Ischemic PreconditioningPhase 2RIC-CORNCT02666235
Remote Ischaemic Conditioning and Coronary Endothelial Function (RIC-COR)
A Phase 2 study testing Remote ischaemic conditioning and Arm cuff placement, no inflation; in people with Ischemic Preconditioning and Coronary Disease, run by NHS National Waiting Times Centre Board at 1 site in United Kingdom.
Trial summary
Intermittent arm cuff inflation reduces the extent of heart muscle injury at the time of cardiovascular injury. The intervention is known as remote ischaemic conditioning (RIC) however the mechanisms by which RIC acts are incompletely understood. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Ischemic Preconditioning, Coronary Disease
- What is being tested?
- Remote ischaemic conditioning and Arm cuff placement, no inflation;
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 2011to May 2016
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 or over
- Known or suspected coronary artery disease
- A clinical indication for coronary angiography.
Who cannot join
- Myocardial infarction within 2 weeks
- History of coronary artery bypass surgery
- Second or third degree atrioventricular block
- Written informed consent.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Golden Jubilee National Hospital
Glasgow, Dunbartonshire, G814DY
About this study
Official title: A Randomised Controlled Trial of the Effect of Remote Ischaemic Conditioning on Coronary Endothelial Function in Patients With Angina.
Intermittent arm cuff inflation reduces the extent of heart muscle injury at the time of cardiovascular injury. The intervention is known as remote ischaemic conditioning (RIC) however the mechanisms by which RIC acts are incompletely understood.
One mechanism that might explain the benefits of RIC is an improvement in coronary artery function which in turn might help improve blood flow to heart muscle.
Read more
The investigators will perform a randomised controlled study of RIC in a minimum of 60 patients with known or suspected angina and in whom coronary angiography with angioplasty would be considered.
Following informed consent before the invasive procedure, the patient will be randomly assigned to the intervention group (cuff inflation protocol) or the control group (cuff placement, no inflation; sham protocol). Following initial coronary angiography, endothelial function will be assessed by intra-coronary infusion of acetylcholine in incremental doses. Coronary diameter will be measured after the procedure using quantitative coronary angiography, by a trained observer blinded to the allocated group. Since a neuro-hormonal response may potentially mediate RIC, a blood test will be performed before and after cuff placement in all patients (active and control groups) to measure circulating molecules known to regulate blood vessel function which may be implicated in a RIC-mediated effect on coronary artery tone.
This study may provide clinically relevant insights into the mechanisms of action of RIC in patients with coronary heart disease.
Read the detailed description
Intermittent arm cuff inflation reduces the extent of heart muscle injury at the time of cardiovascular injury. The intervention is known as remote ischaemic conditioning (RIC) however the mechanisms by which RIC acts are incompletely understood. One mechanism that might explain the benefits of RIC is an improvement in coronary artery function which in turn might help improve blood flow to heart muscle.
The primary aim is to determine whether intermittent inflation of a blood pressure cuff for 5 min periods at 200 mmHg on 4 occasions separated by 5 minute intervals can improve coronary vascular function compared to cuff placement with no cuff inflation. A secondary aim is to determine whether or not RIC alters the circulating concentrations of small molecules and hormones in systemic blood that regulate coronary endothelial function.
The investigators will perform a randomised controlled trial of RIC in a minimum of 60 patients with known or suspected angina and in whom coronary angiography with angioplasty would be considered. A screening log will be prospectively recorded. In order to be enrolled prior knowledge of the coronary anatomy and disease is necessary, and this information can be obtained by screening referrals for invasive angiography following non-invasive CT coronary angiography, or staged invasive management when angioplasty is intended following initial invasive angiography.
The protocol had initially involved two coronary angiograms with coronary reactivity testing on the same day, with the first angiogram taking place before the RIC-COR intervention and the second angiogram taking place immediately afterwards. However, after enrolling 10 participants it was evident that the total procedure time and hospital stay was unduly long and impractical. Therefore, following consultation with the trial biostatistician, funder and ethics committee, the protocol was amended and the initial angiogram was removed (May 2012). There were no other changes to the study design. Following a change in service arrangements for elective referrals for coronary angioplasty in our hospital, and constraints around staff illness and availability, recruitment was temporarily suspended on logistical grounds (September 2013 to November 2014).
