Advisory Panel.

A study of 185 patients reported a 98 percent initial success rate with a "lyse-and-wait" approach (P. Copra, MD, personal communication, August 9, 1999). The technique involved 1 mg of reconstituted alteplase diluted with 10 mL of normal saline injected into the graft. Systemic heparin of 3000-5000 IU was administered through a peripheral intravenous (IV) line. Placement of simple purse-string sutures at the catheter insertion site was recommended for providing immediate hemostasis. Sutures were removed 24 hours later. Another panel member reported a similar "lyse-and wait" technique using a 2 mg dose of reconstituted alteplase.

Catheter Clearance

Several studies have shown that alteplase is safe and effective in the management of occluded central venous catheters. One study that directly compared UK and alteplase found that 2 mg of alteplase instilled for four hours was able to restore patency in catheters that were persistently occluded despite UK treatment (Atkinson, JB et al. J Parent Ent Nutr 1990; 14:310-311). A double-blind, randomized, clinical trial comparing UK and alteplase showed that the alteplase-treated catheters were significantly more likely to have a return to function than the UK-treated catheters: 89 percent versus 59 percent, respectively, p = 0.013 (Haire, WD et al. Thromb Haemost 1994; 72:543-547). This superiority was confirmed radiographically, showing complete resolution of almost twice as many alteplase-treated catheters as UK-treated catheters: 61 percent versus 32 percent, p = 0.042. Moreover, one dose of alteplase was more successful in restoring patency compared to one dose of UK (46 percent versus 18 percent, respectively, p = 0.036). No evidence of bleeding or coagulopathy was seen in either of the studies cited above.

These data led to the Advisory Panel's recommendation that a 2 mg (1 mg/mL) dose of alteplase be used for the clearance of each lumen of an occluded central venous catheter, with a dwell time of up to two hours. For catheter lumens with priming volumes larger than 2 mL, alteplase can be diluted with normal saline to the necessary volume. If the initial lysis attempt is unsuccessful, the panel recommended a repeat alteplase instillation. If these maneuvers are unsuccessful, or if reocclusion occurs again shortly thereafter, the panel advised evaluating the catheter for other causes of malfunction. A prospective clinical trial investigating the safety and efficacy of alteplase for catheter clearance will begin soon in the United States and should provide more information on this issue.

Deep Vein Thrombosis

Heparin anticoagulation followed by long-term warfarin (Coumadin®) is considered the standard therapy for DVT. At least five studies have evaluated systemic thrombolysis for DVT comparing alteplase with heparin. These studies employed intravenous infusions, variable doses, variable infusion times, and used venographic outcome as the endpoint. The incidence of bleeding complications ranged from four percent to 32 percent in these studies.

Studies of intrathrombus alteplase suggest that catheter-directed thrombolysis with alteplase can be safely and effectively used for DVT, provided patients have no contraindications to thrombolytic therapy. Unpublished clinical experience reported by A.J. Comerata, MD, and colleagues showed that catheter-directed alteplase achieved better outcomes compared to systemic infusions, with significant improvements in quality of life. Dr. Comerata suggested that higher doses of alteplase may be needed for this approach as compared to those used for PAOD. Appropriate doses appear to be a 3-5 mg bolus infused directly into the clot, followed by a continuous infusion of 0.05 mg/hour (weight-based regimen) or 3-4 mg/hour (non-weight-based regimen).

Initial experience at Stanford University Medical Center, reported by C. Semba, MD, demonstrated clinical success using a high-volume, low-dose regimen of continuous infusions of alteplase at far lower concentrations for acute iliofemoral DVT (0.5 mg/hour; 0.01 mg alteplase/mL normal saline).

The Advisory Panel agreed that further studies are needed to define the proper dosing regimen for alteplase in catheter-directed thrombolysis for DVT.

Acute Ischemic Stroke

Alteplase is the only thrombolytic agent approved for the intravenous treatment of acute stroke within three hours of symptom onset. However, catheter-based intraarterial thrombolytic therapy appears to be a better method than systemic infusion of thrombolytic therapy. Theoretically, lower doses and improved safety could be achieved by intraarterial thrombolysis. This supposition is based on preliminary evidence suggesting that early intraarterial thrombolysis is more effective and probably safer than early IV administration of a lytic agent, and that early IV administration is as effective as or superior to late intraarterial administration. The consensus of the panel at this time is that early IV administration plus immediate intraarterial therapy is probably the best strategy for acute ischemic stroke.

Although the role of catheter-based alteplase treatment in managing acute stroke remains to be defined, this approach has the potential to reduce long-term adverse events and outcomes. Randomized, controlled trials are needed to verify the role of catheter-directed intraarterial thrombolytic therapy for stroke, as well as the optimal drug, method of administration, dosing, timing, and safety of this approach.

Summary

Alteplase appears to be a safe, effective alternative to UK for catheter-directed therapy. A multidisciplinary Advisory Panel has evaluated the available data regarding the use of alteplase in catheter-directed treatment of PAOD, DVT, thrombosed hemodialysis grafts, and restoring patency to occluded central venous catheters. Dosing recommendations have been made when possible. Alteplase also appears to be useful for intraarterial thrombolytic stroke therapy. Further studies will determine the clinical utility of this approach.