Investigating Different Anticoagulants for Renal Replacement Therapy (RICH)

Regional Citrate Versus Systemic Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Patients With Acute Kidney Injury

The aim of this study is to evaluate the effect of regional citrate anticoagulation within the scope of continuous renal replacement (CRRT) in critically ill patients with acute kidney injury (AKI) on filter life span and 90-day all cause mortality.

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury
• Intervention / Treatment: Drug: Heparin; Drug: Citrate

Detailed Description

Purpose of clinical trial:

To evaluate the effect of regional citrate anticoagulation within the scope of continuous renal replacement (CRRT) in critically ill patients with acute kidney injury (AKI) on filter life span and 90-day all cause mortality.

Patient population: critically ill patients with acute kidney injury requiring renal replacement therapy.

Primary objective:

Anticoagulation of the extracorporeal circuit is required in continuous RRT (CRRT). To this date, it is not clear which anticoagulant should be used for CRRT. Regional citrate anticoagulation (RCA) for CRRT in critically ill patients with AKI prolongs filter life span and reduces 90-day all cause mortality by approximately 8% (from 48% to 40%) compared to systemic heparin anticoagulation for CRRT

• Study Type: Interventional
• Enrollment (Actual): 638
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, D-52074
    • University Hospital Aachen
  • Augsburg, Germany, D-86156
    • Klinikum Augsburg
  • Bad Saarow, Germany, D-15526
    • HELIOS Klinikum Bad Saarow, Dept. of Intensive Care
  • Berlin, Germany, 10117
    • Charité Berlin, Dept. of Anesthesiology and Intensive Care Medicine
  • Berlin, Germany, D-10117
    • Charité Berlin CCM, Medical Department, Division of Nephrology
  • Berlin, Germany, D-13353
    • Charité Berlin CCV, Medical Department, Division of Nephrology
  • Bielefeld, Germany, D-33617
    • Evangelisches Klinikum Bethel gGmbH
  • Bochum, Germany, D-44892
    • Universitätsklinikum Knappschaftskrankenhaus Bochum
  • Bonn, Germany, D-53127
    • University Hospital Bonn, Dept.of Anesthesiology and Intensive Care Medicine
  • Duesseldorf, Germany, D-40225
    • University Hospital Duesseldorf, Dept. of Anaesthesiology
  • Düsseldorf, Germany, D-40225
    • University Hospital Düsseldorf, Dept. of Nephrology
  • Erlangen, Germany, D-91054
    • University Hospital Erlangen
  • Essen, Germany, D-45122
    • University Hospital Essen, Dept. for Nephrology
  • Frankfurt, Germany, D-60590
    • University Hospital Frankfurt, Dept. of Anesthesiology, Intensive-Care Medicine and Pain Therapy
  • Gießen, Germany, D-35392
    • University Hospital Gießen, Dept. of Anesthesiology and Intensive Care
  • Greifswald, Germany, D-17475
    • University Medicine Greifswald
  • Göttingen, Germany, D-37075
    • University Medical Center Göttingen, Dept. for Anesthesiology
  • Halle (Saale), Germany, D-06120
    • University Hospital Halle, Dept. of Anesthesiology and Intensive Care
  • Hamburg, Germany, D-20246
    • University Medical Center Hamburg-Eppendorf, Dept. of Intensive Care
  • Heidelberg, Germany, D-69120
    • University Hospital Heidelberg, Dept. of Anesthesiology
  • Jena, Germany, D-07747
    • University Hospital Jena, Dept. of Anesthesiology and Intensive Care Medicine
  • Kiel, Germany, D-24105
    • University Hospital Schleswig-Holstein, Campus Kiel, Dept. for Anaesthesiology and Intensive Care
  • Köln, Germany, D-51109
    • Klinikum Köln-Merheim, Medizinische Klinik I
  • Leipzig, Germany, D-04103
    • Universitätsklinikum Leipzig
  • Mainz, Germany, D-55131
    • Universitätsmedizin Mainz
  • Muenster, Germany, D-48149
    • University Hospital Muenster
  • München, Germany, D-81675
    • Technical University of Munich University Hospital, Dept. for Anaesthesiology
  • Nürnberg, Germany, D-90419
    • Klinikum Nürnberg
  • Regensburg, Germany, D-93042
    • University Hospital Regensburg, Dept. of Surgery
  • Solingen, Germany, D-42653
    • Municipal Hospital Solingen, Dept. for Nephrology and General Internal Medicine
  • Tuebingen, Germany, D-72076
    • University Hospital Tuebingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Critically ill patients with clinical indication for CRRT (clinical decision to use continuous RRT due to hemodynamic instability)

   Or

   Severe acute kidney injury (KDIGO 3-classification) despite optimal resuscitation

2. At least one of the following conditions

   • Sepsis or septic shock
   • Use of catecholamines (norepinephrine or epinephrine ≥ 0.1 µg/kg/min or norepinephrine ≥ 0.05 µg/kg/min + dobutamine (any dose) or norepinephrine ≥ 0.05 µg/kg/min + vasopressin (any dose) or epinephrine ≥ 0.05 µg/kg/min + norepinephrine ≥ 0.05 µg/kg/min)
   • Refractory fluid overload: worsening pulmonary edema: PaO2/FiO2 < 300 mmHg and/or fluid balance > 10% of body weight)
3. 18-90 years old
4. Intention to provide full intensive care treatment for at least 3 days
5. Written informed consent of the patient or the legal representatives or the authorized representative or the inclusion due to an emergency situation

Exclusion Criteria:

