NIHR DC Discover

NIHR Signal Drugs that stimulate bone marrow might save lives in critically ill trauma patients

Published on 23 August 2016

doi: 10.3310/signal-000280

Erythropoiesis stimulating agents (ESAs) might improve survival of critically ill patients after trauma. These drugs are synthetic versions of erythropoietin, a natural hormone produced by the kidneys. They boost production of red blood cells from the bone marrow; however the survival effect seems to be independent of the effect on red cell production. ESA’s are already commonly used to treat anaemia associated with chronic kidney disease.

This systematic review of trials in critical trauma patients found the survival benefit occurred without an increase in adverse effects, such as blood clots in the leg veins. ESA’s had no effect on the chance of making a good recovery after brain injury. Some questions remain as to whether improvements in neurological outcomes can be expected.

At the moment, these drugs are not approved to treat critically ill people in this way. However, the potential to save 45 lives per 1,000 treated shows promise for confirmation in future trials.

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Why was this study needed?

Injury is the most common cause of death in people below the age of 40 years. The Trauma Audit Research Network estimated that 17,238 people were admitted to hospital with severe trauma in the UK in 2013. Treating trauma patients in critical care is intensive and expensive, and carries high death rates.

Previous trials have investigated the potential of ESAs to save lives, although it’s not clear how they work when used in this way. There have been concerns that these agents may increase the risk of blood clots in the leg veins (deep vein thrombosis) and are possibly linked to other side effects, such as heart attack and stroke.

A review was needed to establish evidence for the effectiveness and safety of ESAs in this patient group.

What did this study do?

The review pooled findings from nine randomised controlled trials comparing erythropoietin with no erythropoietin or placebo in 2,507 trauma patients being treated in critical care. The main outcomes of interest were death rates, brain function, and adverse events such as cardiac arrest, stroke, or clots in the lungs or limbs. Mortality was measured at different time points and with different doses and routes of administration of ESAs (commonly Epoetin alpha).

Four of the nine trials were at high risk of bias. Only two of five trials looked at neurological outcomes and were of sufficient quality to pool in meta-analysis. Two trials assessed ESAs as a transfusion-sparing treatment, and two small trials included people with anaemia. Five trials were conducted in the USA and none in the UK, which may reduce the relevance of the findings to the UK.

What did it find?

  • ESAs reduced the risk of death at different time points (compared to placebo or no ESA treatment) in the eight trials that measured this outcome (relative risk [RR] 0.63, 95% confidence interval [CI] 0.49 to 0.79). This could mean that 45 lives are saved per thousand people treated.
  • ESAs had no effect on the chance of achieving good recovery or moderate disability up to six months after brain injury in two trials at low risk of bias (RR 1.00, 95% CI 0.88 to 1.15).
  • Six trials reported adverse events. There was no significant difference in the risk of deep vein thrombosis between people who received erythropoietin and those who did not. ESAs also had no effect on the chance of blood transfusion or the volume infused.

What does current guidance say on this issue?

There is no guidance that specifically covers the use of ESAs in critical care, apart from to treat anaemia. A NICE guideline was published in 2011 on using erythropoietin to treat anaemia for people with chronic kidney disease.

What are the implications?

Erythropoietin seems a promising treatment to help reduce deaths of trauma patients in critical care units. They do not seem to have any influence on neurological outcomes.

Because ESAs are not approved for this indication clinicians will need to consider where the balance of evidence lies for their patients.  There are remaining uncertainties in the evidence and higher quality research will help to find out which types of patients would gain most from this treatment and whether there is any longer term effect on disability in people with traumatic brain injury.

Citation and Funding

French CJ, Glassford NJ, Gantner D, et al. Erythropoiesis-stimulating agents in critically ill trauma patients: a systematic review and meta-analysis. Ann Surg. 2016. [Epub ahead of print].

No funding was received to support this study.

Bibliography

Clinical Research Network. Critical Care. London: National Institute for Health Research; 2015.

The Faculty of Intensive Care Medicine. Core standards for intensive care units. London: The Faculty of Intensive Care Medicine; 2013.

The Intensive Care Society. Guidelines for the provision of intensive care services. London: The Intensive Care Society; 2015.

ICNARC. The Intensive Care National Audit and Research Centre. London: ICNARC; 2015.

Kehoe A, Smith JE, Edwards A, et al. The changing face of major trauma in the UK. Emergency Medicine Journal. 2015;32(12):911-5.

NHS Choices. Urgent and emergency care services in England. London: Department of Health; updated 2014.

NICE. Chronic kidney disease: managing anaemia. London: National Institute for Health and Care Excellence; 2011.

TARN. The Trauma Audit and Research Network. Salford: The Trauma Audit and Research Network; undated.

Why was this study needed?

Injury is the most common cause of death in people below the age of 40 years. The Trauma Audit Research Network estimated that 17,238 people were admitted to hospital with severe trauma in the UK in 2013. Treating trauma patients in critical care is intensive and expensive, and carries high death rates.

Previous trials have investigated the potential of ESAs to save lives, although it’s not clear how they work when used in this way. There have been concerns that these agents may increase the risk of blood clots in the leg veins (deep vein thrombosis) and are possibly linked to other side effects, such as heart attack and stroke.

A review was needed to establish evidence for the effectiveness and safety of ESAs in this patient group.

What did this study do?

The review pooled findings from nine randomised controlled trials comparing erythropoietin with no erythropoietin or placebo in 2,507 trauma patients being treated in critical care. The main outcomes of interest were death rates, brain function, and adverse events such as cardiac arrest, stroke, or clots in the lungs or limbs. Mortality was measured at different time points and with different doses and routes of administration of ESAs (commonly Epoetin alpha).

