Modified regional citrate anticoagulation is optimal for hemodialysis in patients at high risk of bleeding: a prospective randomized study of three anticoagulation strategies

Abstract

Background: Recommended regular saline flushing presents clinical ineffectiveness for hemodialysis (HD) patients at high risk of bleeding with heparin contraindication. Regional citrate anticoagulation (RCA) has previously been used with a Ca²⁺ containing dialysate with prefiltered citrate in one arm (RCA-one). However, anticoagulation is not always achievable and up to 40% results in serious clotting in the venous expansion chamber. In this study, we have transferred one-quarter of the TSC from the prefiltered to the post filter based on RCA-one, which we have called RCA-two. The objective of this study was to compare the efficacy and safety of RCA-two with either saline flushing or RCA-one in HD patients with a high bleeding risk.

Method: In this investigator-initiated, multicenter, controlled, prospective, randomized clinical trial, 52 HD patients (77 sessions) were randomized to the RCA-2 and RCA-one group in part one of the trial, and 45 patients (64 sessions) were randomized to the RCA-2 and saline group in part two of the trial. Serious clotting events, adverse events and blood analyses were recorded.

Results: Serious clotting events in the RCA-two group were significantly lower compared with the RCA-one and saline group (7.89% vs. 30.77%, P = 0.011; 3.03% vs. 54.84%, P < 0.001, respectively). The median circuit survival time was 240 min (IQR 240 to 240) in the RCA-two group, was significantly longer than 230 min (IQR 155 to 240, P < 0.001) in the RCA-one group and 210 min (IQR 135 to 240, P = 0.003) in the saline group. The majority of the AEs were hypotension, hypoglycemia and chest tightness, most of which were mild in intensity. Eight patients (20.51%) in the RCA-one group, 4 patients (12.90%) in the saline group and 10 patients (26.31%) in the RCA-two group, P > 0.05.

Conclusions: Our data demonstrated that the modified anticoagulation protocol was more effective and feasible during hemodialysis therapy for patients at high risk of bleeding.

Trial registration: GDREC, GDREC2017250H. Registered February 2, 2018; retrospectively registered.

Fig. 1

Schematized extracorporeal circuit and dialysate parameters for three anticoagulation strategies. a the Saline group. b RCA groups. RCA-one: 4% TSC was only continuously infused in position I; RCA-two: 4% TSC was infused in position I and II, simultaneously. c The infusion rate of 4% TSC in RCA-one and RCA-two groups. Abbreviations: RCA, regional citrate anticoagulation; TSC, trisodium citrate.

Fig. 2

Patient flow of the trial. Abbreviations: Saline, saline flushing group; RCA-two, two-stage regional citrate anticoagulation group; RCA-one, one-stage regional citrate anticoagulation group; n: number of patients.

Fig. 3

Efficacy endpoints and cumulative probability of survival for the circuit. a Serious clotting rate (the primary outcome) in part one and part two trial. b The circuit survival time in each group. The median circuit survival time was 230 min (IQR 155 to 240) in the RCA-one group vs. 240 min (IQR 240 to 240) in the RCA-two group (P < 0.001); The median circuit survival time was 210 min (IQR 135 to 240) in the saline group vs. 240 min (IQR 240 to 240) in the RCA-two group (P = 0.003). c The Kaplan–Meier curves for uncensored circuit survival between the RCA-two and RCA-one groups. d The Kaplan–Meier curves for uncensored circuit survival between the RCA-two and Saline groups. The survival analyses were based on the log-rank test. Abbreviations: Saline, saline flushing group; RCA-two, two-stage regional citrate anticoagulation group; RCA-one, one-stage regional citrate anticoagulation group

Fig. 4

The evaluation of TSC overdose and hypocalcemia throughout the treatment. a The percentage of Total calcium to ionized calcium (T/I Ca²⁺) levels below 2.5 at hour 0 and 4 in the RCA-one and RCA-two groups. b The percentage of Total calcium to ionized calcium (T/I Ca²⁺) levels below 2.5 at hour 0 and 4 in the Saline and RCA-two groups. c The mean concentrations of serum iCa from baseline to 4 h in the Saline and RCA-two groups. The change of concentrations of serum-ionized calcium from baseline to endpoint were analyzed with the mixed models for repeated measures with an unstructured residual covariance matrix (main effect of time P = 0.193, anticoagulation group P < 0.001 and interaction effect P = 0.311). d The mean concentrations of serum iCa from baseline to 4 h in the RCA-one and RCA-two groups. The change of concentrations of serum-ionized calcium from baseline to endpoint were analyzed with the mixed models for repeated measures (main effect of time P = 0.492, anticoagulation group P < 0.001 and interaction effect P = 0.021). e The percentage of hypocalcemia events (iCa²⁺ < 0.9 mmol/L) between the RCA-one and RCA-two groups. f The percentage of hypocalcemia events (iCa²⁺ < 0.9 mmol/L) between the Saline and RCA-two groups. (P < 0.05, statistical significance). Abbreviations: Saline, saline flushing group; RCA-two, two-stage regional citrate anticoagulation group; RCA-one, one-stage regional citrate anticoagulation group; n.s., no significant statistical differences; iCa, ionized calcium; TSC, trisodium citrate

Fig. 5

The comparison of values of the internal environmental parameters throughout hemodialysis procedures. PH values between the RCA-two and RCA-one group (a) / the Saline group(b); Serum sodium values between the RCA-two and RCA-one group (c) / the Saline group(d); Serum bicarbonate between the RCA-two and RCA-one group (e) / the Saline group(f). (P < 0.05, statistical significance). Abbreviations: Saline, saline flushing group; RCA-two, two-stage regional citrate anticoagulation group; RCA-one, one-stage regional citrate anticoagulation group