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Citrate-based drugs did not add benefit to the treatment of acute kidney injury (when the kidneys stop working correctly) in intensive care. Research found that these drugs were not associated with benefit over heparin, despite the extra cost.

People with acute kidney injury may need a machine to take over their kidneys’ functions and filter their blood (a process called continuous kidney replacement therapy). Heparin is used during this process to stop the blood from clotting (anticoagulation). In recent years, citrate-based drugs have replaced heparin in many intensive care units.

However, there is little evidence to support the switch to citrate. This study compared the effectiveness and value for money of citrate- versus heparin-based anticoagulation for the treatment of kidney injury in intensive care. 

A large study compared data from intensive care units that continued using heparin, to those that switched to the newer citrate-based drugs. It found no clear benefit from the switch to citrate-based drugs, which were also more expensive in the short-term. 

The results suggest that guidelines should be updated.

Further information on acute kidney injury is available on the NHS website.

What’s the issue?

Acute kidney injury means that someone’s kidneys have stopped working correctly. It is common in people who are seriously ill. In the UK, approximately half of all people admitted to intensive care have acute kidney injury.

About 1 in 10 of people in intensive care with acute kidney injury need continuous kidney replacement therapy, when a machine substitutes for the kidneys’ functions. It filters the blood, removes excess fluid, and maintains the balance of salts and minerals (electrolytes) in the blood.

Normally, heparin is added to stop the blood clotting. An alternative, citrate, is becoming more commonly used. More than half the intensive care units in England and Wales use citrate-based anticoagulation.

Small studies have suggested that citrate-based drugs may reduce a person’s risk of an internal bleed during treatment (for example, a bleed on the brain) but the evidence is inconclusive.  Despite this lack of evidence, clinical guidelines suggest that citrate-based drugs are used in kidney replacement therapy for people with acute kidney injury.

This large study aimed to determine whether patients receiving continuous kidney replacement therapy in intensive care benefit from citrate- rather than heparin-based anticoagulation, and which is better value for money.

What’s new?

The study was based on routinely collected data from a national audit of intensive care units. It included 69,001 people from 181 intensive care units in England and Wales. All had received continuous kidney replacement therapy over a period of 8 years.

The researchers linked this data with information on survival. They also looked at hospital admissions, extra medical support, long-term kidney problems, and treatment costs.

Over half (61%) of the intensive care units surveyed in this study switched from heparin- to citrate-based anticoagulation. The researchers compared people who received kidney replacement therapy after the switch (the citrate group, 8585 people) to those who were treated before the switch, or whose hospitals did not switch (the heparin group, 60,416 people).

The study found that switching to citrate-based anticoagulation was associated with:

  • no difference in deaths 90 days after treatment (54% died in citrate group; 53% in heparin group)
  • people in the citrate group spending slightly more time receiving medical support for their kidneys and heart, compared with the heparin group
  • people in the citrate group spending slightly longer in intensive care than the heparin group.

Switching to citrate-based anticoagulation may have been associated with fewer bleeding episodes (people in the citrate group were 10% less likely to have a bleeding episode than those in the heparin group), but the difference was smaller than previously reported.  

In the short-term (1 year), the switch to citrate-based drugs was associated with an extra cost of £2376 per patient and did not provide value for money. In the long-term (over a person’s lifetime), cost-effectiveness is highly uncertain.

Why is this important?

The switching to citrate-based drugs was not associated with fewer deaths among people with acute kidney injury treated in intensive care. It was not associated with other substantial benefits. In patients treated on an intensive care unit, this research calls into question guidelines suggesting the use of citrate- over heparin-based anticoagulation for kidney replacement therapy.

The research also found that heparin is cheaper for the NHS to deliver in the short term (over 1 year) than citrate-based drugs. Cost-effectiveness over a patient’s lifetime was highly uncertain.

Previous studies have suggested that citrate-based drugs improve patient outcomes and, for example, reduce people’s chance of bleeding internally, compared with heparin. This study found some evidence to support reduced bleeding risk with citrate, but the effects were smaller than have been reported elsewhere.

The study demonstrated that existing, routinely collected data (audits and hospital records) can be used to assess the costs and benefits of a treatment that has already been adopted into clinical practice. Evidence generated from other study methods can be added.  

What’s next?

Current treatment guidelines recommend citrate-based anticoagulation for the treatment of acute kidney injury. This study suggests that guidelines for patients treated on an intensive care unit should state that citrate- is likely to be more expensive than heparin-based anticoagulation. There is also little evidence that it provides benefits for people with acute kidney injury above those seen with heparin.