Following informed consent before the invasive procedure, the patient will be randomly assigned to the intervention group (cuff inflation protocol) or the control group (cuff placement, no inflation; sham protocol). The clinical team will be blind to treatment group assignment.
Clinically-indicated coronary angiography will be performed first, including administration of glyceryl trinitrate (200 - 400 micrograms; short acting preparation) to attenuate coronary artery tone. Based on the angiographic findings, the cardiologist will select a coronary artery with minimal or no evidence of coronary artery disease.
Endothelial function will then be assessed in this artery by intra-coronary infusion of acetylcholine (ACh) in incremental doses. Non-endothelium dependent vasodilation will be assessed using intra-coronary administration of glyceryl trinitrate at the end of the infusion protocol.
An infusion catheter will be used to selectively instrument the coronary artery of interest. The factors that influence the selection of a coronary artery for study include 1) minimal or no angiographic evidence of coronary disease, 2) practical considerations for insertion of an intra-coronary catheter ie. vessel tortuosity, calibre. The coronary reactivity protocol involves intra-coronary administration of study drug at a rate of 2 ml/min for 2 minutes in the following order: 1) 0.9% normal saline; 2) ACh 10-6 Molar (M), 3) ACh 10-5M, 4) ACh 10-4M, 5) 0.9% normal saline; and finally, 6) bolus intra-coronary administration of 200-400 micrograms of glyceryl trinitrate. The patient's clinical response will be assessed prospectively, including with continuous haemodynamic recording (heart rate, rhythm, conduction and aortic blood pressure). A 12-lead electrocardiogram (ECG) and cine coronary angiogram will be obtained synchronously at baseline, at the end of each 2 minute infusion, and following nitrate administration.
Coronary diameter will be measured after the procedure using computer-assisted quantitative coronary analysis (QCA) with custom software (eg Medis, Leiden, Netherlands), by a trained observer blinded to the allocated group. The coronary segment for analysis will be located distal to the infusion catheter in the proximal - mid segment of the right coronary artery or a main branch of the left coronary artery. The segment will have minimal or no angiographic evidence of coronary disease. The length of the segment will be 30 mm. The same angiographic projection will be used for all of the analyses. The software will be calibrated on the catheter. Mean lumen diameter and mean coronary area will be computed.
Epicardial spasm, defined as >90% reduction in coronary artery diameter with ischaemic ST-segment changes on the ECG, and microvascular spasm, defined as ischaemic ST-segment changes without epicardial coronary vasoconstriction >90% will be assessed.
ECG changes, including alterations in atrio-ventricular conduction and ST-segment deviation, will be prospectively recorded.
Since a neuro-hormonal response may potentially mediate RIC, a blood test will be performed before and after cuff placement in all patients (active and control groups) to measure circulating molecules known to regulate blood vessel function.
The study data will be analysed by a biostatistician who is independent of the research team.
If the investigators can discover the effects, if any, of RIC on coronary vascular function, then potentially this information would provide new insights into the mechanisms of action of RIC.
- Conditions
- Ischemic Preconditioning, Coronary Disease
- Being tested
- Remote ischaemic conditioning, Arm cuff placement, no inflation;
- Medical subject headings
- Coronary Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Remote ischaemic conditioningProcedure or surgery
Also called Ischaemic preconditioning, Remote ischemic preconditioning
Intermittent inflation of an arm blood pressure cuff for 5 minute periods at 200 mmHg separated by a 5 minute rest interval, repeated successively on 4 occasions over a 40 minute period. The intervention will take place on the ward with the patient obscured from the clinical team by a drawn curtain. The clinical team and researchers will be masked to the intervention type.
