Alexander Zarbock1, Mira Küllmar1, Detlef Kindgen-Milles2, Carola Wempe1, Joachim Gerss3, Timo Brandenburger2, Thomas Dimski2, Bartosz Tyczynski4, Michael Jahn4, Nils Mülling4, Martin Mehrländer5, Peter Rosenberger5, Gernot Marx6, Tim Philipp Simon6, Ulrich Jaschinski7, Philipp Deetjen7, Christian Putensen8, Jens-Christian Schewe8, Stefan Kluge9, Dominik Jarczak9, Torsten Slowinski10, Marc Bodenstein11, Patrick Meybohm12,13, Stefan Wirtz14, Onnen Moerer15, Andreas Kortgen16, Philipp Simon17, Sean M Bagshaw18, John A Kellum19, Melanie Meersch1. 1. Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany. 2. Department of Anesthesiology and Critical Care Medicine, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany. 3. Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany. 4. Department of Nephrology, University Hospital Essen, Essen, Germany. 5. Department of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany. 6. Department of Intensive Care Medicine, University of Aachen, Aachen, Germany. 7. Department of Anesthesiology and Intensive Care Medicine, University Hospital Augsburg, Augsburg, Germany. 8. University Hospital Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany. 9. University Medical Center Hamburg-Eppendorf, Department of Intensive Care, Hamburg, Germany. 10. Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany. 11. Universitätsmedizin Mainz, Department of Anesthesiology, Mainz, Germany. 12. Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Frankfurt, Frankfurt, Germany. 13. Department of Anesthesiology, University Hospital Würzburg, Würzburg, Germany. 14. Department of Anesthesiology, Intensive Care and Pain Medicine, Helios Klinikum Bad Saarow, Bad Saarow, Germany. 15. Department of Anesthesiology, University Medical Center Göttingen, Göttingen, Germany. 16. Department of Anesthesiology and Intensive Care Medicine, University Hospital Jena, Jena, Germany. 17. Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Leipzig, Germany. 18. Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, Alberta, Canada. 19. Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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 withsystemic 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.
RCT Entities:
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 illpatients, 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 illpatients 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 illpatients 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.
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