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

Coronary Disease Clinical Trial

— RIC-COR  

Official title:

A Randomised Controlled Trial of the Effect of Remote Ischaemic Conditioning on Coronary Endothelial Function in Patients With Angina.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02666235
• Other study ID #: 11/CARD/03
• Secondary ID: R11/A13610/S0704
• Status: Completed
• Phase: Phase 2
• First received: December 24, 2015
• Last updated: July 19, 2016
• Start date: July 2011
• Est. completion date: May 2016

Study information

• Verified date: July 2016
• Source: NHS National Waiting Times Centre Board
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: National Health Service
• Study type: Interventional

Clinical 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.

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: May 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Ischemia
• Ischemic Preconditioning

Intervention

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.
• 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.

Locations

Country	Name	City	State
United Kingdom	Golden Jubilee National Hospital	Glasgow	Dunbartonshire

Sponsors (4)

Lead Sponsor	Collaborator
NHS National Waiting Times Centre Board	Chest, Heart and Stroke Association Scotland, Chief Scientist Office of the Scottish Government, University of Glasgow

Country where clinical trial is conducted

United Kingdom, 

References & Publications (20)

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Loukogeorgakis 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. — View Citation

Loukogeorgakis 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. Epub 2007 Aug 27. — View Citation

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Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, Hill S, Schäufele 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. — View Citation

Pickard JM, Bøtker 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. Review. — View Citation

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Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Dai X, Manlhiot C, Li J, Redington AN. Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res Cardiol. 2012 Mar;107(2):241. doi: 10.1007/s00395-011-0241-5. Epub 2012 Jan 10. — View Citation

Sara 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):1445-53. doi: 10.1016/j.jcin.2015.06.017. — View Citation

Sato 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. — View Citation

Steensrud 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. — View Citation

Wei 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. — View Citation

Wolfrum 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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Intra-procedure	No
Secondary	Circulating molecules reflecting endothelial function and oxidative stress	Circulating concentrations of small molecules and hormones that are mediators of endothelial function and vascular tone.	Peri-procedure; from baseline up to 2 hours	No
Secondary	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.	Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine	No
Secondary	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.	Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine	No
Secondary	Coronary endothelial dysfunction	A decrease in luminal diameter of >20% after intracoronary infusion of acetylcholine.	Intra-procedure - After intracoronary infusion of intra-coronary acetylcholine	No
Secondary	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)	Intra-procedure - After intracoronary injection of glyceryl trinitrate	No
Secondary	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)	Intra-procedure - After intracoronary injection of glyceryl trinitrate	No
Secondary	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).	Intra-procedure - During intra-coronary infusion of acetylcholine	Yes
Secondary	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.	Intra-procedure - During intra-coronary infusion of acetylcholine	Yes
Secondary	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.	Intra-procedure - During intra-coronary infusion of acetylcholine	Yes