Four of the nine trials were at high risk of bias. Only two of five trials looked at neurological outcomes and were of sufficient quality to pool in meta-analysis. Two trials assessed ESAs as a transfusion-sparing treatment, and two small trials included people with anaemia. Five trials were conducted in the USA and none in the UK, which may reduce the relevance of the findings to the UK.

What did it find?

  • ESAs reduced the risk of death at different time points (compared to placebo or no ESA treatment) in the eight trials that measured this outcome (relative risk [RR] 0.63, 95% confidence interval [CI] 0.49 to 0.79). This could mean that 45 lives are saved per thousand people treated.
  • ESAs had no effect on the chance of achieving good recovery or moderate disability up to six months after brain injury in two trials at low risk of bias (RR 1.00, 95% CI 0.88 to 1.15).
  • Six trials reported adverse events. There was no significant difference in the risk of deep vein thrombosis between people who received erythropoietin and those who did not. ESAs also had no effect on the chance of blood transfusion or the volume infused.

What does current guidance say on this issue?

There is no guidance that specifically covers the use of ESAs in critical care, apart from to treat anaemia. A NICE guideline was published in 2011 on using erythropoietin to treat anaemia for people with chronic kidney disease.

What are the implications?

Erythropoietin seems a promising treatment to help reduce deaths of trauma patients in critical care units. They do not seem to have any influence on neurological outcomes.

Because ESAs are not approved for this indication clinicians will need to consider where the balance of evidence lies for their patients.  There are remaining uncertainties in the evidence and higher quality research will help to find out which types of patients would gain most from this treatment and whether there is any longer term effect on disability in people with traumatic brain injury.

Citation and Funding

French CJ, Glassford NJ, Gantner D, et al. Erythropoiesis-stimulating agents in critically ill trauma patients: a systematic review and meta-analysis. Ann Surg. 2016. [Epub ahead of print].

No funding was received to support this study.

Bibliography

Clinical Research Network. Critical Care. London: National Institute for Health Research; 2015.

The Faculty of Intensive Care Medicine. Core standards for intensive care units. London: The Faculty of Intensive Care Medicine; 2013.

The Intensive Care Society. Guidelines for the provision of intensive care services. London: The Intensive Care Society; 2015.

ICNARC. The Intensive Care National Audit and Research Centre. London: ICNARC; 2015.

Kehoe A, Smith JE, Edwards A, et al. The changing face of major trauma in the UK. Emergency Medicine Journal. 2015;32(12):911-5.

NHS Choices. Urgent and emergency care services in England. London: Department of Health; updated 2014.

NICE. Chronic kidney disease: managing anaemia. London: National Institute for Health and Care Excellence; 2011.

TARN. The Trauma Audit and Research Network. Salford: The Trauma Audit and Research Network; undated.

Erythropoiesis-stimulating Agents in Critically Ill Trauma Patients: A Systematic Review and Meta-analysis

Published on 14 April 2016

French, C. J.,Glassford, N. J.,Gantner, D.,Higgins, A. M.,Cooper, D. J.,Nichol, A.,Skrifvars, M. B.,Imberger, G.,Presneill, J.,Bailey, M.,Bellomo, R.

Ann Surg , 2016

OBJECTIVE: To perform a meta-analysis of all relevant randomized controlled trials assessing the effect of erythropoiesis-stimulating agents (ESAs) in critically ill trauma patients. BACKGROUND: ESAs have effects beyond erythropoiesis. The administration of the ESA epoetin alfa to critically ill trauma patients has been associated with a reduction in mortality. METHODS: We performed a systematic review and meta-analysis with trial sequential analysis. We searched Medline, Medline in Process, and other nonindexed citations, EMBASE, and the Cochrane Database from inception until September 9, 2015, for randomized controlled trials comparing ESAs to placebo (or no ESA). RESULTS: We identified 9 eligible studies that randomly assigned 2607 critically ill patients after trauma to an ESA or placebo (or no ESA). Compared with placebo (or no ESA), ESA therapy was associated with a substantial reduction in mortality [risk ratio (RR) 0.63, 95% confidence interval (CI) 0.49-0.79, P = 0.0001, I = 0%). In patients with traumatic brain injury, ESA therapy did not increase the number of patients surviving with moderate disability or good recovery (RR 1.00, 95% CI 0.88-1.15, P = 0.95, I = 0%). With the dosing regimens employed in the included studies, ESA therapy did not increase the risk of lower limb proximal deep venous thrombosis (RR 0.97, 95% CI 0.72-1.29, P = 0.78, I = 0%). CONCLUSIONS: The administration of ESAs to critically ill trauma patients is associated with a significant improvement in mortality without an increase in the rate of lower limb proximal deep venous thrombosis. Given the worldwide public health significance of these findings research to validate or refute them is required.

NHS Choices defines major trauma as multiple serious injuries, including head injuries, life-threatening wounds and multiple fractures that could result in death or serious disability.

Expert commentary

This study demonstrates the importance of meta-analyses to inform future clinical trials and practice. Trauma is a major cause of mortality and disability globally. ESAs have been proposed to reduce blood transfusion but may also improve outcomes after trauma. A recent large multi-centre trial in traumatic brain injury did not demonstrate an improvement in the primary outcome of long-term neurological recovery.

This meta-analysis suggests that ESAs may improve survival rates but also highlights that few trials studied neurological outcomes. Therefore, ESAs remains a possible therapy in trauma but requires a definitive trial to assess the effect on both survival and neurological outcome.

Anthony Gordon, Professor of Anaesthesia and Critical Care, Imperial College / Charing Cross Hospital