NIHR Signal Restricting blood transfusion may not be effective after cardiac surgery

Published on 12 March 2015

This large NIHR-funded randomised trial found that using a lower haemoglobin threshold was no better or cheaper than using a higher one when deciding to transfuse blood after non-emergency cardiac surgery. People with milder anaemia, receiving blood transfusion at a haemoglobin level less than 90g/L (the liberal transfusion group) had similar health outcomes and health costs in the three months after surgery, compared with those only given a transfusion when they developed more severe anaemia at a threshold less than 75g/L (the restricted transfusion group). However, more deaths were recorded in the restricted group. Doctors may need to review recommended transfusion practice after cardiac surgery.

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Why was this study needed?

Existing research has shown conflicting results on the benefits and harms of blood transfusion to manage post-operative anaemia. Observational studies have shown associations between liberal use of blood transfusion and higher infection risk, while clinical trials have suggested that it is safe to use a lower haemoglobin value as the threshold trigger for blood transfusion. However, the few studies that involved planned cardiac surgery found that there was no difference in health outcomes or cost for different blood transfusion thresholds.

Uncertainty about which threshold to use is mirrored in practice; national, regional and local audits in England consistently show inappropriate variation in use of all blood components. To investigate the issue, the NIHR funded the Transfusion Indication Threshold Reduction (TITRe2) trial to compare a liberal blood transfusion threshold of less than 90g/L with a restrictive threshold of less than 75g/L.

What did this study do?

This randomised controlled trial assigned 2,003 patients from 17 UK centres to either a liberal (90g/L) or a restricted (75g/L) transfusion threshold. These levels acted as post-operative triggers for receiving successive units of red blood cells until the recipient’s haemoglobin was above the threshold. Assignment to groups happened when haemoglobin dropped below 90g/L. The main outcome was a major infection or ischaemic event (loss of blood supply to an organ). The trial was well designed and implemented.

Cost analysis included costs of tests, blood products and hospital stay, but not the cardiac operation itself, which would have varied by condition.

What did it find?

  • There was no difference between the groups in the number of patients who experienced the main outcome. A serious infection or ischaemic event occurred in 35.1% of the patients in the restrictive group and 33.0% of the patients in the liberal group (odds ratio, 1.11 95% Confidence Interval[CI] 0.91 to 1.34)
  • 4.2% of participants had died after three months in the restricted threshold group, compared to 2.6% in the liberal threshold group (Hazard ratio 1.64, 95% CI 1.00 to 2.67; p=0.045). As this result was a secondary outcome, and the confidence intervals include the possibility that mortality is the same in the two groups, this result should be interpreted cautiously
  • Total mean costs three months after surgery were similar between the groups: £10,636 in the restrictive group compared with £10,814 in the liberal group.

What does current guidance say on this issue?

While the final decision to authorise a blood transfusion rests on clinical judgement, the Joint UK Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee (JPAC) and The American Association of Blood Banks (AABB) guidelines recommend using restrictive thresholds after cardiac surgery. They state that transfusion should be considered at haemoglobin levels less than 80g/L and are usually indicated at levels less than 70g/L.

At the health service management level, the UK National Blood Transfusion Committee recommends the use of locally agreed triggers for transfusion based on national guidelines. They also recommend the development of systems and protocols that empower laboratory staff to question requests that do not conform to the agreed triggers, and regular local audits of transfusion requests.

What are the implications?

The TITRe2 trial findings challenge current guideline recommendations from the JPAC and AABB. The current recommendations to use restricted transfusion thresholds after cardiac surgery may not be supported by this evidence on effectiveness and cost effectiveness.

The TITRe2 trial differed from earlier large trials of transfusion thresholds in that all the participants had cardiovascular disease. Some of the participants may therefore have been at the limits of their cardiovascular reserve, meaning that their heart was already near its maximum capacity for pumping blood. Such participants may have benefited more from the higher haemoglobin levels compared to participants in other trials without cardiovascular disease. Because of this, the authors suggested that patients with cardiovascular disease may represent a specific high-risk group for whom more liberal transfusion thresholds are to be recommended. This suggestion could be tested in future trials.

Citation

Murphy GJ, Pike K, Rogers CA et al. Liberal or restrictive transfusion after cardiac surgery. New England Journal of Medicine. 2015;372:997-1008. This project was funded by the National Institute for Health Research HTA Programme (project number 06/402/94).

