Effect of Remote Ischaemic preConditioning on clinical outcomes in patients undergoing
Coronary Artery Bypass Graft surgery (ERICCA study):
A multicentre randomised controlled clinical trial
DJ Hausenloy, C Liang, Tim Clayton, G Kunst, S Kolvekar, J Pepper, DM Yellon
Background:
 Given the increasing number of higher-risk patients undergoing cardiac surgery, there is an urgent need
to develop novel cardioprotective strategies to reduce myocardial injury, preserve left ventricular function
and improve clinical outcomes in this patients group.
 We have recently demonstrated in a proof-of-concept clinical study comprising 56 patients that remote
ischaemic preconditioning (RIC)1, using brief ischaemia and reperfusion applied to the upper limb using
a blood pressure cuff is able to reduce myocardial injury (43% reduction in troponin-T) in patients
undergoing elective cardiac surgery at the Heart Hospital 2. We have gone to demonstrate that patients
undergoing cardioprotection using cold-blood cardioplegia alone also benefit from RIC 3.
 Other groups have demonstrated that the RIC stimulus can reduce myocardial injury in children
undergoing corrective cardiac surgery for congenital heart disease 4, in patients undergoing surgery for
repair of an abdominal aortic aneurysm 5;6, and in patients undergoing elective percutaneous coronary
intervention 7.
 We now intend to determine in a large multi-centre clinical study whether RIC using brief upper-limb
ischaemia is able impact on short-term and long-term clinical outcomes in patients undergoing high-risk
cardiac surgery.
Hypothesis: Remote ischemic preconditioning using brief limb ischaemia/reperfusion will improve short-term
and long-term clinical outcomes at one year in patients undergoing high-risk cardiac surgery.
Primary outcome measure:
Major adverse cardiac and cerebrovascular events (MACCE- death from any cause, stroke, myocardial
infarction, or repeat revascularization) at one year.
Secondary outcome measures:
1. Peri-operative myocardial injury over 72 hrs (serum CK-MB/Troponin-T or I 0,6,12,24,48,72).
2. Length of ITU/hospital stay, Inotrope score.
3. Peri-operative renal injury (blood NGAL) 5 samples over 3 days (0, coming off bypass, 12, 24, 48
hours) and incidence of Acute Kidney Injury (AKI). Daily creatinine for hospital stay, 6 weeks and
one year. Hourly urine volumes on ITU and daily urine volumes thereafter.
4. 6 minute walk test at baseline and at 6 weeks and 12 months.
5. Quality of life at baseline, 6 weeks, 3, 6, 9, and 12 months.
Substudy (140 patients): Left ventricular ejection fraction (echo) at baseline, 6 weeks and one year.
(a) Research Design: Multi-centre double-blind randomised controlled clinical trial.
(b) Study Population: High-risk patients (defined by additive Euro-SCORE≥6) undergoing elective
CABG±valve surgery with cold-blood cardioplegia.
(c) Planned Interventions: Remote ischaemic preconditioning (RIC) comprising four 5 min cycles of inflation
(to 200mmHg) and deflation of a cuff placed on upper arm. Sham RIC will comprise four 5 min cycles of
inflation (to 40mmHg) and deflation of a cuff placed on upper arm.
(d) Proposed outcome measures: Primary outcome: Major adverse cardiac (Death, myocardial infarction,
revascularisation) and cerebrovascular events (stroke) or MACCE at one year. Secondary outcomes: Perioperative myocardial and renal injury; Length of ITU/hospital stay and inotrope score; Left ventricular
ejection fraction and 6 minute walk test at baseline, 6 weeks and one year (subgroup analysis); Quality of life
at baseline, 6 weeks, 3 months 6 months, 9 months, and one year.
(e) Assessment and follow up: Outcome measures will be assessed from the patient GP and medical
notes, postal surveys, and 6 week and one year outpatient appointments. Safety will be assessed using a
Standard Operating Procedure.
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(f) Proposed sample size: We plan to recruit 1606 patients through 12 surgical centres. RIC reduced
myocardial injury as measured by troponin-T by 43% in elective CABG surgery patients (EuroSCORE mean
3.0)2. In the recently published SYNTAX study the major adverse cardiac and cerebrovascular events
(MACCE- death from any cause, stroke, myocardial infarction, or repeat revascularization) event rate was
12.4% of patients at 12 months following CABG surgery8. To detect a 35% reduction in this primary endpoint
in the RIPC-treated group (from 12.4% to 8.06%), with a power of 80% and a significance level of 5%, a
sample size of 765 patients will be required for each trial arm (1530 in total). To allow for dropouts (5% as
per SYNTAX study) we plan to recruit 1606 patients in total. It should be noted that our patients will be highrisk (as defined by additive EuroSCORE≥6), and in the SYNTAX study the patient population was low risk
with a mean EuroSCORE of 3.8±2.6.
Echo substudy: In a previous study, ischaemic postconditioning (an endogenous cardioprotective strategy
similar to RIC) has been reported to improve LV ejection fraction by 14.2% (relative increase) from 49% to
56% at one year in ST-elevation myocardial infarction patients 9. The mean difference would thus be 7% with
a pooled SD of 10.5. To demonstrate such a difference as being statistically significant at the 5% level, with
90% power, requires 48 subjects per group (96 in total). We plan to recruit 140 patients from a single site.
