Anticoagulants and antiplatelet agents for preventing central venous haemodialysis catheter malfunction in patients with end-stage kidney disease

Ying Wang, Jessica N Ivany, Vlado Perkovic, Martin P Gallagher, Mark Woodward, Meg J Jardine, Ying Wang, Jessica N Ivany, Vlado Perkovic, Martin P Gallagher, Mark Woodward, Meg J Jardine

Abstract

Background: Catheter malfunction, including thrombosis, is associated with reduced dialysis adequacy, as well as an increased risk of catheter-related bacteraemia and mortality. The role of anticoagulants in the prevention of catheter malfunction remains uncertain.

Objectives: This review aimed to compare the prophylactic effect of different anticoagulant agents, preparations, doses and administration on the incidence of central venous haemodialysis catheter-related malfunction and sepsis in patients with end-stage kidney disease (ESKD).

Search methods: We searched the Cochrane Renal Group's Specialised Register to 7 January 2016 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.

Selection criteria: We included all randomised controlled trials (RCT) assessing anticoagulants compared with conventional care for the prevention of catheter malfunction in adult patients receiving haemodialysis for ESKD.

Data collection and analysis: The primary outcome was catheter malfunction defined as a catheter blood flow of 200 mL/min or less, or as defined by study authors. Secondary outcomes were catheter-related bacteraemia, all-cause mortality and bleeding events. Relative risks (RR) with 95% confidence intervals (CI) for individual studies were pooled using random effects models within treatment classes. Analyses were conducted by class, with subgroup analyses performed of individual agents within classes.

Main results: We included 27 studies (3003 participants) that were followed up for a median of six months. Study interventions included alternative anticoagulant locking solutions (19 studies, 2216 patients), systemic agents (6 studies, 664 patients) and low or no dose heparin (2 studies, 123 patients). The most common comparison treatment was a locking solution of heparin 5000 IU/mL, used in 17 studies. No significant effect on catheter malfunction was observed for alternative anticoagulant locking solutions (RR 0.96, 95% CI 0.74 to 1.26), systemic agents (RR 0.59, 95% CI 0.28 to 1.23), or low or no dose heparin (RR 0.90, 95% CI 0.10 to 8.31). A significant reduction on incidence of catheter-related bacteraemia was observed for alternative anticoagulant locking solutions (RR 0.46, 95% CI 0.32 to 0.66) but not systemic agents (RR 2.41, 95% CI 0.89 to 6.55), and could not be assessed in reports of low or no dose heparin studies. No significant effect on all-cause mortality was observed for alternative anticoagulant locking solutions (RR 0.88, 95% CI 0.54 to 1.43) or systemic agents (RR 0.78, 95% CI 0.37 to 1.65), and was not reported in studies of low or no dose heparin. Bleeding events were only reported in eight studies, including only 2/5 studies of systemic warfarin, with no clear effect demonstrated (RR 1.43, 95% CI 0.86 to 2.39). For individual agents, recombinant tissue plasminogen (rt-PA) was the only locking solution shown to reduce catheter malfunction (RR 0.58, 95% CI 0.37 to 0.91) based on the results of a single study. No significant on catheter malfunction was observed for other individual classes of alternative anticoagulant locking solutions (citrate: RR 1.14, 95% CI 0.76 to 1.69; antibiotic: RR 1.48, 95% CI 0.79 to 2.77; ethanol: RR 0.88, 95% CI 0.21 to 3.67). On the other hand, all individual classes of alternative anticoagulant locking solutions, except ethanol, reduced catheter-related bacteraemia (citrate: RR 0.49, 95% CI 0.36 to 0.68; antibiotic: RR 0.27, 95% CI 0.11 to 0.70; rt-PA: RR 0.35, 95% CI 0.13 to 0.93; ethanol: RR 0.33, 95% CI 0.03 to 4.05). No significant effect on all-cause mortality was observed for any individual agent within the class of alternative locking solutions. Studies were mainly of low quality and underpowered with an average participant number of 75 and study duration of six months. The interpretation of the study evidence was further limited by the variation in tested interventions and outcome reporting.

Authors' conclusions: The relative net benefit of anticoagulant therapies for prevention of catheter malfunction remains uncertain. Multiple agents appear to reduce catheter-related bacteraemia although the lack of clear assessment of harms and the limitations of study quality mean these results should be interpreted with caution. Methodological approaches can be used to avoid methods of reporting unduly affecting on the results of meta-analyses incorporating studies employed mixed reporting methods. Further high quality randomised studies, including safety outcomes, are needed.

Conflict of interest statement

Martin Gallagher has received funding competitive research funding from the Royal Australasian College of Physicians, the Australian National Health and Medical Research Council and the Commonwealth Fund in the last 36 months.
Jessica Ivany: None known
Meg Jardine is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia and the National Heart Foundation. She has received speakers’ fees from Amgen and Roche, funding for a clinical trial from Gambro and serves on Steering Committees for trials funded by Janssen. Her employer conducts clinical trials funded by Servier, Janssen, Roche and Merck. This funding is unrelated to the conduct of this review.
Vlado Perkovic is supported by a fellowship from the Heart Foundation of Australia and a various grants from the Australian National Health and Medical Research Council. He has received speakers' fees from Roche, Servier and Astra Zeneca, funding for a clinical trial from Baxter, and serves on Steering Committees for trials funded by Johnson and Johnson, Boehringer Ingelheim, Vitae and Abbott. His employer conducts clinical trials funded by Servier, Johnson and Johnson, Roche and Merck. This funding is unrelated to the conduct of this review.
Ying Wang: None known
Mark Woodward has a consultancy contract with Amgen and has had consultancy contracts with Novartis and Sanofi, has received lecturing fees from Servier and has served as an expert witness for Bernstein, Litowitz, Berger and Grossmann LLP. This support is unrelated to the conduct of this review.