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Anticoagulation

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 InjuryA Randomized Clinical Trial

Educational Objective
To learn the effect of anticoagulation strategies on dialysis filter life span and patient mortality among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy.

1 Credit CME

JAMA

October 27, 2020

Original Investigation

Article Information and Disclosures

Alexander Zarbock, MD¹;

Mira Küllmar, MD¹;

Detlef Kindgen-Milles, MD²;

et al

Carola Wempe, PhD¹;

Joachim Gerss, PhD³;

Timo Brandenburger, MD²;

Thomas Dimski, MD²;

Bartosz Tyczynski, MD⁴;

Michael Jahn, MD⁴;

Nils Mülling, MD⁴;

Martin Mehrländer, MD⁵;

Peter Rosenberger, MD⁵;

Gernot Marx, MD⁶;

Tim Philipp Simon, MD⁶;

Ulrich Jaschinski, MD⁷;

Philipp Deetjen, MD⁷;

Christian Putensen, MD⁸;

Jens-Christian Schewe, MD⁸;

Stefan Kluge, MD⁹;

Dominik Jarczak, MD⁹;

Torsten Slowinski, MD¹⁰;

Marc Bodenstein, MD¹¹;

Patrick Meybohm, MD^12,13;

Stefan Wirtz, MD¹⁴;

Onnen Moerer, MD¹⁵;

Andreas Kortgen, MD¹⁶;

Philipp Simon, MD¹⁷;

Sean M. Bagshaw, MD¹⁸;

John A. Kellum, MD¹⁹;

Melanie Meersch, MD¹;

for the RICH Investigators and the Sepnet Trial Group

Author Affiliations

¹Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
²Department of Anesthesiology and Critical Care Medicine, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany
³Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany
⁴Department of Nephrology, University Hospital Essen, Essen, Germany
⁵Department of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
⁶Department of Intensive Care Medicine, University of Aachen, Aachen, Germany
⁷Department of Anesthesiology and Intensive Care Medicine, University Hospital Augsburg, Augsburg, Germany
⁸University Hospital Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany
⁹University Medical Center Hamburg-Eppendorf, Department of Intensive Care, Hamburg, Germany
¹⁰Department of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, Berlin, Germany
¹¹Universitätsmedizin Mainz, Department of Anesthesiology, Mainz, Germany
¹²Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Frankfurt, Frankfurt, Germany
¹³Department of Anesthesiology, University Hospital Würzburg, Würzburg, Germany
¹⁴Department of Anesthesiology, Intensive Care and Pain Medicine, Helios Klinikum Bad Saarow, Bad Saarow, Germany
¹⁵Department of Anesthesiology, University Medical Center Göttingen, Göttingen, Germany
¹⁶Department of Anesthesiology and Intensive Care Medicine, University Hospital Jena, Jena, Germany
¹⁷Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Leipzig, Germany
¹⁸Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, Alberta, Canada
¹⁹Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

RICH Investigators and the Sepnet Trial Groupfor the

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Key Points

Question Among critically ill patients with acute kidney injury, what is the effect of a strategy using regional citrate anticoagulation, which consists of administration of citrate to the extracorporeal dialysis circuit, vs systemic heparin anticoagulation, which consists of intravenous heparin application, during continuous kidney replacement therapy on dialysis filter life span and mortality?

Findings In this randomized clinical trial that included 596 patients and that was stopped early, anticoagulation with regional citrate administration, compared with systemic heparin anticoagulation, resulted in significantly longer median filter life span (47 hours vs 27 hours, respectively), and 90-day mortality was 51.2% vs 53.6%, respectively.

Meaning Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, increased filter life span, but the trial was underpowered to reach conclusions regarding mortality.

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

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Article Information

Corresponding Author: Alexander Zarbock, MD, Department of Anesthesiology, Critical Care Medicine and Pain Therapy, University Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany (zarbock@uni-muenster.de).

Accepted for Publication: September 2, 2020.

Published Online: October 23, 2020. doi:10.1001/jama.2020.18618

Author Contributions: Drs Zarbock and Meersch had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Zarbock and Küllmar share first authorship.

Concept and design: Zarbock, Wempe, Gerss, Bodenstein, Meersch.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Zarbock, Gerss, Meersch.

Critical revision of the manuscript for important intellectual content: Zarbock, Küllmar, Kindgen-Milles, Wempe, Brandenburger, Dimski, Tyczynski, Jahn, Mülling, Mehrländer, Rosenberger, Marx, T. Simon, Jaschinski, Deetjen, Putensen, Schewe, Kluge, Jarczak, Slowinski, Bodenstein, Meybohm, Wirtz, Moerer, Kortgen, P. Simon, Bagshaw, Kellum, Meersch.

Statistical analysis: Zarbock, Gerss, Bagshaw.

Obtained funding: Zarbock.

Administrative, technical, or material support: Zarbock, Küllmar, Wempe, Jaschinski, Meersch.

Supervision: Zarbock, T. Simon, Kluge.

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.

Funding/Support: This study was funded by the German Research Foundation (grants ZA 428/10-1, KFO 342/1).

