Efficacy, Safety, and Cost of Thrombolytic Agents for the Management of Dysfunctional Hemodialysis Catheters

A Systematic Review

Daniel Hilleman, Pharm.D., FCCP; Jennifer Campbell, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(10):1031-1040. 

In This Article

Methods for Systematic Review

Study Identification and Selection Criteria

The guidelines defined by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) were used to develop this systematic review.[18] In addition, methods recommended by other authors were followed to identify relevant studies and to evaluate study quality.[19,20] The online databases of PubMed (MEDLINE), EBSCOHost, and the Cochrane Library were searched from January 1975–September 2010 for studies reporting the efficacy and safety of alteplase, reteplase, or tenecteplase in restoring patency of dysfunctional hemodialysis catheters. Studies including only streptokinase or urokinase and studies in patients with catheters used for indications other than hemodialysis were excluded. Studies specifically performed in children requiring hemodialysis were also excluded.

The medical subject heading terms used in the search were thrombolytic, fibrinolytic, alteplase, reteplase, tenecteplase, hemodialysis, catheters, vascular access, dwell, thrombosis, and clotting. A manual search of the bibliographies from the identified reports and reviews was also performed. Only studies published in the English language were included in the analysis; studies available only in abstract form were excluded. Data were extracted and verified independently by both authors.

Studies were included if they reported efficacy in a specific proportion of affected dysfunctional hemodialysis catheters; reported the proportion of patients experiencing an adverse outcome (especially bleeding); and described the type of catheter used, dose of thrombolytic, administration protocol, dwell time, definition of treatment success, time to follow-up for study end points, and sample size.

Efficacy and Safety End Points

The efficacy of thrombolytic therapy in restoring hemodialysis catheter function was calculated by using the definition of treatment success described in each study. The most common definition used was achievement of a dialysis catheter blood flow rate of 300 ml/minute or greater, and/or the ability to begin and/or complete a dialysis session. An average success rate for each thrombolytic agent was calculated as a simple arithmetic mean ± SD. The primary safety end point was any instance of bleeding. The secondary safety end point was any other adverse event reported.

Due to the lack of a sufficient number of adequately designed studies that included a control group, blinding, or randomization, a formal meta-analysis could not be performed.

Economic Analysis

Costs for different thrombolytics were based on current wholesale acquisition costs, with use of a national database reporting prescription costs.[16] The wholesale acquisition cost of Cathflo Activase is $88.83 for a 2-mg/2-ml vial.[16] The wholesale acquisition cost for intravenous alteplase (Activase; Genentech, Inc.) was $3983.09/100 mg.[16] If intravenous alteplase were aliquotted, the acquisition cost of 2 mg would be $79.66. There is probably little cost benefit in aliquotting the 100-mg vial of alteplase into 2-mg aliquots given the relatively small difference in acquisition cost between the products.

The wholesale acquisition cost for tenecteplase (TNKase; Genentech, Inc.) is $2714.25/50-mg vial.[16] The cost of 2 mg of tenecteplase, based on the cost of the 50-mg vial, would be $108.57. An assumption was made that this is what a 2-mg dose of tenecteplase would cost if it becomes commercially available for the indication of catheter clearance in a unit-of-use dosage form.

The wholesale acquisition cost for a 20-unit vial of reteplase (Retavase; EKR Therapeutics, Inc., Bedminster, NJ), is $3413.46.[16] At an average reteplase dose of 0.4 unit/0.4 ml, a total of 50 doses can be aliquotted from a 20-unit vial, resulting in an acquisition cost of $68.27/dose. A work flow analysis study conducted at our institution using pharmacy technicians indicates the cost of aliquotting 50 reteplase doses of 0.4 unit/0.4 ml to be $34.50, or $0.69/dose (unpublished data, 2010). Thus, the cost of a 0.4-unit dose of reteplase would be approximately $69. These doses can be frozen and rethawed up to a maximum of six cycles of freeze and rethaw.[21]

The costs of the different agents were evaluated in relation to their efficacy in restoring catheter function.

