Is there any evidence for tenecteplase in line declotting as an alternative to Cathflo?

Comment by InpharmD Researcher

Despite the lack of direct comparisons between tenecteplase and Cathflo® Activase® (alteplase), available studies, while limited, support use of tenecteplase 2 mg/mL for treatment of occluded central venous catheters (CVC). The majority of available data suggest regular alteplase (which appears to still be available, unlike Cathflo Activase) at doses ranging from 0.5 mg/0.5 mL to 2 mg/3 mL at varying infusion times may be effective for treatment of CVC occlusions. Other thrombolytics studied with less data include reteplase (max dose 0.4 U) and alfimeprase (0.3, 1.0, or 3.0 mg). While urokinase and streptokinase have also been utilized, they are no longer available in the United States.

Background

A 2012 meta-analysis evaluated use of thrombolytics for treating central venous catheter (CVC) occlusions including reteplase, tenecteplase, and alfimeprase. Studies for reteplase show 67-74% clearance after 30–40 minutes, with overall clearance of 80-95% (86% overall clearance). A max dose of 0.4 U was determined to be safe without increased risk of complications. Tenecteplase had demonstrated 81 to 87% clearance initially and 80 to 81% maintenance after 7 days. The dose investigated was weight-based, with weight <30 kg receiving 110% of CVC lumen volume with 2 mg/2 mL; and weight > 30 kg receiving 2 mL of 2 mg/2mL. A study for alfimeprase found 50% clearance after 15 minutes with alfimeprase vs 0% for alteplase, and overall 80% vs 62% clearance. The study utilized 0.3, 1.0, and 3.0 mg doses, which were all deemed more successful than alteplase. Reteplase appears most effective initially at 30–40 minutes, with higher clearance rates than others. It also performs well with longer dwell times and multiple doses. However, more data are required to confirm these findings. [1]

A 2019 meta-analysis evaluated interventions used to treat obstructive events, whether thrombotic or non-thrombotic, in long-term CVC (LT-CVC) in cancer patients. The drugs used for restoration of catheter function were urokinase (53.3%), alteplase (20%), alteplase (13.3%), reteplase (6.7%), recombinant urokinase (6.7%), and staphylokinase (6.7%). A success rate of 84% was found with use of tenecteplase (95% CI, 77.32% to 90.01%) from a sample size of 234 catheters. Of note, the analysis was limited to 2 studies evaluating use of tenecteplase. See Tables 1-2 for more details on tenecteplase for treatment of occluded CVCs. [2]

Another 2019 systematic review and meta-analysis investigated use of alteplase for treatment of occlusions in long-term central venous catheters in pediatric patients with cancer. Of the 10 total trials included, 6 utilized alteplase while the other 4 used urokinase or streptokinase. In most studies, use of low-dose alteplase was reserved for smaller children. Overall, the restoration rate ranged from 50% to 97.5% with the administration time ranging from 30 minutes to 48 hours. Pooled results indicated an overall success rate of 88% (95% confidence interval [CI] 80% to 95%). Included studies reflected significant heterogeneity (I2= 59.2%) due to large dose variations, ranging from 0.5 mg/0.5 mL to 2 mg/3 mL, and varying infusion times, convoluting pooled outcomes when attempting to focus on a single dosing regimen. Despite this, alteplase was considered to be generally well-tolerated in pediatric patients, with a low incidence of adverse events when used to restore central catheter patency. Note that urokinase and streptokinase are no longer commercially available in the United States. Specific data for use of tenecteplase was not discussed. [3]

References:

[1] Baskin JL, Reiss U, Wilimas JA, et al. Thrombolytic therapy for central venous catheter occlusion. Haematologica. 2012;97(5):641-650. doi:10.3324/haematol.2011.050492
[2] da Costa ACC, Ribeiro JM, Vasques CI, De Luca Canto G, Porporatti AL, Dos Reis PED. Interventions to obstructive long-term central venous catheter in cancer patients: a meta-analysis. Support Care Cancer. 2019;27(2):407-421. doi:10.1007/s00520-018-4500-y
[3] da Costa ACC, Vieira NNP, Vasques CI, Ferreira EB, Guerra ENS, Dos Reis PED. Interventions for Occluded Central Venous Catheters: A Meta-analysis. Pediatrics. 2019;144(6):e20183789. doi:10.1542/peds.2018-3789

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there any evidence for tenecteplase in line declotting as an alternative to Cathflo?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Tables 1-2 for your response.