Role of the Funder/Sponsor: The German Research Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

RICH Investigators and Members of the Sepnet Trial Group: The RICH Investigators: Alexander Zarbock, MD; Mira Küllmar, MD; Detlef Kindgen-Milles, MD; Carola Wempe, PhD; Joachim Gerss, PhD; Timo Brandenburger, MD; Thomas Dimski, MD; Bartosz Tyczynski, MD; Michael Jahn, MD; Nils Mülling, MD; Martin Mehrländer, MD; Peter Rosenberger, MD; Gernot Marx, MD; Tim Philipp Simon, MD; Ulrich Jaschinski, MD; Philipp Deetjen, MD; Christian Putensen, MD; Jens-Christian Schewe, MD; Stefan Kluge, MD; Dominik Jarczak, MD; Torsten Slowinski, MD; Marc Bodenstein, MD; Patrick Meybohm, MD; Stefan Wirtz, MD; Onnen Moerer, MD; Andreas Kortgen, MD; Philipp Simon, MD; Melanie Meersch, MD. The Sepnet Trial Group: Alexander Zarbock, MD; Peter Rosenberger, MD; Gernot Marx, MD; Ulrich Jaschinski, MD; Christian Putensen, MD; Stefan Kluge, MD; Dominik Jarczak, MD; Patrick Meybohm, MD; Stefan Wirtz, MD; Philipp Simon, MD; Melanie Meersch, MD. Data acquisition: Johannes Bickenbach, MD, Christian Stoppe, MD, Thomas Breuer, MD (University Hospital Aachen, Department of Intensive Care Medicine, Germany); Claudia Spies, MD (Charité Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine, Germany); Dmytro Khadzynov, MD (Charité Universitätsmedizin Berlin CVK, Medical Department, Division of Nephrology and Internal Intensive Care Medicine, Germany); Friedhelm Bach, MD (Evangelisches Klinikum Bethel, Bielefeld, Germany); Hartmuth Nowak, MD (Universitätsklinikum Knappschaftskrankenhaus Bochum, Department of Anesthesiology and Intensive Care Medicine, Germany); Florian Kögel, MD, Thomas Muders, MD, Stefan Muenster, MD (University Hospital Bonn, Department of Anesthesiology and Intensive Care Medicine, Germany); Carsten Willam, MD (University Hospital Erlangen, Department of Medicine 4, Nephrology and Hypertension, Germany); Simone Lindau, MD, Kai Zacharowski, MD (University Hospital Frankfurt, Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, Germany); Fabian Edinger, MD (University Hospital Gießen, Department of Anesthesiology and Intensive Care Medicine, Germany); Daniel Heise, MD, Andrea Kernchen, Kati Steinhoff (University Medical Center Göttingen, Department of Anesthesiology, Germany); Sixten Selleng, MD (University Medicine Greifswald, Department of Anesthesiology and Intensive Care Medicine, Germany); Olaf Boenisch, MD (University Medical Center Hamburg-Eppendorf, Department of Intensive Care, Germany); Johann Motsch, MD (University Hospital Heidelberg, Department of Anesthesiology, Germany); Frank Blos, MD, Daniel Thomas-Rüddel, MD (University Hospital Jena, Department of Anesthesiology and Intensive Care Medicine, Germany); Falk Fichtner, MD, Michael Roedel, MD, Sebastian Stehr, MD (Department of Anesthesiology and Intensive Care Medicine, Germany); Markus Heim, MD (Technical University of Munich, University Hospital, Department for Anesthesiology, Germany); Andreas Margraf, MD, Jan Rossaint, MD (Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany); Thomas Schrauzer, MD (University Hospital Nürnberg, Department of Intensive Care Medicine, and Institute for Klinikhygiene, Medizinische Mikrobiologie und Klinische Infektiologie Universitätsklinik der Paracelsus Medizinischen Privatuniversität Standort Nürnberg, Germany); Ivan Göcze, MD (University Hospital Regensburg, Department of Surgery, Germany); Peter Heering, MD (Municipal Hospital Solingen, Department for Nephrology and General Internal Medicine, Germany); Stefanie Prohaska, MD, Helene Häberle, MD (Department of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany). Analyses: Clinical Trial Center, University Leipzig, Leipzig, Germany: Holger Bogatsch, MD, Anke Schöler; University Hospital Leipzig. Data and Safety Monitoring Board: Univ-Prof Dr med Hartmut Bürkle (Department of Anesthesiology and Critical Care Medicine, University of Freiburg, Freiburg, Germany); Univ-Prof Dr med Peter Zahn (Department of Anesthesiology, Critical Care Medicine, and Pain Medicine, University of Bochum [Bergmannsheil], Bochum, Germany); Prof Dr Guido Knapp (Department of Statistics, TU Dortmund Universität, Dortmund, Germany).

Meeting Presentation: Presented at ASN Kidney Week, October 23, 2020.

Additional Contributions: We thank all of the study nurses at all participating centers for data entry and the staff in the participating intensive care units for their hard work.

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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 InjuryA Randomized Clinical Trial

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