Comparison of Studies Using Thrombolytic Agents for the Management of Dysfunctional Hemodialysis Catheters

A total of 103 articles were identified during the initial database search. Of these articles, only 18 met the inclusion criteria.[22–39] Review articles, position statements from KDOQI, studies in patients with catheters for indications other than hemodialysis, studies using only urokinase or streptokinase, and studies failing to adequately describe the methods or outcomes of the use of thrombolytics were excluded.

Study Design

Only two of the identified studies used adequate study designs. One study was a randomized, open-label comparison of alteplase given as a short dwell (1 hr) or as a long dwell (48–72 hrs) time.[31] Dwell time had no impact on thrombolytic success in this trial. The second study that used an adequate study design was the Tenecteplase for the Restoration of Function in Dysfunctional Hemodialysis Catheters (TROPICS 3), a randomized, double-blind, placebo-controlled study of tenecteplase in 149 patients with dysfunctional hemodialysis catheters.[38] Tenecteplase given as a 2-mg dose/lumen in 74 patients produced only a 22% success rate in restoring catheter function. Although this was statistically superior to the 5% success rate with placebo, it is substantially lower than the success rates seen in most of the other a dwell time of 72 hours, producing a total success rate of 40%.

The remaining trials were limited in that none included a control group, all were open label indicating that the studies were observational, and most reported data were collected retrospectively. These limitations precluded a formal meta-analysis in which the active treatment would have been compared with a control group. The largest number of studies and the greatest number of catheter treatment episodes were reported with alteplase (Table 1).[22–33] Although 174 patients received reteplase (Table 2) and 297 received tenecteplase (Table 3), the numbers of catheter treatment episodes were roughly equal for reteplase and tenecteplase.[34–39] The number of patients receiving reteplase was about half and the number receiving tenecteplase was about three quarters the number of patients receiving alteplase (406 patients; Table 4).

Doses

The most common dose used with alteplase and tenecteplase was 2 mg in each lumen, resulting in a total dose/patient of 4 mg/treatment episode. A few studies with alteplase used 1 mg in each lumen, reducing the total dose/patient to 2 mg/treatment episode.[22,26,27,29,32] The most common dose used with reteplase was 0.4 unit in each lumen or a total dose of 0.8 unit/treatment episode. In one dose-ranging study, reteplase was given at three different dose levels.[35] The doses of 0.5, 2, and 3 units in each lumen produced total doses of 1, 4, and 6 units/treatment episode, respectively. In this study, the 0.5-unit/lumen dose was equally efficacious as the higher doses. To our knowledge, this study represents the only dose-ranging trial published with thrombolytic therapy in the setting of hemodialysis catheters.

Success Rates

The mean ± SD treatment success rate of dysfunctional hemodialysis catheters reported in the eligible trials was greatest with reteplase at 88 ± 4%, followed by alteplase at 81 ± 37% and tenecteplase at 41 ± 5% (Table 4). There was substantially less variability in the reported treatment success rates with reteplase and tenecteplase than with alteplase. The reported efficacy rates of alteplase and reteplase were generally similar, and greater than the rates reported with tenecteplase. The more consistent effect with reteplase and tenecteplase may be related to the treatment protocols used with these drugs. In the studies with reteplase and tenecteplase, only dwell protocols were used, and most allowed administration of a second dose if catheter function was not restored after the initial dose.[34–39] In the 12 studies with alteplase included in this review, a variety of treatment protocols were used, including push protocols with normal saline after an initial catheter instillation of thrombolytic, continuous infusions, and short- and long-duration dwell protocols.[22–33] Despite the use of different protocols with alteplase, there was no evidence that one type of protocol was more effective than another. There was a wider variability in study results, with alteplase producing a range of treatment success rates as low as 59% to as high as 98%. It should be noted that in the studies using alteplase infusions, higher total doses were used with no evidence of greater clinical benefit. As a result, the cost associated with these protocols would be greater.

Studies of tenecteplase in hemodialysis catheter clearance have reported lower success rates at doses tested than the average success rates reported with the other thrombolytic agents. In the TROPICS 3 study, the treatment success rate after an initial dose of tenecteplase 2 mg/lumen (4-mg total dose/patient) was only 22%.[38] After a protocol amendment allowing the use of a second, open-label dose of tenecteplase with a 72-hour dwell time, the total success rate with tenecteplase was 40%.

