Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Citrate Versus Heparin Anticoagulation in Continuous Venovenous Hemofiltration (CASH-CVVH)

This study has been completed.
Sponsor:
Collaborator:
Dirinco B.V.
Information provided by (Responsible Party):
S.A. Nurmohamed, Free University Medical Center
ClinicalTrials.gov Identifier:
NCT00209378
First received: September 13, 2005
Last updated: April 1, 2013
Last verified: April 2013

September 13, 2005
April 1, 2013
May 2005
May 2012   (final data collection date for primary outcome measure)
Mortality [ Time Frame: Day 28 after ICU admission ] [ Designated as safety issue: Yes ]
  • Filterlife (first filter and total amount of filters in 72 hrs)
  • Bleedingcomplications
Complete list of historical versions of study NCT00209378 on ClinicalTrials.gov Archive Site
  • Laboratory markers of inflammation, endothelial dysfunction and coagulation [ Time Frame: 72 hours ] [ Designated as safety issue: Yes ]
  • Filter life (first filter and total amount of filters in 72 hours) [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
  • Bleeding complications [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Laboratory markers of inflammation, endothelial dysfunction and coagulation
Not Provided
Not Provided
 
Citrate Versus Heparin Anticoagulation in Continuous Venovenous Hemofiltration
Citrate Versus Heparin Anticoagulation in Continuous Venovenous Hemofiltration in Critically Ill Patients With Acute Renal Failure: A Randomized Clinical Trial

The purpose of this study is to compare citrate regional anticoagulation with systemic heparinization in continuous venovenous hemofiltration. The investigators' hypothesis is, that regional citrate anticoagulation with replacement solution containing trisodium citrate, will be associated with lower mortality and less bleeding complications compared to heparin, with also a better filter survival.

Acute renal failure occurs in about 20% of critically ill patients and is associated with increased morbidity and mortality, in spite of modern renal replacement techniques. The latter include continuous venovenous hemofiltration (CVVH) techniques, necessitating anticoagulation of blood entering the extracorporeal circuit to prevent premature clot formation and hemofilter dysfunction. Heparin is commonly used for that purpose, but carries a serious risk of bleeding complications and heparin induced thrombocytopenia. In a subgroup of critically ill patients systemic anticoagulation is absolutely contraindicated. Citrate-anticoagulant CVVH carries the potential advantage of less bleeding complications and prolonged filter survival, but carries the risk of hypocalcaemia, when citrate is inappropriately or insufficiently counteracted by calcium infusion after passage of blood through the filter. In addition, when too much citrate enters the circulation, a metabolic alkalosis may develop, since citrate is converted to bicarbonate by the liver.

Moreover, continuous filtration techniques may attenuate a potentially harmful exaggerated immune response, particularly when high volume filtration (> 6 L/h) is used. Also, the type of anticoagulation may modulate immune responses, as known from biocompatibility studies in intermittent hemodialysis.

In the first part of the research proposal concerning high bleeding risk patients a comparison will be made in a prospective sequential cohort study between no anticoagulation and citrate regarding filter survival time, bleeding risk, dialyser efficacy, circulating immune mediators (such as neutrophil elastase and myeloperoxidase, interleukins, platelet-activating factors, activated complement products, soluble cytokine receptors and adhesion molecules), metabolic balance, and acute renal failure duration. Also, filter survival time will be assessed. The purpose of the second part of the current research proposal is to evaluate in a randomised controlled clinical trial in 350 critically ill patients (18-80 years) with acute renal failure, (2 arms of 175 patients), without an increased bleeding risk (thrombocytes > 40 x 10^9/L, APTT < 60 sec, PT-INR < 2) whether citrate CVVH is better than bicarbonate-heparin CVVH in terms of the same parameters as in the first part of the study but with the addition of mortality as the primary endpoint.

For this purpose a simple predilution system and citrate adjustment protocol will be used and compared to standard heparin dosing. This replacement solution shall be custom made, containing trisodium citrate, no lactate or bicarbonate, no calcium and a low sodium content.

Main objective: Investigation of the mortality during continuous venovenous hemofiltration with systemic anticoagulation with heparin compared with regional anticoagulation with trisodium citrate and also the investigation of the filter survival. Our hypothesis is, that regional citrate anticoagulation with replacement solution containing trisodium citrate, will be associated with less bleeding complications compared to heparin, with also a better filter survival. Most important we want to evaluate the hypothesis that treatment with citrate will result in a lower mortality compared to treatment with systemic heparinization.

Regional anticoagulation with trisodium citrate may also have some potential effects on the immune response as known from biocompatibility studies in intermittent hemodialysis. Bioincompatibility leads to polymorphonuclear cell degranulation as indicated by the release of intracellular granule products such as myeloperoxidase, lactoferrin, lysozyme and elastase. Citrate anticoagulation may lead to a lower polymorphonuclear cell degranulation, since cations play a pivotal role in the process of cell activation and citrate creates an almost calcium-free environment within the dialyser by its virtue to chelate calcium.

Primary endpoints:

Mortality at day 28 after inclusion will be evaluated. Survival time of the first hemofilter used will be determined, including the cause of filter termination and the number of filters used in the first 72 hours; the average filter patency time will be calculated.

Citrate CVVH is stopped and thus also the study, if the patient fulfils one of the following criteria:

  1. Total to ionised calcium ratio of more than 2.5.
  2. Persistent metabolic alkalosis with a B.E. of more than 10.
  3. Clinical signs of hypocalcaemia: tetanic symptoms or prolonged QT interval
  4. Progressive non-lactic acidosis (pH < 7.20) during CVVH combined with an increase in anion gap (> 13) without the presence of endo- or exogenous acids other than citrate suggesting citrate accumulation

Patients on heparin developing a HIT will continue CVVH with danaparoid anticoagulation. Patients on heparin developing a bleeding episode will continue CVVH with regional citrate anticoagulation.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Acute Kidney Injury
  • Other: regional anticoagulation with citrate
    Regional anticoagulation with trisodium citrate is compared with standard systemic heparinization.
    Other Name: HFCitPre
  • Other: HfCitPre
    regional anticoagulation with citrate containing replacement solution
    Other Name: HfCitPre
  • Active Comparator: heparin
    Citrate regional anticoagulation is compared with standard systemic heparinization.
    Intervention: Other: regional anticoagulation with citrate
  • Active Comparator: Citrate
    regional anticoagulation with citrate containing replacement solution
    Intervention: Other: HfCitPre

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
139
May 2012
May 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients admitted on the Intensive Care Unit (ICU) requiring continuous venovenous hemofiltration.
  • No high bleeding risk. A high bleeding risk is defined as a platelet count below 40 x 10^9/L or APTT of more than 60 seconds or a PT-INR of more than 2.0 or a recent major bleeding or significant active bleeding i.e. requirement for more than two units of packed red blood cells as a transfusion within 24 hours of initiation of CVVH.

Exclusion Criteria:

  • Less than 18 or over 80 years of age.
  • Patients administered heparin or coumarins for other reasons will also be excluded.
  • Patients with a HIT in known history will also be excluded.
Both
18 Years to 80 Years
No
Contact information is only displayed when the study is recruiting subjects
Netherlands
 
NCT00209378
03.187
No
S.A. Nurmohamed, Free University Medical Center
Free University Medical Center
Dirinco B.V.
Study Director: Piet M ter Wee, MD, PhD VU University Medical Center
Study Director: Johan Groeneveld, MD, PhD VU University Medical Center
Principal Investigator: Shaikh A Nurmohamed, MD VU University Medical Center
Free University Medical Center
April 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP