A Phase III,Randomized, Double-Blind,Placebo-Controlled Study of Tenecteplase for Improvement of Hemodialysis Catheter Function: TROPICS 3

Background and objectives: Despite widespread use of tunneled hemodialysis (HD) catheters, their utility is limited by the development of thrombotic complications. To address this problem, this study investigated whether the thrombolytic agent tenecteplase can restore blood flow rates (BFRs) in dysfunctional HD catheters.Design, setting, participants, & measurements: In this randomized, double-blind study, patients with dysfunctional tunneled HD catheters, defined as a BFR <300 ml/min at −250 mmHg pressure in the arterial line, received 1-hour intracatheter dwell with tenecteplase (2 mg) or placebo. The primary endpoint was the percentage of patients with BFR ≥300 ml/min and an increase of ≥25 ml/min above baseline 30 minutes before and at the end of HD. Safety endpoints included the incidence of hemorrhagic, thrombotic, and infectious complications.Results: Eligible patients (n = 149) were treated with tenecteplase (n = 74) or placebo (n = 75). Mean baseline BFR was similar for the tenecteplase and placebo groups at 151 and 137 ml/min, respectively. After a 1-hour dwell, 22% of patients in the tenecteplase group had functional catheters compared with 5% among placebo controls (P = 0.004). At the end of dialysis, mean change in BFR was 47 ml/min in the tenecteplase group versus 12 ml/min in the placebo group (P = 0.008). Four catheter-related bloodstream infections (one tenecteplase, three placebo) and one thrombosis (tenecteplase) were observed. There were no reports of intracranial hemorrhage, major bleeding, embolic events, or catheter-related complications.Conclusions: Tenecteplase improved HD catheter function and had a favorable safety profile compared with placebo.Effective hemodialysis (HD) requires reliable vascular access. Arteriovenous fistulas and grafts are preferred over catheters for their higher patency rates, prolonged survival, and lower complication rates (1–3). However, HD catheters are used by most dialysis patients to provide temporary access or to allow maturation of surgically placed fistulas (4). Tunneled catheters may also be used because of comorbidities or exhaustion of all graft and fistula sites (5,6).HD catheters must be carefully managed to mitigate a high complication rate. For example, catheter thrombosis is estimated to occur at a frequency of 0.5 to 3.0 events/1000 catheter-days (7–9). Among patients who experience access loss, catheter thrombosis is the precipitating event in 30% to 40% (1). Thrombotic obstruction of the catheter lumen reduces blood flow rate (BFR), frequently impeding the delivery of adequate HD. Treatment of partial occlusions of catheter lumens is often postponed by catheter line reversal, contributing to recirculation without addressing the underlying thrombus. The National Kidney Foundation''s Kidney Disease Outcomes Quality Initiative guidelines for HD vascular access advise against regular use of line reversal to manage low BFR (1).Maintenance of catheter patency is critical because many patients rely on catheter access for HD, and catheter insertion sites are limited. Administration of a thrombolytic directly into a dysfunctional HD catheter lumen may provide a way to salvage catheters with suboptimal BFRs while minimizing the risk of adverse events (AEs) associated with systemic delivery of these agents and avoid the need for catheter replacement. Previous studies evaluating the efficacy of alteplase or reteplase for clearance of HD catheters have yielded conflicting results (10–25). Limitations of prior studies include differences in trial design, sample size, thrombolytic dose, and definitions of treatment success. Until now there have been no large-scale, randomized, double-blind controlled trials using well defined efficacy and safety endpoints. As a result, many questions remain regarding the efficacy and safety of thrombolytics in the treatment of dysfunctional HD catheters.Tenecteplase is a recombinant serine protease that binds to fibrin and converts thrombus-bound plasminogen to plasmin, thereby stimulating local fibrinolysis. Tenecteplase has three engineered amino acid changes, resulting in greater fibrin specificity and an increased resistance to plasminogen activator inhibitor-1 compared with alteplase (26,27). When injected systemically, tenecteplase has a plasma half-life of approximately 22 minutes (28) and is primarily cleared by the liver (29). However, when tenecteplase is administered intraluminally for HD catheter dysfunction and subsequently withdrawn, circulating tenecteplase levels are not expected to reach detectable concentrations (30). Tenecteplase maintained clot lysis ability for 72 hours in a catheter in in vitro studies (Genentech data on file). In this study, we compared the efficacy of tenecteplase with placebo in improving BFR in dysfunctional HD catheters.