Bibliography

Carson, JL, Grossman BJ, Kleinman S, et al Red blood cell transfusion: a clinical practice guideline from the AABB. Annals of Internal Medicine 2012; 157: 49-58.

Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database of Systematic Reviews 2012;(4): CD002042.

NICE. The guidelines manual. Chapter 7. Assessing cost effectiveness. London: National Institute for Health and Care Excellence; 2012.

NHS Blood and Transplant. About blood [webpage]. London: National Health Service; 2015

National Blood Transfusion Committee. Patient blood management. [London]: Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee; 2014

Norfolk, D (editor), JPAC - Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee 7.1.1.2. Red cell transfusion in surgery. In: Handbook of Transfusion Medicine 5th Edition. London: United Kingdom Blood Services; 2014

Why was this study needed?

Existing research has shown conflicting results on the benefits and harms of blood transfusion to manage post-operative anaemia. Observational studies have shown associations between liberal use of blood transfusion and higher infection risk, while clinical trials have suggested that it is safe to use a lower haemoglobin value as the threshold trigger for blood transfusion. However, the few studies that involved planned cardiac surgery found that there was no difference in health outcomes or cost for different blood transfusion thresholds.

Uncertainty about which threshold to use is mirrored in practice; national, regional and local audits in England consistently show inappropriate variation in use of all blood components. To investigate the issue, the NIHR funded the Transfusion Indication Threshold Reduction (TITRe2) trial to compare a liberal blood transfusion threshold of less than 90g/L with a restrictive threshold of less than 75g/L.

What did this study do?

This randomised controlled trial assigned 2,003 patients from 17 UK centres to either a liberal (90g/L) or a restricted (75g/L) transfusion threshold. These levels acted as post-operative triggers for receiving successive units of red blood cells until the recipient’s haemoglobin was above the threshold. Assignment to groups happened when haemoglobin dropped below 90g/L. The main outcome was a major infection or ischaemic event (loss of blood supply to an organ). The trial was well designed and implemented.

Cost analysis included costs of tests, blood products and hospital stay, but not the cardiac operation itself, which would have varied by condition.

What did it find?

  • There was no difference between the groups in the number of patients who experienced the main outcome. A serious infection or ischaemic event occurred in 35.1% of the patients in the restrictive group and 33.0% of the patients in the liberal group (odds ratio, 1.11 95% Confidence Interval[CI] 0.91 to 1.34)
  • 4.2% of participants had died after three months in the restricted threshold group, compared to 2.6% in the liberal threshold group (Hazard ratio 1.64, 95% CI 1.00 to 2.67; p=0.045). As this result was a secondary outcome, and the confidence intervals include the possibility that mortality is the same in the two groups, this result should be interpreted cautiously
  • Total mean costs three months after surgery were similar between the groups: £10,636 in the restrictive group compared with £10,814 in the liberal group.

What does current guidance say on this issue?

While the final decision to authorise a blood transfusion rests on clinical judgement, the Joint UK Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee (JPAC) and The American Association of Blood Banks (AABB) guidelines recommend using restrictive thresholds after cardiac surgery. They state that transfusion should be considered at haemoglobin levels less than 80g/L and are usually indicated at levels less than 70g/L.

At the health service management level, the UK National Blood Transfusion Committee recommends the use of locally agreed triggers for transfusion based on national guidelines. They also recommend the development of systems and protocols that empower laboratory staff to question requests that do not conform to the agreed triggers, and regular local audits of transfusion requests.

What are the implications?

The TITRe2 trial findings challenge current guideline recommendations from the JPAC and AABB. The current recommendations to use restricted transfusion thresholds after cardiac surgery may not be supported by this evidence on effectiveness and cost effectiveness.

The TITRe2 trial differed from earlier large trials of transfusion thresholds in that all the participants had cardiovascular disease. Some of the participants may therefore have been at the limits of their cardiovascular reserve, meaning that their heart was already near its maximum capacity for pumping blood. Such participants may have benefited more from the higher haemoglobin levels compared to participants in other trials without cardiovascular disease. Because of this, the authors suggested that patients with cardiovascular disease may represent a specific high-risk group for whom more liberal transfusion thresholds are to be recommended. This suggestion could be tested in future trials.

Citation

Murphy GJ, Pike K, Rogers CA et al. Liberal or restrictive transfusion after cardiac surgery. New England Journal of Medicine. 2015;372:997-1008. This project was funded by the National Institute for Health Research HTA Programme (project number 06/402/94).

