Remote Ischaemic Conditioning and Coronary Endothelial Function (RIC-COR) (RIC-COR)

October 27, 2024 updated by: Colin Berry, NHS National Waiting Times Centre Board

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Dunbartonshire
      • Glasgow, Dunbartonshire, United Kingdom, G814DY
        • Golden Jubilee National Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age 18 or over
  2. Known or suspected coronary artery disease
  3. A clinical indication for coronary angiography.

Exclusion Criteria:

  1. Myocardial infarction within 2 weeks
  2. History of coronary artery bypass surgery
  3. Second or third degree atrioventricular block
  4. Written informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Remote ischaemic conditioning
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.
Procedure: Remote ischaemic conditioning
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.
Other Names:
  • Remote ischemic preconditioning
  • Ischaemic preconditioning
Sham Comparator: Control group
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.
Procedure: Arm cuff placement, no inflation;
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.
Other Names:
  • Sham procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Intra-procedure

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Circulating molecules reflecting endothelial function and oxidative stress
Time Frame: Peri-procedure; from baseline up to 2 hours
Circulating concentrations of small molecules and hormones that are mediators of endothelial function and vascular tone.
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
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.
Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Mean percentage coronary vasoconstriction
Time Frame: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
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.
Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
Coronary endothelial dysfunction
Time Frame: Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine
A decrease in luminal diameter of >20% after intracoronary infusion of acetylcholine.
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
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)
Intra-procedure - After intracoronary injection of glyceryl trinitrate
Mean percentage coronary vasodilatation
Time Frame: Intra-procedure - After intracoronary injection of glyceryl trinitrate
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)
Intra-procedure - After intracoronary injection of glyceryl trinitrate
Epicardial coronary artery spasm
Time Frame: Intra-procedure - During intra-coronary infusion of acetylcholine
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).
Intra-procedure - During intra-coronary infusion of acetylcholine
Microvascular spasm
Time Frame: Intra-procedure - During intra-coronary infusion of acetylcholine
Microvascular spasm was diagnosed when angina occurred with typical ischaemic ST-segment changes in the absence of epicardial coronary constriction >90% diameter reduction.
Intra-procedure - During intra-coronary infusion of acetylcholine
ST-segment deviation
Time Frame: Intra-procedure - During intra-coronary infusion of acetylcholine
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.
Intra-procedure - During intra-coronary infusion of acetylcholine

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NHS National Waiting Times Centre Board

Collaborators

University of Glasgow
Chief Scientist Office of the Scottish Government
Chest, Heart and Stroke Association Scotland

Investigators

  • Principal Investigator: Colin Berry, PhD FRCP, Golden Jubilee National Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2011

Primary Completion (Actual)

May 1, 2016

Study Completion (Actual)

May 1, 2016

Study Registration Dates

First Submitted

December 24, 2015

First Submitted That Met QC Criteria

January 24, 2016

First Posted (Estimated)

January 28, 2016

Study Record Updates

Last Update Posted (Actual)

October 29, 2024

Last Update Submitted That Met QC Criteria

October 27, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11/CARD/03
  • R11/A136 (Other Grant/Funding Number: Chest Heart & Stroke Scotland)
  • 10/S0704/52 (Other Identifier: West of Scotland Research Ethics Service)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

There is no data sharing plan, but we have no objection

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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