In the open-label TROPICS 4 study, 223 patients with dysfunctional hemodialysis catheters received tenecteplase 2 mg in each lumen with a dwell time of 1 hour.[39] The initial success rate was 34% (76/223). All of the patients failing the initial tenecteplase dose were eligible to receive a second dose of tenecteplase with a dwell time of 72 hours. Only 116 of the 147 eligible patients received the second dose, with a success rate of 49% (57/116). Why 31 patients did not receive the second dose of drug was not adequately described. Because the administration of the second dose of tenecteplase included only a portion of the eligible patients, the success rates in these two patient groups were counted separately in the calculation of tenecteplase's cumulative success rate.

An attempt was made to evaluate the relationship between dwell time (in protocols using dwell treatment) and catheter clearance success rates for the three thrombolytic agents. With alteplase, there were eight treatment cohorts using dwell times ranging from 30 minutes to 96 hours.[23,29–33] In the only published study that we found comparing the impact of different dwell times on catheter clearance success rates, patients were randomly assigned to alteplase using a dwell time of 1 hour or to alteplase using a dwell time of 48–72 hours.[31] There was no significant difference in catheter clearance rates with alteplase based on dwell time in this study.

In the four studies of reteplase, three used 30-minute dwell times allowing for a second dwell time of 30 minutes for treatment failures.[34,36,37] Success rates in these three studies were 91%, 88%, and 85%, respectively. Only one reteplase study used a long dwell time (average 33 hrs).[35] Success rate in this study was 87%. It appears that high catheter clearance success rates can be achieved with relatively short dwell times with reteplase.

In the two tenecteplase studies, catheter clearance success rates after an initial 60-minute dwell time were only 22% and 34%, respectively.[38,39] After allowing an additional 72-hour dwell time, success rates with tenecteplase improved to 40% and 49%, respectively. It appears that based on limited data, longer dwell times may be associated with higher success rates with tenecteplase.

Adverse Effects

Adverse effects associated with the use of these low doses of catheter-based thrombolytic therapy were rare. Most trials reported no adverse outcomes. No serious bleeding events attributed to thrombolytic therapy were reported in any of the trials. One thrombotic event (deep vein thrombosis) was reported in each of the two tenecteplase trials.[38,39]

Cost

The followings costs were used for purposes of estimating the comparative costs of the three thrombolytic agents: $89 for alteplase 2 mg/2 ml; $69 for reteplase 0.4 unit/0.4 ml, and $108 for tenecteplase 2 mg/2 ml. Given the relatively similar average catheter clearance rates with alteplase and reteplase, the lower cost associated with reteplase ($20/dose or $40/treatment episode) would favor its use over alteplase. The lower treatment success rates and higher cost associated with tenecteplase would make this agent less attractive compared with the other available agents for hemodialysis catheter clearance.

Comparison of Reteplase, Alteplase, and Tenecteplase

The most experience with thrombolytic therapy in catheter clearance has been in the management of dysfunctional central venous catheters, which are most commonly used to administer parenteral nutrition, antibiotics, chemotherapeutic agents, and other drugs that need to be administered over long periods of time.[1–3] Alteplase is the only thrombolytic agent approved by the FDA for the management of dysfunctional central venous catheters. Tenecteplase is FDA approved for the treatment of ST-segment elevation myocardial infarction and is under consideration by the FDA for approval for the treatment of dysfunctional central venous catheters.[17] Reteplase is only approved for the treatment of ST-segment elevation myocardial infarction. No thrombolytic is currently approved for the treatment of dysfunctional hemodialysis catheters. Hence, the objective of this systematic review was to identify the available clinical evidence regarding the efficacy, safety, and cost of using alteplase, reteplase, and tenecteplase for the management of dysfunctional hemodialysis catheters.