Bibliography

Carson, JL, Grossman BJ, Kleinman S, et al Red blood cell transfusion: a clinical practice guideline from the AABB. Annals of Internal Medicine 2012; 157: 49-58.

Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database of Systematic Reviews 2012;(4): CD002042.

NICE. The guidelines manual. Chapter 7. Assessing cost effectiveness. London: National Institute for Health and Care Excellence; 2012.

NHS Blood and Transplant. About blood [webpage]. London: National Health Service; 2015

National Blood Transfusion Committee. Patient blood management. [London]: Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee; 2014

Norfolk, D (editor), JPAC - Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee 7.1.1.2. Red cell transfusion in surgery. In: Handbook of Transfusion Medicine 5th Edition. London: United Kingdom Blood Services; 2014

Liberal or restrictive transfusion after cardiac surgery

Published on 12 March 2015

Murphy, G. J.,Pike, K.,Rogers, C. A.,Wordsworth, S.,Stokes, E. A.,Angelini, G. D.,Reeves, B. C.

N Engl J Med Volume 372 , 2015

BACKGROUND: Whether a restrictive threshold for hemoglobin level in red-cell transfusions, as compared with a liberal threshold, reduces postoperative morbidity and health care costs after cardiac surgery is uncertain. METHODS: We conducted a multicenter, parallel-group trial in which patients older than 16 years of age who were undergoing nonemergency cardiac surgery were recruited from 17 centers in the United Kingdom. Patients with a postoperative hemoglobin level of less than 9 g per deciliter were randomly assigned to a restrictive transfusion threshold (hemoglobin level <7.5 g per deciliter) or a liberal transfusion threshold (hemoglobin level <9 g per deciliter). The primary outcome was a serious infection (sepsis or wound infection) or an ischemic event (permanent stroke [confirmation on brain imaging and deficit in motor, sensory, or coordination functions], myocardial infarction, infarction of the gut, or acute kidney injury) within 3 months after randomization. Health care costs, excluding the index surgery, were estimated from the day of surgery to 3 months after surgery. RESULTS: A total of 2007 patients underwent randomization; 4 participants withdrew, leaving 1000 in the restrictive-threshold group and 1003 in the liberal-threshold group. Transfusion rates after randomization were 53.4% and 92.2% in the two groups, respectively. The primary outcome occurred in 35.1% of the patients in the restrictive-threshold group and 33.0% of the patients in the liberal-threshold group (odds ratio, 1.11; 95% confidence interval [CI], 0.91 to 1.34; P=0.30); there was no indication of heterogeneity according to subgroup. There were more deaths in the restrictive-threshold group than in the liberal-threshold group (4.2% vs. 2.6%; hazard ratio, 1.64; 95% CI, 1.00 to 2.67; P=0.045). Serious postoperative complications, excluding primary-outcome events, occurred in 35.7% of participants in the restrictive-threshold group and 34.2% of participants in the liberal-threshold group. Total costs did not differ significantly between the groups. CONCLUSIONS: A restrictive transfusion threshold after cardiac surgery was not superior to a liberal threshold with respect to morbidity or health care costs. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN70923932.).

Human-derived blood products are limited in supply, and are costly to produce and administer. Therefore clinical practice generally aims to balance patient safety while minimising the amount transfused. Currently about 8,000 units of blood are required each day to meet UK hospital demand, supplied by 1.6 million donors. There are four UK Blood Services: NHS Blood and Transplant, Northern Ireland Blood Transfusion Service, Scottish National Blood Transfusion Service and Welsh Blood Service. They work together to maintain common standards for blood donation, testing and blood products. The Joint UKBTS Professional Advisory Committee (JPAC) is responsible for producing guidelines for the Blood Transfusion Services in the UK, known as the “Red Book”. In 2011 the UK Blood Services issued 2.1 million units of red cells, 300,000 platelet doses, 288,000 units of fresh frozen plasma and 126,000 units of cryoprecipitate.

Author commentary

About 85% of transfusion decisions are based primarily on the patient’s haemoglobin level. Our rigorous trial showed that using a restricted transfusion threshold after cardiac surgery is not safer or more cost effective than using a liberal one. Further trials and a systematic review in progress at the moment will contribute more evidence on the topic. In the meantime current guideline recommendations to use restrictive thresholds in this context should be treated with caution.

Professor Gavin J Murphy, British Heart Foundation Professor of Cardiac Surgery, University of Leicester