What data supports the use of taurolidine/heparin (Defencath)?

Comment by InpharmD Researcher

Available studies and pooled data have frequently found taurolidine/heparin (Defencath®) to significantly reduce the incidence of catheter-related bloodstream infections in hemodialysis patients with central venous catheters (CVC) compared to heparin alone. In some studies, taurolidine/heparin was also combined with citrate. However, the most recent guidelines from the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) state there is inadequate evidence to make a recommendation on the comparative use of various CVC-locking agents, including taurolidine.

Background

According to the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline for vascular access, there is inadequate evidence to make a recommendation on the comparative use of the following central venous catheter (CVC) locking agents for CVC dysfunction or infection prophylaxis: tinzaparin versus unfractionated heparin, taurolidine/citrate versus heparin with or without gentamicin, neutral valve connector (Tego [ICU Medical]) versus citrate (46.7%) locking solution. It is recommended that larger multicenter randomized controlled trials are needed to evaluate citrate and taurolidine. [1]

A 2020 meta-analysis investigated the efficacy and safety of antimicrobial lock solutions for prevention of central-line-associated bloodstream infection (CLABSI). A total of 49 randomized controlled trials (N= 7,020 patients) were included for analysis. Patients were ages 18 years or older, on dialysis, and trials reported either primary (catheter-related bloodstream infection [CRBSI] and bleeding rates) or secondary (catheter malfunction, exit-site infection, and all-cause mortality) parameters. Subgroup analysis demonstrated that seven antibiotics (cloxacillin, cefotaxime, linezolid, vancomycin, gentamicin, minocycline, and taurolidine) were effective for prevention of CRBSI. However, the lack of head-to-head trials prevents hierarchical classification of antibiotics. Data for taurolidine was mainly based on 4 studies of taurolidine/citrate or taurolidine/urokinase, with only one involving use of taurolidine/heparin as the control group. Pairwise meta-analysis for taurolidine reports a risk ratio (RR) of 0.29 (95% confidence interval [CI] 0.03 to 2.50) and network meta-analysis reports a RR of 0.32 (95% CI 0.19 to 0.56). [2]

A 2021 systematic review and meta-analysis investigated the efficacy of antibiotic and antimicrobial lock solutions for prevention of hemodialysis CRBSI. A total of 26 studies were included, encompassing a total of 4,967 patients. Antibiotic interventions (n= 889 patients) included gentamicin (most common), as well as minocycline, vancomycin, trimethoprim, and cefotaxime. A proportion of patients were also treated with various non-antibiotic antimicrobial solutions (n= 1,662). Four studies compared 1.35% taurolidine and 4% sodium citrate vs. heparin. All included studies reported incidence of catheter-related bacteremia (CRB), with an overall pooled RR showing intervention was associated with a 30% lower incidence of CRB compared to heparin (RR 0.30; 95% CI 0.25 to 0.36; p<0.001). When evaluating subgroups, administration of antibiotics specifically resulted in a 28% decrease in CRB episodes compared to heparin (RR 0.28; 95% CI 0.21 to 0.37; p<0.0001). Conversely, administration of antimicrobial solutions was associated with 32% reduced risk of CRB compared to patients in the heparin control group (RR 0.32; 95% CI 0.25 to 0.41; p<0.0001). Neither of these two interventions was favored over the other, as both were determined to be effective in reducing CRBSI. [3]

A 2022 systematic review and meta-analysis evaluates the efficacy of taurolidine in antibiotic lock solutions for patients with CVC-related bloodstream infections. Fourteen randomized controlled trials with a total of 1,219 patients were included that assessed taurolidine lock solutions with or without heparin and/or citrate versus regular saline or heparin locks; one study used citrate locks as a comparator. Findings were reported as a pooled incidence rate ratio (IRR), comprising incidence rates (IR) of CVC-related bloodstream infections per 1,000 CVC-days. Overall, taurolidine lock solutions were favored, with a pooled IRR of 0.30 (95% CI 0.19 to 0.46; 9 studies; 918 patients). Adverse events, reported in ten studies, were mild and limited in incidence. Although taurolidine lock solutions appear to be a promising avenue for prophylaxis, quality of evidence is low with a high risk of bias, and more robust studies should be undertaken to provide firm conclusions on its efficacy. [4]