1. Patients with increased bleeding risk (e.g. an active bleeding from ulcers in the gastro-intestinal tract, hypertension with a diastolic blood pressure higher than 105 mm Hg, injuries (intracranial hemorrhage, aneurysm of brain arteries) of or surgical procedures on the central nervous system if a heparinization with a target aPTT 45-60 s is not allowed by the treating neurologist or neurosurgeon, severe retinopathies, bleeding into the vitreum, ophthalmic surgical procedures)) or injuries, active tuberculosis; infective endocarditis)
2. Disease or organ damage related with hemorrhagic diathesis (coagulopathy, thrombocytopenia, severe liver or pancreas disease)
3. Dialysis-dependent chronic kidney insufficiency
4. Need of therapeutic systemic anticoagulation
5. Allergic reaction to one of the anticoagulants or ingredients, Heparin-induced thrombocytopenia
6. AKI caused by permanent occlusion or surgical lesion of the renal artery
7. AKI caused by (glomerulo)nephritis, interstitial nephritis, vasculitis or postrenal obstruction
8. Do-not-resuscitate order
9. Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura
10. Persistent and severe lactate acidosis in the context of an acute liver failure and/or shock
11. Kidney transplant within the last 12 months
12. Pregnancy and nursing period
13. Abortus imminens
14. No hemofiltration machine free for use at the moment of inclusion
15. Participation in another clinical intervention trial in the last 3 months
16. Persons with any kind of dependency on the investigator or employed by the sponsor or investigator
17. Persons held in an institution by legal or official order

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: heparin anticoagulation; Systemic anticoagulation of the continuous renal replacement therapy with heparin. Dose will be titrated to maintain aPTT (activated partial thromboplastin time) between 45-60s)	Drug: Heparin
Experimental: citrate anticoagulation; Regional anticoagulation of the continuous renal replacement therapy with citrate. Target posthemofilter ionized calcium level: 0.25-0.35 mmol/l	Drug: Citrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CRRT-filter life span in hours	It will be reported how long the filter will be used during CRRT	during continuous renal replacement therapy up to 1 year
Overall survival in a 90day follow-up period		90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU length of stay in days	The primary ICU stay will be documented.	up to 1 year
Hospital length of stay in days		up to 1 year
duration of renal replacement therapy	within 1 year after randomization	1 year
Bleeding complication		intraoperative
Number of patients with administration of red blood cells		intraoperative
Rate of infection		during primary ICU stay up to 1 year
Major adverse kidney events		day 28, 60, 90 and after 1 year after start of CRRT
Complications of therapy		intraoperative
Recovery of renal function	The recovery of renal function will be defined as composite endpoint consisting of lack of dialysis dependency and serum creatinine level no more than 0.5 mg/dl above the baseline value)	day 28, 60, 90 and 1 year after start of CRRT
Number of participants with hemodialysis		day 28, 60, 90 and 1 year after start of CRRT
Mortality		day 28, 60 and 1-year

Other Outcome Measures

Outcome Measure	Time Frame
SOFA Scores (Sepsis-related Organ Failure Assessment score)	day 1-14, 21 and 28 during ICU stay
serum creatinine level in mg/dL	Day 0, day 1, day 3, day 5 and 1 day after CRRT cessation
plasma urea concentration in mg/dl	Day 0, day 1, day 3, day 5 and 1 day after CRRT cessation
glomerular filtration rate	Day 0, day 1, day 3, day 5 and 1 day after CRRT cessation

Collaborators and Investigators

• Sponsor: University Hospital Muenster
• Collaborators: German Research Foundation; University of Leipzig
• Investigators: Study Chair: Alexander Zarbock, MD, University Hospital Muenster

Publications and helpful links

General Publications

• Tsujimoto H, Tsujimoto Y, Nakata Y, Fujii T, Takahashi S, Akazawa M, Kataoka Y. Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy. Cochrane Database Syst Rev. 2020 Dec 14;12(12):CD012467. doi: 10.1002/14651858.CD012467.pub3.
• Zarbock A, Kullmar M, Kindgen-Milles D, Wempe C, Gerss J, Brandenburger T, Dimski T, Tyczynski B, Jahn M, Mulling N, Mehrlander M, Rosenberger P, Marx G, Simon TP, Jaschinski U, Deetjen P, Putensen C, Schewe JC, Kluge S, Jarczak D, Slowinski T, Bodenstein M, Meybohm P, Wirtz S, Moerer O, Kortgen A, Simon P, Bagshaw SM, Kellum JA, Meersch M; RICH Investigators and the Sepnet Trial Group. 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. JAMA. 2020 Oct 27;324(16):1629-1639. doi: 10.1001/jama.2020.18618.
• Meersch M, Kullmar M, Wempe C, Kindgen-Milles D, Kluge S, Slowinski T, Marx G, Gerss J, Zarbock A; SepNet Critical Care Trials Group. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill patients with acute kidney injury (RICH) trial: study protocol for a multicentre, randomised controlled trial. BMJ Open. 2019 Jan 21;9(1):e024411. doi: 10.1136/bmjopen-2018-024411.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): April 3, 2019
• Study Completion (Actual): January 3, 2020

Study Registration Dates

• First Submitted: January 19, 2016
• First Submitted That Met QC Criteria: January 29, 2016
• First Posted (Estimate): February 1, 2016

Study Record Updates

• Last Update Posted (Actual): February 19, 2020
• Last Update Submitted That Met QC Criteria: February 18, 2020
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: anticoagulation; AKI; CRRT; KDIGO
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin
• Other Study ID Numbers: UKM 14_0066; 2014-004854-33 (EudraCT Number); 03-AnIt-14 (Other Identifier: Dept. of Anesthesiology, Intensive Care and Pain Medicine)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO