NIHR Signal Large trial finds no benefit from restricting limb blood supply before heart surgery

Published on 18 January 2016

Early small studies suggested that a period of restriction of blood supply to the arm just before cardiac surgery might confer some protection to the heart during surgery (please see ‘A review of restricting blood supply to a limb before heart surgery highlights the need for better evidence’). The NIHR funded this large, multi-centre trial to investigate whether controlled restriction of blood circulation to the arm immediately before heart bypass surgery could reduce deaths, heart attacks or strokes as measured one year after the operation. This larger study found no benefit. Casting doubt on the reliability of the earlier, smaller trials and the review.

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Why was this study needed?

Coronary heart disease – where the blood vessels supplying the heart muscle itself become narrowed or blocked – is the world’s most common cause of death. Surgery using grafts to bypass blockages in blood vessels around the heart (coronary artery bypass surgery), is a common treatment for the condition. Around 20,000 such operations are carried out in the UK each year. During and shortly after bypass surgery, heart attacks occur in 5 to 10% of patients and are the main cause of death. Strokes affect 1 to 2%.

A recent review of the available evidence found heart surgery survival improved after restricting blood circulation in a limb. However, the trials which were included in that review were small and at risk of bias. The review authors said that large, well designed trials were needed to strengthen the evidence on this procedure.

What did this study do?

The NIHR-funded ERICCA trial took place at 30 UK hospitals and included 1612 participants. From these participants, 801 received restriction of blood circulation to an arm (remote ischaemic conditioning) and 811 received a sham procedure. Both approaches involved the act of inflating a pressure cuff around the arm in a standard fashion, but with the air valve open for the sham procedure. Eligible participants had a known high risk of complications as measured by a standard heart risk score and were due to undergo coronary bypass surgery, with or without heart valve replacement. The main outcome was a combination of death rate from heart-related causes, need for further surgery and rate of heart attacks and strokes. These were all measured one year after the operation.

The trial was designed carefully. The patients, anaesthetists, cardiac surgeons, intensive care unit staff, ward staff and study investigators collecting and analysing the data were all unaware of the treatment assignments. This reduced risk of bias. The researchers also estimated first how many recruits were required in each arm to be able to show a difference of 28% if one existed. However, for practical reasons anaesthetic approaches were not standardised and therefore reflect better current UK practice. Overall, we can be confident in the quality and applicability of the trial to UK practice.

What did it find?

  • By one year, there was no significant difference in major adverse events including heart-related deaths, heart attacks, strokes or need for further surgery between the two groups (26.5% or 212 in the intervention group and 27.7% or 225 in the sham procedure group).
  • The death rate was higher, numerically, in the intervention group, but the difference was not significant (5.9% compared with 3.9%, P=0.08).
  • There was no significant difference between the groups for the trial’s secondary outcomes, for example blood Troponin T levels as an indicator of short-term heart damage.
  • Although the trial protocol did not specify which anaesthetic type to use, the authors noted that over 92% of trial participants received propofol. Propofol was used as standard in a similar 2015 multi-centre trial which also found no benefit from using restriction of limb blood supply (Meybohm et al 2015).

What does current guidance say on this issue?

There is currently no UK guidance on controlled restriction of circulation to a limb and its impact on heart surgery survival.

What are the implications?

By finding no benefit for restricting blood supply to a limb, this trial and a second large trial studying similar outcomes in the short term (Meybohm et al 2015), both contradicted the findings of a 2015 review of small trials (Zangrillo et al 2015). The technique has not yet become mainstream UK practice. The findings of these two, large, reliable trials do not support any proposal that it should do so or be recommended in guidelines. However, the way that remote ischaemic conditioning could work to protect the heart is not fully understood yet, so further studies may help.

Citation

Hausenloy D, Candilio L,  Ariti C, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Eng J Med. 2015;373(15):1408-17.

This project was funded by the National Institute for Health Research and Medical Research Council Efficiency and Mechanism Evaluation Programme (project number 09/100/05) and the British Heart Foundation.

Bibliography

Meybohm P, Bein B, Brosteanu O, et al. A multicenter trial of remote ischemic preconditioning for heart surgery.  N Eng J Med. 2015:373(15):1397-1407.

NHS Choices. Coronary artery bypass graft [internet]. London: Department of Health; 2014.

Zangrillo A, Musu M, Greco T, et al. Additive Effect on Survival of Anaesthetic Cardiac Protection and Remote Ischemic Preconditioning in Cardiac Surgery: A Bayesian Network Meta-Analysis of Randomized Trials. PloS One. 2015;10(7):e0134264.

Zaugg M, Lucchinetti E. Remote ischemic preconditioning in cardiac surgery – ineffective and risky? N Engl J Med. 2015: 373(15):1470-1472.

Why was this study needed?

Coronary heart disease – where the blood vessels supplying the heart muscle itself become narrowed or blocked – is the world’s most common cause of death. Surgery using grafts to bypass blockages in blood vessels around the heart (coronary artery bypass surgery), is a common treatment for the condition. Around 20,000 such operations are carried out in the UK each year. During and shortly after bypass surgery, heart attacks occur in 5 to 10% of patients and are the main cause of death. Strokes affect 1 to 2%.

A recent review of the available evidence found heart surgery survival improved after restricting blood circulation in a limb. However, the trials which were included in that review were small and at risk of bias. The review authors said that large, well designed trials were needed to strengthen the evidence on this procedure.

What did this study do?

The NIHR-funded ERICCA trial took place at 30 UK hospitals and included 1612 participants. From these participants, 801 received restriction of blood circulation to an arm (remote ischaemic conditioning) and 811 received a sham procedure. Both approaches involved the act of inflating a pressure cuff around the arm in a standard fashion, but with the air valve open for the sham procedure. Eligible participants had a known high risk of complications as measured by a standard heart risk score and were due to undergo coronary bypass surgery, with or without heart valve replacement. The main outcome was a combination of death rate from heart-related causes, need for further surgery and rate of heart attacks and strokes. These were all measured one year after the operation.

The trial was designed carefully. The patients, anaesthetists, cardiac surgeons, intensive care unit staff, ward staff and study investigators collecting and analysing the data were all unaware of the treatment assignments. This reduced risk of bias. The researchers also estimated first how many recruits were required in each arm to be able to show a difference of 28% if one existed. However, for practical reasons anaesthetic approaches were not standardised and therefore reflect better current UK practice. Overall, we can be confident in the quality and applicability of the trial to UK practice.

What did it find?

  • By one year, there was no significant difference in major adverse events including heart-related deaths, heart attacks, strokes or need for further surgery between the two groups (26.5% or 212 in the intervention group and 27.7% or 225 in the sham procedure group).
  • The death rate was higher, numerically, in the intervention group, but the difference was not significant (5.9% compared with 3.9%, P=0.08).
  • There was no significant difference between the groups for the trial’s secondary outcomes, for example blood Troponin T levels as an indicator of short-term heart damage.
  • Although the trial protocol did not specify which anaesthetic type to use, the authors noted that over 92% of trial participants received propofol. Propofol was used as standard in a similar 2015 multi-centre trial which also found no benefit from using restriction of limb blood supply (Meybohm et al 2015).

What does current guidance say on this issue?

There is currently no UK guidance on controlled restriction of circulation to a limb and its impact on heart surgery survival.

What are the implications?

By finding no benefit for restricting blood supply to a limb, this trial and a second large trial studying similar outcomes in the short term (Meybohm et al 2015), both contradicted the findings of a 2015 review of small trials (Zangrillo et al 2015). The technique has not yet become mainstream UK practice. The findings of these two, large, reliable trials do not support any proposal that it should do so or be recommended in guidelines. However, the way that remote ischaemic conditioning could work to protect the heart is not fully understood yet, so further studies may help.

Citation

Hausenloy D, Candilio L,  Ariti C, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Eng J Med. 2015;373(15):1408-17.

This project was funded by the National Institute for Health Research and Medical Research Council Efficiency and Mechanism Evaluation Programme (project number 09/100/05) and the British Heart Foundation.

Bibliography

Meybohm P, Bein B, Brosteanu O, et al. A multicenter trial of remote ischemic preconditioning for heart surgery.  N Eng J Med. 2015:373(15):1397-1407.

NHS Choices. Coronary artery bypass graft [internet]. London: Department of Health; 2014.

Zangrillo A, Musu M, Greco T, et al. Additive Effect on Survival of Anaesthetic Cardiac Protection and Remote Ischemic Preconditioning in Cardiac Surgery: A Bayesian Network Meta-Analysis of Randomized Trials. PloS One. 2015;10(7):e0134264.

Zaugg M, Lucchinetti E. Remote ischemic preconditioning in cardiac surgery – ineffective and risky? N Engl J Med. 2015: 373(15):1470-1472.

Remote ischemic preconditioning and outcomes of cardiac surgery

Published on 8 October 2015

Hausenloy, D; Candilio1, L; Ariti, C; Evans, R; Jenkins, DP; Kolvekar, S; Knight, R; Kunst, G; Laing, C; Nicholas, J; Pepper, J; Ritchie, A; Robertson, S; Xenou, M; Clayton, T; Yellon, D; on behalf of the ERICCA trial investigators†

New England Journal of Medicine Volume 373 Issue 15 , 2015

BACKGROUND Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery.

During heart surgery blood flow to the heart may be temporarily reduced which can cause damage to tissues. Restricting blood flow to a limb (remote ischaemic preconditioning) before surgery may release protective substances which might lessen damage to the heart and other organs. This can be done simply and cheaply using a pressure cuff or tourniquet, for example, which is then released soon before surgery on the heart begins.

Expert commentary

It has been difficult to translate the substantial laboratory benefits of remote ischaemic (and volatile agent) preconditioning into clinical practice, with at best marginal benefit using composite endpoints being observed in clinical studies to date. This study probably puts the nail in the coffin of remote ischaemic preconditioning as a viable clinical mechanism for improving outcomes after cardiac surgery. The reasons for the lack of success are likely multifactorial, including the quality of current intraoperative myocardial protection, the technical excellence of the surgery and perioperative care, and the co-morbid disease state of the patients.

Dr David Smith, Consultant Cardiac Anaesthetist, Southampton University Hospital, and Senior Lecturer in Anaesthesia, University of Southampton