Arm cuff placement, no inflation;Procedure or surgery
Also called Sham procedure
Sham procedure involving arm cuff placement, no inflation: A blood pressure cuff will be placed on the arm for 40 minutes. The cuff will not be inflated. The patient will be in bed behind a curtain on the cardiology ward. The curtain will obscure the patient from the attending cardiology team. The clinical team and researchers will be masked to the intervention type.
| Study group | Role | What they receive |
|---|---|---|
| Remote ischaemic conditioning | Active comparator | Intermittent inflation of a forearm blood pressure cuff for 5 minute periods at 200 mmHg separated by a 5 minute rest interval, repeated successively on 4 occasions over a 40 minute period. The intervention will take place on the ward with the patient obscured from the clinical team by a curtain. Receives: Procedure: Remote ischaemic conditioning |
| Control group | Sham comparator | Sham intervention: Arm cuff placement but without inflation during a 40 minute period. A curtain will obscure the patient from the clinical team during this time. Arm cuff placement, no inflation. Receives: Procedure: Arm cuff placement, no inflation; |
What is being measured
The primary outcome is the main question the study is designed to answer.
Coronary artery diameter change
The net percentage change in mean coronary artery diameter (endothelial function) following intra-coronary administration of study drug (ACh or glyceryl trinitrate) compared to baseline.
Measured: Intra-procedure
Secondary outcomes (9)
Circulating molecules reflecting endothelial function and oxidative stress
Circulating concentrations of small molecules and hormones that are mediators of endothelial function and vascular tone.
Measured: Peri-procedure; from baseline up to 2 hours
Mean percentage change in coronary lumen diameter (delta CAD)
The investigators aim to assess the percentage change from baseline in mean coronary lumen diameter, if any, in response to graded doses (10-6M, 10-5M, 10-4M) of intra-coronary acetylcholine infusion with each dose administered over a 2 minute period.
Measured: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Mean percentage coronary vasoconstriction
The investigators aim to assess the vasoconstrictor response, if any, to graded doses (10-6M, 10-5M, 10-4M) of intra-coronary acetylcholine infusion with each dose administered over a 2 minute period.
Measured: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Coronary endothelial dysfunction
A decrease in luminal diameter of >20% after intracoronary infusion of acetylcholine.
Measured: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Mean percentage change in coronary lumen diameter (delta CAD)
The investigators aim to assess the percentage change from baseline in mean coronary lumen diameter, if any, following intracoronary injection of glyceryl trinitrate (200-400 micrograms)
Measured: Intra-procedure - After intracoronary injection of glyceryl trinitrate
Mean percentage coronary vasodilatation
The investigators aim to assess the percentage change from baseline in mean coronary lumen diameter, if any, following intracoronary injection of glyceryl trinitrate(200-400 micrograms)
Measured: Intra-procedure - After intracoronary injection of glyceryl trinitrate
Epicardial coronary artery spasm
Epicardial coronary artery spasm is defined as a reduction in coronary diameter >90% following intracoronary acetylcholine in comparison with baseline resting condition following intracoronary glyceryl trinitrate administration in any epicardial coronary artery segment together with symptoms and ST segment deviation on the ECG. Epicardial artery spasm may be focal or diffuse. Focal constriction was defined as a circumscribed transient vessel narrowing within the borders of 1 isolated or 2 neighbouring coronary segments. Diffuse constriction was diagnosed when the vessel narrowing was observed in ≥2 adjacent coronary segments. Proximal spasm was defined as vasoconstriction occurring in segments 1, 5, 6, or 11. Mid-vessel spasm was recorded when occurring in segments 2, 3, or 7, whereas distal spasm was defined as that occurring in segments 4, 8, 9, 10, 12, 13, 14, or 15. This approach is in line with the guideline recommendations by COVADIS (Eur Heart J 2015; PMID: 26245334).
Measured: Intra-procedure - During intra-coronary infusion of acetylcholine
Microvascular spasm
Microvascular spasm was diagnosed when angina occurred with typical ischaemic ST-segment changes in the absence of epicardial coronary constriction >90% diameter reduction.