A dated 2014 meta-analysis also studied the use of antimicrobial lock solutions to prevent CLABSIs, based on data from 23 randomized studies (n= 2,896 patients). Most of the sample consisted of adult hemodialysis patients. Antimicrobial lock solutions utilized included taurolidine (1 study), taurolidine/citrate (2 studies), and taurolidine/citrate with heparin (1 study), as well as ethanol and heparin, gentamicin citrate, vancomycin and heparin, linezolid and heparin, and others. When comparing use of all antimicrobial lock solutions, a 69% reduction in CLABSI rate was reported (RR 0.31; 95% CI 0.24 to 0.40) compared to heparin. No significant increase in catheter failure was reported due to non-infectious complications. All-cause mortality was comparable between groups. For taurolidine specifically, a subgroup analysis indicated a RR of 0.24 (95% CI 0.12 to 0.46) compared to heparin; however, the formulation of taurolidine used may not have been the specific combination utilized in Defencath. Overall, results indicated use of antimicrobial lock solutions are effective for prevention of CVC infections. The authors discussed that utilization of antimicrobial lock therapy may be of limited utility in critically ill and oncology patients with catheters in continuous use while being more beneficial for patients with long-term catheters. Evidence determining optimal dwell time and concentration for various lock solutions is still lacking. [5]

References:

[1] Lok CE, Huber TS, Lee T, et al. KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update [published correction appears in Am J Kidney Dis. 2021 Apr;77(4):551. doi: 10.1053/j.ajkd.2021.02.002]. Am J Kidney Dis. 2020;75(4 Suppl 2):S1-S164. doi:10.1053/j.ajkd.2019.12.001
[2] Sheng KX, Zhang P, Li JW, et al. Comparative efficacy and safety of lock solutions for the prevention of catheter-related complications including infectious and bleeding events in adult haemodialysis patients: a systematic review and network meta-analysis. Clin Microbiol Infect. 2020;26(5):545-552. doi:10.1016/j.cmi.2019.12.003
[3] Abdul Salim S, Masoud AT, Thongprayoon C, et al. Systematic Review and Meta-Analysis of Antibiotic and Antimicrobial Lock Solutions for Prevention of Hemodialysis Catheter-Related Infections. ASAIO J. 2021;67(10):1079-1086. doi:10.1097/MAT.0000000000001382
[4] van den Bosch CH, Jeremiasse B, van der Bruggen JT, et al. The efficacy of taurolidine containing lock solutions for the prevention of central-venous-catheter-related bloodstream infections: a systematic review and meta-analysis. J Hosp Infect. 2022;123:143-155. doi:10.1016/j.jhin.2021.10.022
[5] Zacharioudakis IM, Zervou FN, Arvanitis M, Ziakas PD, Mermel LA, Mylonakis E. Antimicrobial lock solutions as a method to prevent central line-associated bloodstream infections: a meta-analysis of randomized controlled trials. Clin Infect Dis. 2014;59(12):1741-1749. doi: 10.1093/cid/ciu671

Literature Review

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

What data supports the use of taurolidine/heparin (Defencath)?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→



Please see Tables 1-2 for your response.


 

Taurolidine/Heparin Lock Solution and Catheter-Related Bloodstream Infection in Hemodialysis A Randomized, Double-Blind, Active-Control, Phase 3 Study

Design

Prospective, randomized, double-blind, active-control, multicenter, phase 3 study

N= 806

Objective

To compare the efficacy and safety of a taurolidine/heparin catheter lock solution versus heparin in preventing catheter‐related bloodstream infections (CRBSIs) in participants receiving hemodialysis via central venous catheter (CVC)

Study Groups

Taurolidine/Heparin (n= 403)

Heparin (n= 403)

Inclusion Criteria

Aged 18 years or older; kidney failure; undergoing hemodialysis ≥2 times per week in an outpatient hemodialysis unit; using a permanent tunneled cuffed silicone or polyurethane CVC; catheters in place for ≥14 days; catheters used successfully to dialyze the participant ≥2 times before enrollment

Exclusion Criteria

Treatment with antibiotics ≤14 days of enrollment; catheter exit-site infection; thrombolytic treatment in current catheter ≤30 days of randomization; systemic immunosuppression; malignancy with life expectancy ≤6 months

Methods

Patients were randomized (1:1) to either taurolidine/heparin (13.5 mg/mL and 1,000 units/mL) or heparin (1,000 units/mL) to be instilled after hemodialysis. Lock solutions were replaced at subsequent dialysis sessions. Patients remained in the study until: (1) had a CRBSI; (2) completed all assessments through study closure; (3) withdrew from the study; (4) had catheter removed for any reason; or (5) transferred to a non-study site. Blood cultures were taken after suspicion of CRBSIs, with medical records from an acute care setting (e.g., hospital or dialysis unit) used to confirm diagnosis. Vital signs and laboratory testing were conducted every 4 weeks, with a final safety visit at 28 days after removal of the last dose of study drug.

Duration

Safety follow-up: 28 days

Outcome Measures

Primary: Time to CRBSI

Secondary: Impact of study drug on catheter functioning and included catheter removal for any reason and loss of catheter patency

Baseline Characteristics

 

Taurolidine/Heparin (n= 403)

Heparin (n= 403)

 

Age, years

61 61   

Female

184 (46%) 154 (38%)  

White

248 (62%) 262 (65%)  

Time since first dialysis, months**

21.2 19.8  

Catheter location

Jugular vein

Subclavian vein

Others*

 

371 (92%)

30 (7%)

2 (<1%)

 

365 (91%)

31 (8%)

6 (1%)

 

* The classification of participants as others was due to site staff data entry errors. Catheter location (jugular or subclavian) for these participants was confirmed after data entry and documented in study records.