 

TROPICS 1: A Phase III, Randomized, Double-blind, Placebo-controlled Study of Tenecteplase for Restoration of Function in Dysfunctional Central Venous Catheters

Design

Randomized, double-blind, placebo-controlled trial

N= 97

Objective

To evaluate the efficacy and safety of the thrombolytic tenecteplase (TNK), a fibrin-specific recombinant tissue plasminogen activator, for restoring function to dysfunctional central venous catheters (CVCs)

Study Groups

Placebo-TNK-TNK (n= 47)

TNK-TNK-Placebo (n= 50)

Inclusion Criteria

Adult and pediatric patients with CVC occlusion; single-, double-, or triple-lumen catheters (including umbilical catheters and implanted ports); clinically stable, as judged by the study investigators; had CVCs with the ability to infuse fluids at the volume necessary to instill study drug

Exclusion Criteria

CVCs inserted less than 2 days before study treatment or CVCs known to be dysfunctional for more than 7 days; CVCs internally coated with a therapeutic agent; known bacteremia or known or suspected infection in the CVC; use of a power injector; evidence of mechanical, nonthrombotic occlusion; thrombolytic use in the previous 24 hours; heparin or other anticoagulant use in the previous 24 hours (except prophylaxis or low-dose infusion)

Methods

Eligible patients were stratified based on weight (<30 kg and ≥30 kg) before being randomized. Groups were randomized in the order of instillation application. The first group received placebo, then tenecteplase, then tenecteplase; the second group received tenecteplase, then tenecteplase, then placebo.

Patients weighing ≥30 kg received 2 mg of study drug in 2 mL. Patients weighing <30 kg received instillations of study drug equal to 110% of the internal lumen volume of the dysfunctional CVC, but not more than 2 mL (2 mg). 

After the first dose was instilled, the solution was left to dwell for 15±5 minutes, after which the CVC was assessed. If function was not restored, the solution was left to dwell for another 15 minutes. For CVCs that remained dysfunctional after 30 minutes, the solution was left to dwell for an additional 90±10 minutes.

If patency was not restored after 120 minutes, the study drug was withdrawn and dose 2 was given. The same procedure repeated until 3 doses were assessed (if patency was not restored).

Duration

Up to 120 minutes after each dose

Outcome Measures

CVC restoration (defined as the successful withdrawal of at least 3 mL of blood or fluid and infusion of 5 mL of normal saline)

Baseline Characteristics

 

Placebo-TNK-TNK (n= 47)

TNK-TNK-Placebo (n= 50)

 

Age, years

42 ± 28 37 ± 27  

Female

66% 52%  

White

77% 72%  

Weight, kg

62 ± 29 66 ± 32  

CVC type

Port

Single lumen

Double lumen

Triple lumen

 

53%

13%

32%

2%

 

74%

2%

20%

4%

 

Days since CVC insertion (range)

Days since CVC dysfunction (range)

69 (4-2,388)

1 (1-8)

81 (7-1,153)

1 (1-8)

 

Results

Endpoint

Placebo-TNK-TNK (n= 47)

TNK-TNK-Placebo (n= 50)

p-value

Catheter restoration within 120 minutes (first dose)

Restoration within 30 minutes

23%

19%

60%

44%

0.0002

0.009

Restoration after 2nd dose

85% 88% ---

In both groups combined, 87% (95% confidence interval, 80% to 93%) of patients experienced restoration of catheter function within 120 minutes after the administration of up to two doses of tenecteplase.

Of 65 tenecteplase patients who had patency restored and were evaluated over the next 7 days, 80% still had functional CVCs.

Adverse Events

Four serious adverse events occurred in three patients: pancytopenia, Escherichia coli sepsis, mental status change, and nonocclusive venous clot

Study Author Conclusions

Tenecteplase was efficacious for restoration of catheter function in these study patients with dysfunctional CVCs.

InpharmD Researcher Critique

Limitations of this study include the small sample size and exclusion of CVCs with long-lasting dysfunction. Strengths of this study include the randomized, blinded, controlled design and heterogeneity in patient population and catheter type.

References:

Gabrail N, Sandler E, Charu V, et al. TROPICS 1: a phase III, randomized, double-blind, placebo-controlled study of tenecteplase for restoration of function in dysfunctional central venous catheters. J Vasc Interv Radiol. 2010;21(12):1852-1858. doi:10.1016/j.jvir.2010.09.002

 

A Phase III, Open-Label, Single-Arm Study of Tenecteplase for Restoration of Function in Dysfunctional Central Venous Catheters

Design

Prospective, observational, multicenter, cohort study

N= 246

Objective

To evaluate, in a phase III, single-arm study, the safety and efficacy of the thrombolytic agent tenecteplase in restoring function to dysfunctional central venous catheters (CVCs) in adult and pediatric patients

Study Groups

Tenecteplase (N= 246)

Inclusion Criteria

Dysfunctional CVCs (<3 mL of blood could be withdrawn or 1 mL for patients weighing <10 kg); had single-, double-, or triple-lumen catheters, including umbilical catheters or implanted ports; clinically stable condition in the opinion of the investigator; able to have fluids infused at the volume necessary to instill study drug into CVC

Exclusion Criteria

Presence of hemodialysis catheters or catheters internally coated with a therapeutic agent; used power injectors; CVCs inserted <2 days; evidence of mechanical, nonthrombotic occlusion; previous treatment with tenecteplase or another thrombolytic agent within 28 days

Methods

Patients at 43 centers in the United States and Canada were identified who had dysfunctional catheters. Patients received a maximum of two doses of tenecteplase instilled within the dysfunctional CVC lumen. If multiple lumens were dysfunctional, one lumen was selected by the investigator for treatment and the same lumen was used for all treatments and assessments for the duration of the study. 

Patients weighing ≥30 kg received 2 mg (2 mL) of tenecteplase, whereas patients weighing <30 kg received tenecteplase instillations equal to 110% of the internal lumen volume of the dysfunctional CVC, not to exceed 2 mg (2 mL). After the first instillation, CVC function was assessed at 15, 30, and 120 minutes.

If CVC function was not restored after 2 hours, the first dose was withdrawn and a second dose instilled; the same assessment protocol was repeated.  If CVC function was restored at any assessment after the first or second dose, tenecteplase was withdrawn and no additional treatment was administered.

Duration

Up to 2 hours after teneceteplase instillation

Outcome Measures

CVC function restoration within 120 minutes (defined by successful withdrawal of at least 3 mL of blood or fluid and infusion of 5 mL of normal saline solution)

Baseline Characteristics

 

Tenecteplase (N= 246)

Age, years (range)

44 (0-92)

Female

63%

White

84%

Weight, kg (range)

66 (6-198)

CVC type

Port

Single lumen

Double lumen

Triple lumen

 

70%

15%

15%

1%

Time since CVC insertion, days (range)

Time since CVC dysfunction, days (range)

165 (5-3,529)

1 (0-1,472)

Results

Endpoint

Tenecteplase (N= 246)

Tenecteplase instillations

One

Two

 

76%

24%

Restoration of CVC within 120 mins of first dose

177 (72%)

CVC restoration by catheter type

Port

Single lumen

Double lumen

 

133/171 (78%)

33/37 (89%)

32/36 (89%)

After a maximum of two doses of tenecteplase, 200 patients (81%; 95% CI, 76%– 86%) experienced restoration of CVC function.

Of 137 who had catheter patency restored, 111 (81%) showed maintained patency after one week.

Adverse Events

Common adverse events: fever (2%), neutropenia (1%), nausea (1%)

Six serious adverse events were reports: 2 catheter-related bloodstream infections, 1 dehydration, 1 port malfunction, 1 fever, and 1 hypersensitivity

No cases of intracranial hemorrhage, major bleeding, thrombosis, embolism, or catheter-related complications were reported

Study Author Conclusions

Consecutive administration of one or two doses of tenecteplase into CVCs showed efficacy in the restoration of catheter function in patients with dysfunctional CVCs.

InpharmD Researcher Critique

Limitations of this study include the single cohort without a comparison and the high incidence of port malfunctions, limiting generalizability to other CVC types. Patients with port catheters had lower patency restoration rates than those with other types, perhaps because of the larger intraluminal volume and additional reservoir capacity of ports. Strengths of this study include the prospective, multicenter design.



References:

Tebbi C, Costanzi J, Shulman R, et al. A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters. J Vasc Interv Radiol. 2011;22(8):1117-1123. doi:10.1016/j.jvir.2011.02.034