Measured: Intra-procedure - During intra-coronary infusion of acetylcholine
ST-segment deviation
ST-segment deviation from the iso-electric line due to ST-segment elevation or ST-segment depression, is a manifestation of myocardial ischaemia. Since remote ischaemic conditioning is postulated to mitigate myocardial ischaemia, the presence and extent of ST-segment deviation will be assessed.
Measured: Intra-procedure - During intra-coronary infusion of acetylcholine
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2016 (estimated)
- Study startJul 2011
- Primary completionMay 2016
- Study completionMay 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (21)Papers the sponsor has linked to this study.
- Other trials for Ischemic PreconditioningStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Care provider, Investigator, Outcomes assessor
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- NHS National Waiting Times Centre Board
- Sponsor type
- University, hospital or other
- Collaborators
- University of Glasgow, Chest, Heart and Stroke Association Scotland, Chief Scientist Office of the Scottish Government
- Responsible party
- Principal investigator, Colin Berry, NHS National Waiting Times Centre Board
- Investigators
- Colin Berry, PhD FRCP, Principal investigator, Golden Jubilee National Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02666235
- Sponsor's protocol ID
- 11/CARD/03
- Other IDs
- R11/A136, 10/S0704/52
- Acronym
- RIC-COR
- Status last verified
- Oct 2024
- First submitted
- 24 Dec 2015
- Last updated
- 29 Oct 2024
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No: There is no data sharing plan, but we have no objection
Publications
Corcoran D, Young R, Cialdella P, McCartney P, Bajrangee A, Hennigan B, Collison D, Carrick D, Shaukat A, Good R, Watkins S, McEntegart M, Watt J, Welsh P, Sattar N, McConnachie A, Oldroyd KG, Berry C. The effects of remote ischaemic preconditioning on coronary artery function in patients with stable coronary artery disease. Int J Cardiol. 2018 Feb 1;252:24-30. doi: 10.1016/j.ijcard.2017.10.082.
PubMed 29249435Cannon RO 3rd, Epstein SE. "Microvascular angina" as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988 Jun 1;61(15):1338-43. doi: 10.1016/0002-9149(88)91180-0. No abstract available.
PubMed 3287885Wei J, Mehta PK, Johnson BD, Samuels B, Kar S, Anderson RD, Azarbal B, Petersen J, Sharaf B, Handberg E, Shufelt C, Kothawade K, Sopko G, Lerman A, Shaw L, Kelsey SF, Pepine CJ, Merz CN. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc Interv. 2012 Jun;5(6):646-53. doi: 10.1016/j.jcin.2012.01.023.
PubMed 22721660Sato K, Kaikita K, Nakayama N, Horio E, Yoshimura H, Ono T, Ohba K, Tsujita K, Kojima S, Tayama S, Hokimoto S, Matsui K, Sugiyama S, Yamabe H, Ogawa H. Coronary vasomotor response to intracoronary acetylcholine injection, clinical features, and long-term prognosis in 873 consecutive patients with coronary spasm: analysis of a single-center study over 20 years. J Am Heart Assoc. 2013 Jul 15;2(4):e000227. doi: 10.1161/JAHA.113.000227.
PubMed 23858100Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, Hill S, Schaufele T, Mahrholdt H, Kaski JC, Sechtem U. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation. 2014 Apr 29;129(17):1723-30. doi: 10.1161/CIRCULATIONAHA.113.004096. Epub 2014 Feb 26.
PubMed 24573349Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease. JACC Cardiovasc Interv. 2015 Sep;8(11):1445-1453. doi: 10.1016/j.jcin.2015.06.017.
PubMed 26404197Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol. 2012 Feb 14;59(7):655-62. doi: 10.1016/j.jacc.2011.11.015.
PubMed 22322081Pries AR, Badimon L, Bugiardini R, Camici PG, Dorobantu M, Duncker DJ, Escaned J, Koller A, Piek JJ, de Wit C. Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation. Eur Heart J. 2015 Dec 1;36(45):3134-46. doi: 10.1093/eurheartj/ehv100. Epub 2015 Jun 25. No abstract available.