The researchers hope that intensive care clinicians, pharmacists and NHS commissioners (who monitor needs and purchase treatments) will take this research into account when treating people for acute kidney injury in intensive care.

The researchers recommend similar clinical and cost-effectiveness analyses in other treatment areas. These methods could identify potential savings for the NHS.

This analysis relied on information recorded in databases. Future research could explore how to account for possible trends in the quality of routinely collected data.

A limitation of the study was that it looked at overall data for intensive care units. It did not assess data from individual people with acute kidney injury. Where an intensive care unit indicated that it had switched from heparin- to citrate-based anticoagulation, it was assumed that all patients from that point onwards received citrate. However, it is likely that some people would have received heparin after the switch. Future studies comparing heparin- to citrate-based drugs could therefore assess data from individual patients.

You may be interested to read

This Alert is based on: Gould D.W., and others. Heparin versus citrate anticoagulation for continuous renal replacement therapy in intensive care: the RRAM observational study. Health Technology Assessment 2022;26:13

General information regarding kidney injury and available treatments is available on the NHS website.

Another study comparing the effectiveness of citrate versus heparin among people with kidney injury: Zarbock A. and others. 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. JAMA 2020;324:16

Review of treatments for preventing blood clotting during continuous renal replacement therapy: Tsujimoto H, and others. Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy. Cochrane Database of Systematic Reviews 2020;3:CD012467

Funding: This study was funded by the NIHR Health Technology Assessment programme.

Conflicts of Interest: The study authors declare no conflicts of interest.

Disclaimer: NIHR Alerts are not a substitute for professional medical advice. They provide information about research which is funded or supported by the NIHR. Please note that views expressed in NIHR Alerts are those of the author(s) and reviewer(s) at the time of publication. They do not necessarily reflect the views of the NHS, the NIHR or the Department of Health and Social Care.


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Comments

Study author

Our study did not find a clear benefit for citrate-based anti-coagulation versus heparin-based anticoagulation in preventing deaths of people with acute kidney injury in intensive care. People in intensive care units that used citrate spent longer on kidney and heart support compared with those that continued to use heparin.

There is insufficient evidence of differences in patient outcome to support recommending either method of anticoagulation over the other. Guidelines should indicate that citrate is likely to be substantially more expensive than heparin.

Similar studies in intensive care units should examine other changes to clinical practice that are based on limited evidence.”

Peter Watkinson, Chief Investigator, Professor of Intensive Care Medicine, Nuffield Department of Clinical Neurosciences, University of Oxford

Intensive Care Clinician

I am confident that the findings of the study are robust. Using heparin instead of citrate could save the NHS money and potentially improve patient outcomes. For our local unit, this is important information

Christian Peter Subbe, Acute, Respiratory & Critical Care Medicine Consultant, Bangor, Wales

Member of the public

The study team acknowledges that the results represent average effects. They are not based on patient-level data so may not fully capture the range of effects or outcomes of switching from heparin to citrate anticoagulation. There isn’t much reference to the patient experience. For example, would patients have different side effects, or any other improved outcomes, with citrate compared with heparin?

It would be interesting to know what triggered the general shift towards the use of citrate in the first place.

Nathan Davies, Project Manager, Wales

Intensive Care Clinician

About 6 years ago, the critical care unit in which I work transitioned to using citrate as our first-choice anti-clotting treatment, but we still use heparin in certain circumstances. This research may discourage units currently using heparin from switching to citrate. I suspect that units already using citrate will be less inclined to change back to heparin.

There appears to be no evidence that citrate is harmful to patient outcomes and the main disadvantage is cost. But the study could have considered a wider range of the perceived benefits of citrate. For example, a reduction in bleeding complications, uninterrupted therapy and faster resolution of imbalances of salts and minerals in the blood. I am not convinced that citrate therapy should be judged on mortality and costing alone.

The citrate group was much smaller than the heparin group which was not taken into account. Neither was clinicians’ familiarity with the two different regimes. Clinicians who are more familiar with citrate may be able to use it in a more cost-effective manner.

It is good to see audit data being used to carry out large studies in an area that struggles to recruit people for research. This study is a fantastic example of what can be achieved.

Alastair Glossop, Consultant in Critical Care and Anaesthesia, Sheffield Teaching Hospitals NHS Foundation Trust

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