(g) Statistical analysis: Survival analyses will be carried out for clinical endpoints. MACCE; hazard ratios
and confidence intervals will be calculated using Cox’s proportional hazards modelling. All analyses will be
carried out on an intention to treat basis. There is no planned interim analysis. There is a planned subgroup
analysis of LV ejection fraction.
(h) Project timetables including recruitment rate: The planned duration of the study will be 48 months: (1)
0-6 months-Study preparation; (2) 6-30 months-Patient recruitment; (3) 18-42 months- 1 year follow-up; (4)
42-48 months- Assessment of clinical outcomes and cost-effectiveness, data analysis, writing-up and
dissemination of research findings. Over the 24 month recruitment period we would expect to recruit about
134 high-risk CABG patients through each of the 12 recruiting centres, which equates to 1.7 patients per
week from each centre. Each centre operates on about 7-10 high-risk surgical patients per week, meaning
that we would have to recruit at least 25% of the eligible patients.
(i) Cardiac surgery centres
1. UCLH Heart Hospital
2. Golden Jubilee Hospital
3. Royal Brompton Hosp
4. Harefield Hospital
5. King’s College Hospital
6. Papworth Hospital
7. Hammersmith Hospital
8. St Thomas Hospital
9. St Bart’s Hospital
10. London Chest Hospital
11. Essex CTC
12. Royal Sussex,Brighton
13. Wolverhampton Hospital
14. Edinburgh Royal Infirmary
15. Bristol Royal Infirmary
16. Manchester Royal Infirmary
Shyam Kolvekar
Geoff Berg
John Pepper
John Pepper
Jatin Desai
David Jenkins
Prakash Punjabi
Chris Blauth
Rakesh Uppal
Rakesh Uppal
Andrew Ritchie
Uday Trivedi
Moninder Bhabra
Renzo Pessotto
Raimondo Ascione
Dan Keenan
Trial Steering Committee (TSC)
Prof Sir David Taggart (independent chair)
Two Service Users (two previous CABG±valve patients)
Prof Derek Yellon, Dr Derek Hausenloy, Dr Shyam Kolvekar, Prof John Pepper, Prof Michael Marber, Prof
Liam Smeeth, Dr Gudrun Kunst, Dr Chris Laing, Dr Luciano Candilio, Mr Tim Clayton and Ms Rosemary
Knight.
Trial Management Group (TMG)
Dr Derek Hausenloy, Mr Tim Clayton, Ms Rosemary Knight, Mr Steve Robertson.
Data and Ethics Monitoring Committee (DMEC)
Dr Rajesh Kharbanda, Mr Adrian Marchbank,Prof Jean Morris.
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Flow diagram
ERICCA: Overview
Enrollment
High-risk patients (EuroSCORE≥6), CABG valve surgery, cold blood cardioplegia
Analysis
Follow-up
Allocation
Pre-admission clinic :
Baseline blood tests, 6 min walk test,
echo and HRQOL assessment.
Patients randomised
on am of surgery (N= )
Allocated to RIC treatment arm (N= )
Blood pressure cuff used to apply RIC protocol
Bloods taken for Trop-T/I at 0,6,12,24,48,72 hrs
NGAL
Patient reviewed in OPA clinic at 6 weeks (N=)
HRQOL at 3, 6, 9 mths (N=)
Patient reviewed in research OPA at 1 year (N=)
Patient data analysed at one year (N= )
Excluded from analysis (N= )
Allocated to control arm (N= )
Un-inflated cuff placed on arm as control protocol
Bloods taken for Trop-T/I at 0,6,12,24,48,72 hrs
NGAL
Patient reviewed in OPA clinic at 6 weeks (N=)
HRQOL at 3, 6, 9 mths (N=)
Patient reviewed in research OPA at 1 year (N=)
Patient data analysed at one year (N= )
Excluded from analysis (N= )
References
1.
Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application.
Cardiovasc Res. 2008;79:377-386.
2.
Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, et al. Effect of remote ischaemic
preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised
controlled trial. Lancet. 2007;370:575-579.
3.
Venugopal V, Hausenloy DJ, Ludman A, Di Salvo CM, Kolvekar S, Yap J, et al. Remote Ischaemic
preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold blood cardioplegia:a
randomised controlled trial. Heart. 2009.
4.
Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, et al. Randomized controlled trial of
the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in
humans. J Am Coll Cardiol. 2006;47:2277-2282.
5.
Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, et al. Remote ischemic preconditioning reduces
myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial.
Circulation. 2007;116:I98-105.
6.
Walsh SR, Boyle JR, Tang TY, Sadat U, Cooper DG, Lapsley M, et al. Remote ischemic preconditioning for renal
and cardiac protection during endovascular aneurysm repair: a randomized controlled trial. J Endovasc Ther.
2009;16:680-689.
7.
hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, et al. Cardiac Remote Ischemic
Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial. Circulation.
2009;119:820-827.
8.
Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary
intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med.
2009;360:961-972.
9.
Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G, et al. Long-term benefit of postconditioning.
Circulation. 2008;117:1037-1044.
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