PubMed 26112888Pickard JM, Botker HE, Crimi G, Davidson B, Davidson SM, Dutka D, Ferdinandy P, Ganske R, Garcia-Dorado D, Giricz Z, Gourine AV, Heusch G, Kharbanda R, Kleinbongard P, MacAllister R, McIntyre C, Meybohm P, Prunier F, Redington A, Robertson NJ, Suleiman MS, Vanezis A, Walsh S, Yellon DM, Hausenloy DJ. Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop. Basic Res Cardiol. 2015 Jan;110(1):453. doi: 10.1007/s00395-014-0453-6. Epub 2014 Dec 2.
PubMed 25449895Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol. 2011 Jun 21;8(11):619-29. doi: 10.1038/nrcardio.2011.85.
PubMed 21691310Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993 Mar;87(3):893-9. doi: 10.1161/01.cir.87.3.893.
PubMed 7680290Loukogeorgakis SP, Williams R, Panagiotidou AT, Kolvekar SK, Donald A, Cole TJ, Yellon DM, Deanfield JE, MacAllister RJ. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation. 2007 Sep 18;116(12):1386-95. doi: 10.1161/CIRCULATIONAHA.106.653782. Epub 2007 Aug 27.
PubMed 17724264Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol. 2005 Aug 2;46(3):450-6. doi: 10.1016/j.jacc.2005.04.044.
PubMed 16053957Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, Redington A. Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1598-603. doi: 10.1152/ajpheart.00396.2010. Epub 2010 Aug 27.
PubMed 20802131Wolfrum S, Schneider K, Heidbreder M, Nienstedt J, Dominiak P, Dendorfer A. Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform. Cardiovasc Res. 2002 Aug 15;55(3):583-9. doi: 10.1016/s0008-6363(02)00408-x.
PubMed 12160956
Study at a glance
From the registry record, last updated by the sponsor on 29 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised Controlled Trial of the Effect of Remote Ischaemic Conditioning on Coronary Endothelial Function in Patients With Angina.
- ClinicalTrials.gov ID
- NCT02666235
- Acronym / sponsor ID
- RIC-COR / 11/CARD/03
- Conditions
- Ischemic Preconditioning, Coronary Disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- NHS National Waiting Times Centre BoardUniversity, hospital or other
- Collaborators
- University of Glasgow, Chest, Heart and Stroke Association Scotland, Chief Scientist Office of the Scottish Government
- Study start
- Jul 2011 (actual)
- Primary completion
- May 2016 (actual)
- Study completion
- May 2016 (actual)
- First posted
- 28 Jan 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Intermittent arm cuff inflation reduces the extent of heart muscle injury at the time of cardiovascular injury. The intervention is known as remote ischaemic conditioning (RIC) however the mechanisms by which RIC acts are incompletely understood.
One mechanism that might explain the benefits of RIC is an improvement in coronary artery function which in turn might help improve blood flow to heart muscle.
The investigators will perform a randomised controlled study of RIC in a minimum of 60 patients with known or suspected angina and in whom coronary angiography with angioplasty would be considered.
Following informed consent before the invasive procedure, the patient will be randomly assigned to the intervention group (cuff inflation protocol) or the control group (cuff placement, no inflation; sham protocol). Following initial coronary angiography, endothelial function will be assessed by intra-coronary infusion of acetylcholine in incremental doses. Coronary diameter will be measured after the procedure using quantitative coronary angiography, by a trained observer blinded to the allocated group. Since a neuro-hormonal response may potentially mediate RIC, a blood test will be performed before and after cuff placement in all patients (active and control groups) to measure circulating molecules known to regulate blood vessel function which may be implicated in a RIC-mediated effect on coronary artery tone.
This study may provide clinically relevant insights into the mechanisms of action of RIC in patients with coronary heart disease.