Most of the identified studies did not use study designs appropriate for a formal meta-analysis. Only two of the published studies had an adequate study design.[31,38] In the first study, in which patients were randomly assigned to receive alteplase with either a short or a long dwell time, dwell duration had no impact on the treatment success rate (Table 1).[31] In the second study (the TROPICS 3 study), patients were randomly assigned to receive tenecteplase 2 mg/lumen with a 60-minute dwell time or placebo in a doubleblind fashion, but success rate results were disappointing after the single dose of tenecteplase.[38] After a protocol amendment (an additional openlabel, 2-mg/lumen dose with a 72-hr dwell time), however, the total success rate improved (Table 3). Although the design of the TROPICS 3 study was adequate, it was underpowered considering the relative efficacy of tenecteplase compared with placebo. A sample of 150 patients was calculated to provide a power of greater than 90% to detect an initial tenecteplase efficacy of 25% against a placebo success rate of 5%, using a twosided χ2 test at the 0.05 level of significance. Tenecteplase failed to achieve the 20% greater efficacy compared with placebo. A similar success rate was reported with tenecteplase in the larger (223 patients) open-label TROPICS 4 study (34% after initial dose and 49% after second dose with longer dwell time; Table 3).[39] It is impossible to determine an actual overall success rate in this study, however, as not all initial treatment failures systematically received the second dose.

Alteplase and reteplase produced treatment success rates that were generally similar (81% and 88%, respectively). The wider variability in success rates with alteplase, which was already discussed, most likely resulted from the wider array of administration protocols used with alteplase. Alteplase does have the advantage of being available as a 2-mg vial, and the dose is relatively easy to prepare and administer. In clinical practice today, push protocols and thrombolytic infusions with alteplase have been largely abandoned in favor of dwell protocols.

The hemodialysis catheter clearance success rates of alteplase and reteplase were approximately double the rate observed with tenecteplase. This finding is not readily explained by differences in the pharmacologic properties of these agents. Alteplase was the first tissue plasminogen activator produced by recombinant DNA technology.[40] In addition, alteplase was the first fibrin-specific plasminogen activator and is approved for ST-segment elevation myocardial infarction, thrombotic stroke, and central venous catheter clearance.[15,41] Alteplase has been largely replaced in the treatment of ST-segment elevation myocardial infarction with other fibrin-specific thrombolytic agents that can be given by bolus administration, which include reteplase and tenecteplase.[40]

Reteplase is a novel plasminogen activator, designed by protein engineering, that consists of the kringle 2 and protease domains of alteplase, and is not glycosylated at the consensus sequences because of its expression in Escherichia coli.[42] Tenecteplase is a 527–amino acid glycoprotein developed by introducing the following modifications to the complementary DNA for natural human tissue plasminogen activator: a substitution of threonine 103 with asparagine and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetraalanine substitution at amino acids 296–299 in the protease domain.[43] Alteplase has a half-life of about 3 minutes compared with a half-life of 13–16 minutes for reteplase and 20–24 minutes for tenecteplase.

When compared with alteplase in patients with acute myocardial infarction, reteplase has been shown to achieve more rapid clot lysis.[44] In an experimental dynamic clot lysis assay, the doseresponse curves demonstrated superiority of reteplase over alteplase.[42] These differences suggest that there may be differences in the mechanism of clot lysis between the agents. This may also explain the higher catheter clearance rates observed with reteplase at shorter dwell times compared with the other agents. Unfortunately, no direct comparisons among alteplase, reteplase, and tenecteplase have been performed in hemodialysis catheter clearance. Hence, the reasons for the lower success rates in hemodialysis catheter clearance observed with tenecteplase remain unexplained.

Given the generally similar success rates of alteplase and reteplase for hemodialysis catheter clearance, the comparative cost between the agents becomes a relatively more important issue that may influence drug product selection. When the acquisition costs of aliquotted reteplase are compared with alteplase, reteplase is approximately $40/treatment episode less expensive than alteplase and $60/treatment episode less than tenecteplase. Reteplase requires that aliquotted doses be prepared under sterile conditions, which are associated with both time and cost. Institutions choosing to use aliquotted reteplase would need to consider their own estimates for these costs. As stated earlier, our estimate for aliquotting reteplase was a modest $0.69/dose.

Despite its cost advantages, the inconvenience of aliquotting reteplase and then freezing and thawing the product would have to be balanced against the volume of thrombolytic therapy used at a specific institution. The requirement that reteplase be prepared under sterile conditions may also limit its use at freestanding hemodialysis clinics. At institutions where exceptionally low volumes of thrombolytic therapy are used, the agent that is easier to use may have an advantage. However, at institutions where the volume of use of thrombolytic therapy is large, the cost savings associated with reteplase would be an important consideration in drug product selection and formulary decisions.

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