Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial

Abstract

Importance: Although current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses.

Objective: To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality.

Design, setting, and participants: A parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled.

Interventions: Patients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy.

Main outcomes and measures: Coprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections.

Results: Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002).

Conclusions and relevance: Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality.

Trial registration: ClinicalTrials.gov Identifier: NCT02669589.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Zarbock reported receiving grants from Baxter, Fresenius, Astute Medical, and Astellas and receiving personal fees from Fresenius, AM Pharma, and BioMerieux. Dr Brandenburger reported receiving personal fees from Fresenius Medical Care. Dr Dimski reported receiving personal fees from Fresenius. Dr Marx reported receiving grants from B. Braun Meslungen AG, Adrenomed AG, and Biotest; receiving personal fees from B. Braun Meslungen AG and Adrenomed AG; serving as president of the German Society of Telemedicine; and that he is cofounder of Clinnomics. Dr T. Simon reported receiving personal fees from Sphingotec GmbH, B. Braun AG, and Biotest AG. Dr Kluge reported receiving personal fees from Baxter and Fresenius Medical Care. Dr Slowinski reported receiving grants from Fresenius Medical Care and receiving personal fees from Fresnius Medical Care and Gambro. Dr Moerer reported receiving grants from CSL Behring and receiving personal fees from Gettinge. Dr Bagshaw reported receiving personal fees from Baxter and receiving personal fees from BioPorto and CNA Diagnostics. Dr Meersch reported receiving personal fees from Astute Medical, FMC, and Baxter. No other disclosures were reported.

Figures

Figure 1.. Participant Flow in the RICH Trial

Abbreviations: ICU, intensive care unit; RICH, Regional Citrate vs Systemic Heparin Anticoagulation for Continuous Kidney Replacement Therapy in Critically Ill Patients with Acute Kidney Injury. aSevere sepsis or septic shock, use of vasopressor, refractory fluid overload. bRandomization was performed centrally in a 1:1 proportion using the Pocock minimization method of stratified randomization, accounting for the factors study center, sex, cardiovascular Sequential Organ Failure Assessment (SOFA) score (0-2 vs 3-4), and presence or absence of oliguria., cReasons for including but not analyzing patients were refusal of the guardianship procedure by the local court, no written consent of guardian prior to the death of the patient, no written consent of the guardian at all, or timeline issues (details reported in Supplement 3)

Figure 2.. Kaplan-Meier Curves With Hall-Wellner Confidence Bands

A, Time (hours) from start of kidney replacement therapy to filter replacement. All circuits were observed to failure or 72 hours. B, 90-day overall mortality, with median (interquartile range) observation time 90 days. Ticks perpendicular to curves indicate censored patients (n = 19).