Detailed description
Intermittent arm cuff inflation reduces the extent of heart muscle injury at the time of cardiovascular injury. The intervention is known as remote ischaemic conditioning (RIC) however the mechanisms by which RIC acts are incompletely understood. One mechanism that might explain the benefits of RIC is an improvement in coronary artery function which in turn might help improve blood flow to heart muscle.
The primary aim is to determine whether intermittent inflation of a blood pressure cuff for 5 min periods at 200 mmHg on 4 occasions separated by 5 minute intervals can improve coronary vascular function compared to cuff placement with no cuff inflation. A secondary aim is to determine whether or not RIC alters the circulating concentrations of small molecules and hormones in systemic blood that regulate coronary endothelial function.
The investigators will perform a randomised controlled trial of RIC in a minimum of 60 patients with known or suspected angina and in whom coronary angiography with angioplasty would be considered. A screening log will be prospectively recorded. In order to be enrolled prior knowledge of the coronary anatomy and disease is necessary, and this information can be obtained by screening referrals for invasive angiography following non-invasive CT coronary angiography, or staged invasive management when angioplasty is intended following initial invasive angiography.
The protocol had initially involved two coronary angiograms with coronary reactivity testing on the same day, with the first angiogram taking place before the RIC-COR intervention and the second angiogram taking place immediately afterwards. However, after enrolling 10 participants it was evident that the total procedure time and hospital stay was unduly long and impractical. Therefore, following consultation with the trial biostatistician, funder and ethics committee, the protocol was amended and the initial angiogram was removed (May 2012). There were no other changes to the study design. Following a change in service arrangements for elective referrals for coronary angioplasty in our hospital, and constraints around staff illness and availability, recruitment was temporarily suspended on logistical grounds (September 2013 to November 2014).
Following informed consent before the invasive procedure, the patient will be randomly assigned to the intervention group (cuff inflation protocol) or the control group (cuff placement, no inflation; sham protocol). The clinical team will be blind to treatment group assignment.
Clinically-indicated coronary angiography will be performed first, including administration of glyceryl trinitrate (200 - 400 micrograms; short acting preparation) to attenuate coronary artery tone. Based on the angiographic findings, the cardiologist will select a coronary artery with minimal or no evidence of coronary artery disease.
Endothelial function will then be assessed in this artery by intra-coronary infusion of acetylcholine (ACh) in incremental doses. Non-endothelium dependent vasodilation will be assessed using intra-coronary administration of glyceryl trinitrate at the end of the infusion protocol.
An infusion catheter will be used to selectively instrument the coronary artery of interest. The factors that influence the selection of a coronary artery for study include 1) minimal or no angiographic evidence of coronary disease, 2) practical considerations for insertion of an intra-coronary catheter ie. vessel tortuosity, calibre. The coronary reactivity protocol involves intra-coronary administration of study drug at a rate of 2 ml/min for 2 minutes in the following order: 1) 0.9% normal saline; 2) ACh 10-6 Molar (M), 3) ACh 10-5M, 4) ACh 10-4M, 5) 0.9% normal saline; and finally, 6) bolus intra-coronary administration of 200-400 micrograms of glyceryl trinitrate. The patient's clinical response will be assessed prospectively, including with continuous haemodynamic recording (heart rate, rhythm, conduction and aortic blood pressure). A 12-lead electrocardiogram (ECG) and cine coronary angiogram will be obtained synchronously at baseline, at the end of each 2 minute infusion, and following nitrate administration.
Coronary diameter will be measured after the procedure using computer-assisted quantitative coronary analysis (QCA) with custom software (eg Medis, Leiden, Netherlands), by a trained observer blinded to the allocated group. The coronary segment for analysis will be located distal to the infusion catheter in the proximal - mid segment of the right coronary artery or a main branch of the left coronary artery. The segment will have minimal or no angiographic evidence of coronary disease. The length of the segment will be 30 mm. The same angiographic projection will be used for all of the analyses. The software will be calibrated on the catheter. Mean lumen diameter and mean coronary area will be computed.
Epicardial spasm, defined as >90% reduction in coronary artery diameter with ischaemic ST-segment changes on the ECG, and microvascular spasm, defined as ischaemic ST-segment changes without epicardial coronary vasoconstriction >90% will be assessed.
