Argatroban Versus Heparin Catheter Locks for Haemodialysis Central Venous Catheters: A Single-Centre Randomized Controlled Trial

Abstract

Introduction : Argatroban is a promising locking solution regarding antithrombotic properties but has rarely been reported before. The objective of this study was to preliminarily verify the safety and effectiveness of argatroban as a catheter lock compared with sodium heparin.

Methods : This was an open-label randomized controlled trial of 50 consenting haemodialysis patients in one dialysis unit. Intervention: 2 weeks of use of 0.5 mg/mL argatroban or 1000 IU/mL heparin locked postdialysis in the dead space of the central venous catheter. Primary outcome of change from baseline (before a dialysis session) in the activated partial thromboplastin time (aPTT) 30 min after locking. Secondary outcomes were changes in aPTT between baseline and before the next dialysis session, catheter thrombosis defined by catheter eradication or the use of urokinase lock and infusion, catheter-related bacteremia and exit-site infection, and bleeding events.

Results: The aPTT measured 30 min after locking was significantly higher in the heparin group than in the argatroban group (P<0.001). In addition, within-group comparisons showed that in the heparin group, the aPTT measured 30 minutes post locking was significantly higher than that measured at baseline and the end of the 1st HD (P<0.001), whereas the argatroban group showed no significant change in aPTT 30 minutes post locking compared to baseline and post HD values (P>0.05). Other secondary end points did not differ.

Conclusion: This study shows that argatroban can provide antithrombotic effects similar to those of heparin without affecting systemic coagulation. Argatroban locking solution is an effective short-term locking solution.

Keywords

• Central venous catheter
• Argatroban
• Locking solution
• Safety

Citation

Sun X, Wang Y, Zhang Q, Zhou J, Ping Li, et al, (2024) Argatroban Versus Heparin Catheter Locks for Haemodialysis Central Venous Catheters: A Single-Centre Randomized Controlled Trial. J Nephrol Kidney Dis 5: 7.

Introduction

Catheter dysfunction and catheter-related infection are two of the major causes of increased morbidity and mortality among haemodialysis patients [1]. Catheter locking is the main method used to prevent central venous catheter (CVC) dysfunction and CRBSI. Based on the Kidney Disease Outcomes Quality Initiative [2], a low concentration (<5%) of citrate locking solution is a good option; however, it cannot completely prevent catheter thrombosis. Similarly, heparin locking solution cannot completely prevent catheter thrombosis. Citrate inhibits coagulation by chelating calcium ions, but it has no effect on the return of thrombin and fibrinogen to the CVC from circulation. Therefore, catheter thrombosis cannot be completely prevented by citrate. The anticoagulant effect of heparin in the CVC depends on the infiltration of anti-thrombin returning to the CVC from the circulation, but this may not completely inhibit thrombin activity; therefore, catheter thrombosis can be only partly prevented by heparin.

Argatroban is a synthetic small molecule that is a direct, competitive, and selective thrombin inhibitor. Moreover, argatroban can directly bind to the catalytic active site of thrombin and inhibit free thrombin in circulation as well as thrombin bound to fibrin thrombi without the need for antithrombin to block the positive feedback of the coagulation cascade, which indirectly inhibits thrombin production [3]. Even if a small amount of argatroban slowly enters the blood circulation after CVC locking, argatroban, with a plasma half-life of 39 to 51 min [4], can be rapidly metabolized without affecting systemic coagulation or increasing the risk of bleeding. Therefore, argatroban has the pharmacological characteristics required for the effective prevention of CVC thrombosis and dysfunction.

We hypothesized that argatroban can be used as a new, safe and effective CVC locking solution, and we designed this clinical trial to compare the effectiveness of argatroban 0.5 mg/mL versus heparin 1000 U/mL locking solutions on coagulation and CVC dysfunction prevention in HD patients to provide basic data for further clinical evidence-based research.

Materials and Methods

Trial oversight
A prospective, randomized, parallel-group open-label single-centre trial was conducted in the haemodialysis room of the Nephrology Department of the General Hospital of the Chinese People’s Liberation Army. The study was approved by the Research Ethics Committee of the General Hospital of the Chinese People’s Liberation Army (Ethics No. S2018-055-01) and registered in the China Clinical Trial Registry (No. ChiCTR1800017105). Written informed consent was obtained from all patients. The clinical trial was conducted in accordance with the Declaration of Helsinki [5], and Good Clinical Practice guidelines [6].

Inclusion and exclusion criteria

The inclusion criteria were as follows: (i) age≥18 years; (ii) initial dialysis patients who just entered regular dialysis with a CVC at jugular or femoral sites; and (iii) BFR (blood flow rate) of TCC (tunnelled central venous catheters) ≥250 ml/min and UCC (untunnelled central venous catheters) ≥200 ml/min at the start of the study.