** Taurolidine/heparin, n=403; heparin, n=402

Results

Endpoint

Taurolidine/Heparin (n= 

Heparin

HR (95% CI); p-value

Interim efficacy and futility analyses

Total number of patients

Participants with CRBSI

CRBSIs per 1,000 catheter days (95% CI)

 

327

6 (2%)

0.14 (0.06 to 0.30)

 

326

22 (7%)

0.49 (0.32 to 0.75)

0.28 (0.11 to 0.70); 0.003 

Study completion

Total number of patients

Participants with CRBSI

CRBSIs per 1,000 catheter days (95% CI)

 

397

9 (2%)

0.13 (0.07 to 0.26)

 

398

32 (8%)

0.46 (0.33 to 0.66)

0.29 (0.14 to 0.62); 0.001 

Any TEAE

Mild

Moderate

Severe

Life-threatening

314 (79%)

91 (23%)

112 (28%)

89 (22%)

22 (6%)

315 (79%)

80 (20%)

102 (26%)

112 (28%)

21 (5%)

 

Drug-related TEAE

17 (4%)

13 (3%)  

Abbreviations: CRBSI, catheter‐related bloodstream infection; CI, confidence interval; HR, hazard ratio; treatment-emergent adverse events

No significant differences were reported between groups for time to catheter removal for any reason (taurolidine/heparin 197 days vs. heparin 225 days; HR 1.08; 95% CI 0.90 to 1.29).

No reported TEAEs due to infrequent inadvertent flushing of taurolidine/heparin through the catheter into the body; no serious TEAEs were considered related to the study drug. The most common cause of death was cardiac disorders (5 patients per treatment group).

Adverse Events

See Results

Study Author Conclusions

Taurolidine/heparin reduced the risk of developing a CRBSI in study participants receiving hemodialysis via CVC compared with heparin with a comparable safety profile.

InpharmD Researcher Critique

Notably, this study was sponsored by the manufacturers of Defencath (CorMedix Inc.). Still, this study provides more robust data for use of taurolidine/heparin in preventing CRBSIs, with notably minimal adverse events. 

References:

Agarwal AK, Roy-Chaudhury P, Mounts P, Hurlburt E, Pfaffle A, Poggio EC. Taurolidine/Heparin Lock Solution and Catheter-Related Bloodstream Infection in Hemodialysis: A Randomized, Double-Blind, Active-Control, Phase 3 Study. Clin J Am Soc Nephrol. 2023;18(11):1446-1455. doi:10.2215/CJN.0000000000000278

 

Postmarketing experience with Neutrolin® (taurolidine, heparin, calcium citrate) catheter lock solution in hemodialysis patients

Design

Retrospective, observational, multi-center study

N= 201

Objective

To assess the catheter-related bloodstream infections (CRBSI) rate impact of Neutrolin® when used in routine practice

Study Groups

Study cohort (N= 201)

Inclusion Criteria

Hemodialysis patients; receiving dialysis via new tunnelled central venous catheters

Exclusion Criteria

Hospitalized in past 6 months due to CRBSI or catheter thrombosis

Methods

Data were derived from a surveillance program monitoring Neutrolin use of patients who received Neutrolin 2-3 times weekly, and patients were followed until failure of catheter due to clotting or CRBSI or removal of catheter due to fistula maturation.

Duration

January 2014 to September 2016

Outcome Measures

Adverse drug reactions

Baseline Characteristics

 

Study cohort (N= 201)

Total dialysis sessions

15,706

Results

Endpoint

Neutrolin rate (95% confidence interval)

Infection

0.28 (0.15-0.47)

Catheter failure thrombosis

0.15 (0.05-0.31) 

Infection is likely CRBSI. Of the raw data, there was 13 episodes of infection in 47 patients over 118 days, and 7 episodes of catheter failure in 47 patients over 118 days.

Adverse Events

Two patients experienced occasional transient dysgeusia. No discontinuation due to adverse events was reported.

Study Author Conclusions

In conclusion, Neutrolin®, when used in conjunction with guideline-based catheter care, can reduce the rate of both CRBSI and catheter thrombosis relative to recent historical controls.

InpharmD Researcher Critique

Neutrolin is the marketed brand name for DefenCath, approved by the European Union. Postmarketing experience for Neutrolin was compared to historical controls (1 prior to guideline institution and 1 after). Additionally, the study was funded by CorMedix.

References:

Reidenberg BE, Wanner C, Polsky B, et al. Postmarketing experience with Neutrolin® (taurolidine, heparin, calcium citrate) catheter lock solution in hemodialysis patients. Eur J Clin Microbiol Infect Dis. 2018;37(4):661-663. doi:10.1007/s10096-017-3157-7