The Heparin Citrate Study


A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults

Gattas DJ. Journal Crit Care Med 2015;43(8):1622-9. doi: 10.1097/CCM.0000000000001004

Clinical Question

  • In critically ill patients requiring continuous renal replacement therapy (CRRT), does regional anticoagulation with citrate prolong circuit life compared to heparin and protamine?


  • Randomised controlled trial
  • Multicenter
  • Randomisation stratified by study site
  • Each site used a randomly generated sequence of numbers in permuted block sizes of 4,6 and 10 to allocated study groups
  • Intention to treat analysis
  • Clinicians unblinded. The statistician was blinded to group allocation until completion of the primary outcome analysis
  • Sample size calculation: 218 study subjects provided 80% power to detect a difference in mean circuit survival of 4 hours


  • Seven ICUs: Six Australian and one New Zealand
    • Four tertiary referral units and three metropolitan
  • May 2010 – January 2013


  • Inclusion: acute renal failure requiring CRRT and suitable for regional anticoagulation of the CRRT circuit; clinical equipoise regarding the method of circuit allocation
  • Exclusion: expected stay in ICU less than 24 hours; age less than 18 years; pregnant or breastfeeding; suspected ischemic hepatitis or liver failure; known allergy to heparin or protamine; suspected or confirmed heparin induced thrombocytopenia (HIT); chronic kidney disease requiring dialysis prior to ICU admission.
  • 212 patients randomised. 857 circuits
  • Baseline characteristics between groups were similar in respect to severity of illness and common renal and haematological laboratory results. More patients were admitted to the ICU from the Emergency Department in the heparin group compared with the citrate group (35.5% vs 22.9%)


  • Regional citrate anticoagulation with maintenance of systemic normocalcemia


  • Regional heparin anticoagulation with protamine reversal to avoid systemic anticoagulation


  • Primary outcome: functional circuit life was longer in the group receiving citrate anticoagulation
    • median circuit life of first circuit: 39.2 hours [95% CI, 32.1–48.0] vs 22.8 hours [95% CI, 13.3–34.0] P=0.0037
    • circuits clotting: 57.9% vs 66.4% P < 0.02
    • median circuit life of clotted circuits: 16.5 hours (IQR 21.1 hours) vs 11.8 hours (IQR 14.3 hours) P =< 0.0001
    • the hazard ratio for a filter clotting in the heparin group (compared to citrate) was 2.03 (95% CI 1.36-3.03) P=<0.005

Circuit stopped if one of following occured: transmembrane pressure across the circuit exceeded 300 mm Hg; visible clot was obstructing flow through the machine; the blood pump was unable to rotate due to clot obstruction; other (free-text entry by bedside staff)

  • Secondary outcomes: No statistical difference between groups
    • change in interleukin-6, interleukin-8, and interleukin-10 between randomsation and 48–72 hours later
    • ICU mortality: 26.7% in citrate group vs 23.4% in the heparin group P=0.58
    • ICU length of stay: 9 days vs 9 days P=0.79
    • hospital mortality: 31.4% vs 29% P=0.7
    • red cells transfused:
      • patients transfused: 52% vs 47% P=0.58
      • mean volume of red cells: 908 vs 872 P=0.83
    • duration of CRRT
      • total patient time on circuit in hours: 8282 vs 8015
      • medial hours per patient on circuit: 55.7 vs 50.6 P=0.6
  • Adverse outcomes: there were more adverse events in the heparin group (11 events, three serious) compared with the citrate group (two events, one serious) although this did not reach statistical significance (P= 0.011 for all events). The most common adverse event was suspected or confirmed HIT, resulting in discontinuation of study treatment

Authors’ Conclusions

  • Regional citrate and calcium anticoagulation prolongs CRRT circuit life compared with regional heparin and protamine anticoagulation, does not affect cytokine levels, and is associated with fewer adverse events


  • RCT
  • Multi-centre (although 74% of the patients were from two centres)
  • Statistician was blinded to group allocation until after primary analysis
  • No patients lost to follow up
  • Large trial compared to previous trials (857 circuits)
  • Examined other factors that could have affected filter life, including coagulation screens, platelet counts, catheter insertion sites, renal replacement modality, blood flow rates and ratio of pre- & post-dilution


  • More patients were admitted to the ICU from the Emergency Department in the heparin group compared with the citrate group (35.5% vs 22.9%)
  • Unblinded
  • Underpowered to detect important patient-centered outcomes such as mortality, time in ICU, time in hospital and renal recovery
  • A cost analysis would have been useful
  • large number of patients excluded from study limits external validity – 1219 patients excluded due to not meeting inclusion critera (these all presumably treated with CRRT)

The Bottom Line

  • In patients needing continuous renal replacement therapy, regional anticoagulation with citrate and calcium extends filter life in comparison with regional heparin and systemic reversal with protamine
  • Given the greater efficiency and safety of citrate, serious consideration should be given to its use as first line anticoagulation in continuous renal replacement.

External Links


Summary author: Phil McGlone
Summary date: 23rd April 2016
Peer-review editor: Steve Mathieu

Declaration of interest: Celia Bradford is an editor for TBL. She is a grant applicant, investigator and an author of this paper. She has not been involved in writing or reviewing this summary and critique


  • Duncan Chambler

    Great summary. Thanks Phil and the team.
    This study adds to the growing evidence that citrate is a better method. However I agree with Phil that external validity is possibly limited by selection bias and the regular use of protamine (not typical UK practice from my experience). I worry about the clinically relevant mortality difference although I recognise this is not statistically significant – true negative or false negative though?
    Is the next step a non-inferiority cost and safety analysis trial? Or should we just change to citrates circuits?

  • Neil Richardson

    Just change to citrate circuits.

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