The exclusion criteria were as follows: (i) catheter malfunction defined as a BFR of TCC <250 mL/min, UCC <200 ml/min; (ii) allergy to used drugs; (iii) major haemorrhage in the previous 4 weeks; (ⅳ) history of CVC infection or catheter failure or HIT (heparin-induced thrombocytopenia); and (ⅴ) systemic infection or concurrent malignancy.

Study drug and procedure standards
In the argatroban group, 4 mL of argatroban (10 mg/20 mL vial, g, produced by TIPR Pharmaceutical Responsible Co., Ltd, Tianjin, China) was extracted and administered via catheter at a dose of 0.5 mg/mL using a 4 mL isovolumetric lock by nurses in the HD centre. In the heparin group, 1 mL of heparin sodium (12,500 units/2 mL vial, produced by SPH No.1 Biochemical & Pharmaceutical Co., Ltd.) was diluted with 5 mL of normal saline and prepared as a 1:5 (approximately 1000 IU/mL) heparin locking solution by HD nurses.

Both groups underwent dialysis during the treatment period with a frequency of 3 sessions per week, and the locking solution remained in the catheter lumen until the next haemodialysis session. The catheter outlet was checked during each dialysis session. If there were any signs of potential catheter infection (redness, exudate, or tenderness at the exit site), a sensitivity test was performed, a swab culture from the exit site was taken, and a blood culture taken from the lumen was increased if there was a fever. In the occurrence of a drug allergy that could not be relieved by treatment with anti-allergic drugs or if the patient could not tolerate the adverse reactions of the study drug, the patient was withdrawn from the study.

Study-specific blood samples were collected at baseline (before the first dialysis session) examination before administration of the study drug. Additional samples were collected before and after the first dialysis session as well as after administration of the lock solution (Visit 1), before the second dialysis session (Visit 2), and before and after the seventh dialysis session (Visit 3). In addition, within 3 days of discontinuing the study drug, the radiologist performed an ultrasound scan of the
central vein to detect the presence of clinically significant venous thromboembolism. General clinical data and coagulation status data were collected during the follow-up period to assess catheter function and any catheter-related infections and bleeding events. Concomitant medications and adverse events were also recorded.

Outcome measures

Primary outcome: Change in aPTT between blood samples taken at baseline (before the first dialysis session) and 30 minutes postadministration of the locking solution in the argatroban and heparin groups.
Secondary outcomes
• Changes from baseline (before the first dialysis session) in aPTT before the next dialysis session;
• 2-week cumulative survival rate of CVC (defined by mean blood flow of TCC≥250 ml/min, mean blood flow of UCC≥200 ml/ min);
• 2-week catheter thrombosis-free rates (ultrasound examination shows no thrombus);
• During the 2-week trial, bleeding events such as skin, gum, or gastrointestinal bleeding occurred;
• 2-week catheter-related blood infection (CRBSI) rates: CRBSI was defined by one of the following events: any purulent
secretion present at the exit site of the catheter, any tunnelled catheter-related infection present and any symptoms of
catheter-related blood infection (such as fever and shivering present).

Sample size calculation

The sample size was calculated based on the primary outcome of this study (changes in aPTT from baseline at 30 minutes after CVC locking). According to previous clinical studies [7-9], and clinical experience, we estimated that the aPTT value measured at 30 min after CVC locking would be approximately 20 ± 18 seconds higher than the baseline in the heparin group, and the changes in aPTT at 30 minutes after CVC locking from the baseline were expected to be 15 seconds lower in the argatroban group than in the heparin group. With a power of 80%, a significance level (α) of 0.05 and a beta of 0.8, a sample size of 48 cases was needed, according to PASS15.0 software. Considering that the patients included in the group were initial dialysis patients and assuming a dropout rate of 20% during treatment, a sample size of 60 cases (30 cases/group) was needed. No interim analysis was planned during the study.

Randomization and blinding

This was an open-label study; therefore, no blinding method was needed. The patients who satisfied the inclusion and exclusion criteria and provided informed consent were randomly allocated to the two arms in a 1:1 ratio via a random number sequence generated by computer software.

Statistical analysis

All analyses were performed with R version 4.1.2, and the baseline characteristics of the enrolled patients were analysed with the compareGroups package. For baseline parameter differences in the two groups, one-way analysis of variance (ANOVA) was performed for continuous variables, and the Wilcoxon rank-sum test and Fisher’s exact test were used for categorical variables to assess differences between intent-to-treat (ITT) groups. The FMSB package was used to analyse the median difference and binary odds ratio (OR) of continuous data, as well as the 95% confidence interval (CI) of the mean value and proportion difference. For all analyses, the conventional standard of statistical significance was used (P<0.05).

Results

In this clinical trial, the clinicians at our research centre recruited patients, and all the patients signed the informed consent form with knowledge. The first patient was enrolled on September 3, 2018, with a trial duration of approximately 4 years and 1 month. The trial ended on September 27, 2022.

Participants

Initially, we assumed a dropout rate of 20% during treatment; we obtained a dropout rate of 8%, so fifty patients (argatroban, 27; heparin 1000 u/mL, 23) were randomized to two arms during the 2-week trial. Analysis was performed according to the intention-to-treat principle (ITT) in accordance with the full analysis set (FAS) and safety data set (SS) for all patients who were randomized and had received at least one recorded treatment with safety indicators recorded. A total of 277 HD sessions (argatroban, 152; heparin 1000 u/mL, 125) were completed for all patients, and four patients discontinued due to catheter replacement or returned locally for HD treatment during the second visit period (Figure 1).

Figure 1: Consort diagram

A total of 46 patients completed all study requirements for inclusion in the per protocol (PP) data set, including 25 patients in the argatroban group and 21 patients in the heparin group (Figure 1).

Baseline characteristics

The mean age of the study participants was 47.5 years; 33 patients were male. Baseline characteristics are summarized in Table 1.

The internal jugular vein was the main insertion site for all patients in the two groups and accounted for most of the insertions (76.0%). Twentyeight dialysis catheters were tunnelled catheters. The patients in the two groups were homogenously distributed regarding age, sex, cause of end-stage renal disease (ESRD), cause of end-stage renal disease (ESRD), catheter site, catheter type, catheter length and other baseline laboratory characteristics (P>0.05), apart from the albumin level being lower in the argatroban group (33.4 ± 4.8 vs. 36.2 ± 3.7 g/L, P=0.04).

Comparison of aPTT changes between the argatroban and heparin groups before and after locking solution

The aPTT measured 30 min after locking was significantly higher in the heparin group than in the argatroban group (P<0.001). In addition, within-group comparisons showed that in the heparin group, the aPTT measured 30 minutes post locking was significantly higher than that measured at baseline and the end of the 1st HD (P<0.001), whereas the
argatroban group showed no significant change in aPTT 30 minutes post locking compared to baseline and post HD values (P>0.05) (Table 2 and Figure 2).

Table 2: Comparison of aPTT Changes between the Argatroban and Heparin Groups before and after CVC Locking Solution

Note: #: P < 0.05 compared to baseline; # #: P < 0.001 compared to baseline; * *: Compared to the end of the 1st HD, P < 0.001.

Figure 2: Comparison of the Changes in aPTT between Groups before and after CVC Locking Solution.
Note: #: P < 0.05 compared to baseline; # #: P < 0.001 compared to baseline; * *: P < 0.001 compared to the end of the 1st HD.

Comparison of the incidence of clinical events between the argatroban and heparin groups during the 2-week follow-up

Secondary outcome variables demonstrated statistically nonsignificant between-group differences. In the argatroban group,
4/25 (16.0%) patients lost catheters due to catheter thrombosis, and no CRBSIs occurred, while in the heparin group, 4/21 (19.0%) patients lost catheters due to catheter thrombosis, and 1/21 (4.76%) CRBSIs occurred during the 2-week follow-up period. This corresponds to 85.5 CD/1000 HD and 0 CRBSI/1000 HD in the argatroban group and 72 CD/1000 HD and 8 CRBSI/1000 HD in the heparin group. The argatroban group was found to have a higher rate of catheter thromboses (P =0.08). There were no bleeding events in either group (Table 3).

Comparison of laboratory indexes between the argatroban group and heparin group before and after intervention

No statistically significant differences were found between the two groups at baseline and postintervention in terms of haemoglobin, haematocrit, platelets, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glucose, serum albumin, serum creatinine, serum urea, serum uric acid, serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, APTT, PT, INR, TT, D dimer and antithrombin activity (P>0.05). Nevertheless, at the end of the 2-week follow-up, the PT and INR levels in the heparin group were significantly higher than those in the argatroban group (P<0.05); however, both values were within the normal range (Table 4).

Note: #: P < 0.05 compared to baseline; *: P < 0.001 compared to heparin

Adverse events

In the argatroban group, 5 patients (20%) developed symptoms that included limb numbness, nausea, headache or decreased platelets. In the heparin group, adverse events occurred in 2 patients (9.5%), including 1 patient with abdominal distension and 1 patient with fever and sepsis (considered unrelated to drugs). All patients with adverse events spontaneously recovered without special intervention. There were no serious adverse events or adverse events that could be attributed to the locking solutions.

Discussion

Argatroban, a direct thrombin inhibitor, has the following characteristics: ① its direct inactivation of thrombin has no direct
effect on the production of thrombin, and its effect does not depend on antithrombin III; ② it inactivates liquid phase thrombin in addition to the thrombin bound to fibrin thrombus; ③ it blocks positive feedback of the coagulation waterfall, thereby indirectly inhibiting the production of thrombin; ④ at therapeutic doses, it has no effect on platelet function and does not lead to thrombocytopenia; ⑤ it has a good dose‒response relationship, and its anticoagulation effects and safety profile can be reliably predicted; and ⑥ it is strongly correlated with aPTT and is easy to monitor clinically. Moreover, a stable anticoagulation level can be reached 1~3 h after intravenous administration of argatroban, which has a half-life of 40~50 min. One to two hours after drug administration is discontinued, aPTT can return to normal levels, and this recovery is not affected by age, sex or renal function [10]. In addition, since argatroban is imported from the arterial end of the blood purification pipeline, it can achieve full anticoagulation of the filter and can be quickly metabolized after being returned to the body without affecting the blood coagulation process in vivo. The dialyzer limits clearance of argatroban and does not require frequent dose adjustments [11,12]. Therefore, argatroban is widely used in extracorporeal circulation anticoagulant therapy, such as blood purification.

This trial is the first to evaluate the effectiveness and safety of argatroban as a locking solution for CVC through a prospective randomized controlled design. The results showed that in the argatroban group, the aPTT value measured 30 min after locking was not significantly different from the aPTT values at baseline and at the end of the first HD session before locking (P>0.05). Meanwhile, the aPTT change 30 min after locking from baseline and the aPTT changes measured between 30 min after locking and at the end of the first HD session were significantly higher in the heparin group. These results suggest that the argatroban lock did not affect the patients’ systemic coagulation status; however, the heparin 1000 U/mL lock affected systemic coagulation and may have increased the risk of bleeding.

Although some research results show that 1000 U/mL heparin locking solution has no significant effect on blood coagulation status [7,13,14], the results of this trial showed that the aPTT value 30 minutes after catheter locking with 1000 U/mL heparin was significantly higher than the aPTT values at the end of HD (before catheter locking) and at baseline. The reasons for this are as follows: ① The weight of domestic HD patients is typically lower than that of foreign patients; and ②
although aPTT at the end of HD is not significantly different from baseline (before dialysis), the level of anticoagulants in the blood circulation may have reached a critical threshold at the end of HD. Even if a small amount of heparin leaks into the blood circulation from the CVC, the aPTT may also be significantly prolonged.

The results of this experiment showed that during the 2-week follow-up period of the argatroban and heparin groups, there was no significant difference in the CVC cumulative catheter survival rate, catheter thrombosis-free rate, urokinase treatment rate or CRBSI incidence rate. This suggests that argatroban 0.5 mg/mL and heparin 1000 U/mL had the same effect in preventing CVC dysfunction and CRBSI.

In addition, there was no significant difference in laboratory indicators between baseline and the end of the follow-up period between the two groups. At the end of the 2-week follow-up, the PT and INR levels in the heparin group were significantly higher than those in the argatroban group (P<0.05), suggesting that the 0.5 mg/mL argatroban and 1000 U/ mL heparin locking solutions do not affect the coagulation status. These results indicate that argatroban is a safe and effective short-term CVC locking solution.

Conclusion

This study shows that argatroban can provide similar antithrombotic effects with better safety outcomes compared to heparin. Catheter survival and catheter-related blood stream infection were not significantly different, but there was a trend towards an increased rate of thrombosis in the argatroban group even if not significant. The limitation is that the short follow-up period may have underpowered this study. Widespread and long-term use of argatroban catheter locks is not justified by this study. However, this study provides basic data and will inform an adequately powered multicentre trial to definitively examine the efficacy and safety of argatroban locks as a short-term alternative to current therapies used in the prevention of catheter thrombosis in dialyzing patient catheters.

Acknowledgements

We acknowledge all the staff and HD nurses in our HD centre, TIPR Pharmaceutical Responsible Co., Ltd, Tianjin (China), and SPH No.1 Biochemical & Pharmaceutical Co., Ltd. for providing us argatroban and heparin, respectively.

Study Protocol: https://apm.amegroups.com/article/view/61198/ html 

Consent for Publication

All authors have provided consent for publication.

Ethics Approval and Consent To Participate

This study was approved by the Medical Ethics Committee of the Chinese People’s Liberation Army General Hospital on 31 May 2018 (journal number: S2018-055-01). Patients who agree to participate and sign the informed consent will be involved.

Funding

This work was supported by the National Natural Science Foundation of China under Grant 92049103.

Data Availability Statement

The data sets generated during the study are available from the corresponding author upon reasonable request.

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