ECG changes, including alterations in atrio-ventricular conduction and ST-segment deviation, will be prospectively recorded.
Since a neuro-hormonal response may potentially mediate RIC, a blood test will be performed before and after cuff placement in all patients (active and control groups) to measure circulating molecules known to regulate blood vessel function.
The study data will be analysed by a biostatistician who is independent of the research team.
If the investigators can discover the effects, if any, of RIC on coronary vascular function, then potentially this information would provide new insights into the mechanisms of action of RIC.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Remote ischaemic conditioning | Active comparator | Procedure: Remote ischaemic conditioningIntermittent inflation of a forearm blood pressure cuff for 5 minute periods at 200 mmHg separated by a 5 minute rest interval, repeated successively on 4 occasions over a 40 minute period. The intervention will take place on the ward with the patient obscured from the clinical team by a curtain. |
| Control group | Sham comparator | Procedure: Arm cuff placement, no inflation;Sham intervention: Arm cuff placement but without inflation during a 40 minute period. A curtain will obscure the patient from the clinical team during this time. Arm cuff placement, no inflation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Age 18 or over
- Known or suspected coronary artery disease
- A clinical indication for coronary angiography.
Key exclusion criteria (4 listed)
- Myocardial infarction within 2 weeks
- History of coronary artery bypass surgery
- Second or third degree atrioventricular block
- Written informed consent.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Remote ischaemic conditioningAlso: Ischaemic preconditioning, Remote ischemic preconditioningIntermittent inflation of an arm blood pressure cuff for 5 minute periods at 200 mmHg separated by a 5 minute rest interval, repeated successively on 4 occasions over a 40 minute period. The intervention will take place on the ward with the patient obscured from the clinical team by a drawn curtain. The clinical team and researchers will be masked to the intervention type. | Procedure or surgery | Remote ischaemic conditioning |
| Arm cuff placement, no inflation;Also: Sham procedureSham procedure involving arm cuff placement, no inflation: A blood pressure cuff will be placed on the arm for 40 minutes. The cuff will not be inflated. The patient will be in bed behind a curtain on the cardiology ward. The curtain will obscure the patient from the attending cardiology team. The clinical team and researchers will be masked to the intervention type. | Procedure or surgery | Control group |
Primary outcome
Coronary artery diameter change
Time frame: Intra-procedure
The net percentage change in mean coronary artery diameter (endothelial function) following intra-coronary administration of study drug (ACh or glyceryl trinitrate) compared to baseline.
9 secondary outcomes
Circulating molecules reflecting endothelial function and oxidative stress
Time frame: Peri-procedure; from baseline up to 2 hours
Mean percentage change in coronary lumen diameter (delta CAD)
Time frame: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Mean percentage coronary vasoconstriction
Time frame: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Coronary endothelial dysfunction
Time frame: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Mean percentage change in coronary lumen diameter (delta CAD)
Time frame: Intra-procedure - After intracoronary injection of glyceryl trinitrate
Mean percentage coronary vasodilatation
Time frame: Intra-procedure - After intracoronary injection of glyceryl trinitrate
Epicardial coronary artery spasm
Time frame: Intra-procedure - During intra-coronary infusion of acetylcholine
Microvascular spasm
Time frame: Intra-procedure - During intra-coronary infusion of acetylcholine
ST-segment deviation
Time frame: Intra-procedure - During intra-coronary infusion of acetylcholine
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Oct 2024.
- Background: PubMed 29249435Corcoran D, Young R, Cialdella P, McCartney P, Bajrangee A, Hennigan B, Collison D, Carrick D, Shaukat A, Good R, Watkins S, McEntegart M, Watt J, Welsh P, Sattar N, McConnachie A, Oldroyd KG, Berry C. The effects of remote ischaemic preconditioning on coronary artery function in patients with stable coronary artery disease. Int J Cardiol. 2018 Feb 1;252:24-30. doi: 10.1016/j.ijcard.2017.10.082.
- Background: PubMed 3287885Cannon RO 3rd, Epstein SE. "Microvascular angina" as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988 Jun 1;61(15):1338-43. doi: 10.1016/0002-9149(88)91180-0. No abstract available.
- Background: PubMed 22721660Wei J, Mehta PK, Johnson BD, Samuels B, Kar S, Anderson RD, Azarbal B, Petersen J, Sharaf B, Handberg E, Shufelt C, Kothawade K, Sopko G, Lerman A, Shaw L, Kelsey SF, Pepine CJ, Merz CN. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc Interv. 2012 Jun;5(6):646-53. doi: 10.1016/j.jcin.2012.01.023.
- Background: PubMed 23858100Sato K, Kaikita K, Nakayama N, Horio E, Yoshimura H, Ono T, Ohba K, Tsujita K, Kojima S, Tayama S, Hokimoto S, Matsui K, Sugiyama S, Yamabe H, Ogawa H. Coronary vasomotor response to intracoronary acetylcholine injection, clinical features, and long-term prognosis in 873 consecutive patients with coronary spasm: analysis of a single-center study over 20 years. J Am Heart Assoc. 2013 Jul 15;2(4):e000227. doi: 10.1161/JAHA.113.000227.
- Background: PubMed 24573349Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, Hill S, Schaufele T, Mahrholdt H, Kaski JC, Sechtem U. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation. 2014 Apr 29;129(17):1723-30. doi: 10.1161/CIRCULATIONAHA.113.004096. Epub 2014 Feb 26.
- Background: PubMed 26404197Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease. JACC Cardiovasc Interv. 2015 Sep;8(11):1445-1453. doi: 10.1016/j.jcin.2015.06.017.
- Background: PubMed 22322081Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol. 2012 Feb 14;59(7):655-62. doi: 10.1016/j.jacc.2011.11.015.
- Background: PubMed 26112888Pries AR, Badimon L, Bugiardini R, Camici PG, Dorobantu M, Duncker DJ, Escaned J, Koller A, Piek JJ, de Wit C. Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation. Eur Heart J. 2015 Dec 1;36(45):3134-46. doi: 10.1093/eurheartj/ehv100. Epub 2015 Jun 25. No abstract available.
- Background: PubMed 25449895Pickard JM, Botker HE, Crimi G, Davidson B, Davidson SM, Dutka D, Ferdinandy P, Ganske R, Garcia-Dorado D, Giricz Z, Gourine AV, Heusch G, Kharbanda R, Kleinbongard P, MacAllister R, McIntyre C, Meybohm P, Prunier F, Redington A, Robertson NJ, Suleiman MS, Vanezis A, Walsh S, Yellon DM, Hausenloy DJ. Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop. Basic Res Cardiol. 2015 Jan;110(1):453. doi: 10.1007/s00395-014-0453-6. Epub 2014 Dec 2.
- Background: PubMed 21691310Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol. 2011 Jun 21;8(11):619-29. doi: 10.1038/nrcardio.2011.85.
- Background: PubMed 7680290Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993 Mar;87(3):893-9. doi: 10.1161/01.cir.87.3.893.
- Background: PubMed 17724264Loukogeorgakis SP, Williams R, Panagiotidou AT, Kolvekar SK, Donald A, Cole TJ, Yellon DM, Deanfield JE, MacAllister RJ. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation. 2007 Sep 18;116(12):1386-95. doi: 10.1161/CIRCULATIONAHA.106.653782. Epub 2007 Aug 27.
- Individual participant dataSharing planned: No. There is no data sharing plan, but we have no objection
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Colin Berry, PhD FRCP principal investigator
Golden Jubilee National Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Remote ischaemic conditioning and Arm cuff placement, no inflation; in people with Ischemic Preconditioning and Coronary Disease, run by NHS National Waiting Times Centre Board at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Coronary artery diameter change (time frame: Intra-procedure). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02666235, which also lists 21 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2024; AzTrials last refreshed its copy on 2 Nov 2026.