CORonary MICrovascular Angina (CorMicA)

Coronary Disease Clinical Trial

— CorMicA  

Official title:

CORonary MICrovascular Angina (CorMicA): a Randomised, Controlled, Pilot Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03193294
• Other study ID #: 16CARD25
• Status: Completed
• Phase: N/A
• Start date: November 7, 2016
• Est. completion date: November 6, 2019

Study information

• Verified date: March 2020
• Source: NHS National Waiting Times Centre Board
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Angina is form of chest pain that is due to a lack of blood to the heart muscle. Angina is commonly triggered by stress and exertion, and is a common health problem worldwide. The diagnosis and treatment of angina is usually focused on detection of blockages in heart arteries, and relief of this problem with drugs, stents or bypass surgery. However, about one third of all invasive angiograms that are performed in patients with angina do not reveal any blockages. Many of such patients may have symptoms due to narrowings in the very small micro vessels (too small to be seen on an angiogram). The purpose of this research is to undertake a 'proof-of-concept' clinical trial to gather information as to whether routine tests of small vessel function in the heart might help identify patients with a stable coronary syndrome due to a disorder of coronary function (vasospastic or microvascular angina), and appropriately rule out this problem in patients with normal test results. The diagnostic strategy enables stratification of patient sub-groups to optimized therapy (personalised medicine). Evidence of patient benefits in this study would support the plan for a larger study that would be designed to impact on healthcare costs and patient reported outcome measures (PROMS).

Description:

Background: Patients with a stable coronary syndromes include those with obstructive coronary artery disease (CAD) or ischaemia with no obstructive CAD (INOCA). Disorders of coronary vasomotion leading to microvascular and vasospastic angina are debilitating, prognostically important health problems. Use of coronary function tests with thresholds (normal/abnormal) that are linked to evidence-based treatment (start/stop) could be useful to diagnose (rule-in/rule-out) these conditions, but, evidence is lacking.

Design: (1) A proof-of-concept, randomised controlled stratified medicine trial of a clinical strategy informed by invasive tests of coronary function and linked guideline-based treatment decisions vs. standard care using angiography only in 150 patients; (2) A nested observational imaging sub-study using quantitative stress perfusion cardiac magnetic resonance (CMR). CONSORT guidelines will be followed.

Objectives: (1) To assess whether a diagnostic strategy involving tests of coronary function changes the diagnosis and treatment and improves health and economic outcomes; (2) To assess the diagnostic accuracy of novel MRI methods for abnormal perfusion due to microvascular disease.

Methods: Patients undergoing invasive coronary angiography for the investigation of known or suspected angina and who do not have either structural heart disease or a systemic health problem that would explain those symptoms will be invited to participate. Written informed consent is required for participation. Eligibility is further confirmed at the time of the coronary angiogram by exclusion of obstructive (>50% stenosis, fractional flow reserve <=0.80) coronary artery disease (CAD). After the angiogram, eligible participants will be randomised immediately in the catheter laboratory to test disclosure (intervention group) or measurement without disclosure (control group). Coronary function will be assessed using a diagnostic guidewire and intra-coronary infusions of acetylcholine (10-6M, 10-5M, -10-4M) and a bolus of glyceryl trinitrate (300 micrograms). The guidewire-derived parameters include fractional flow reserve (FFR), coronary flow reserve (CFR), index of microvascular resistance (IMR) and the resistance reserve ratio (RRR). Participants who are enrolled but not randomised will enter a follow-up registry. The endotypes (diagnostic strata) are: obstructive CAD, coronary vasospastic angina, microvascular angina, endothelial dysfunction (no angina), normal (non-cardiac, normal coronary function results, no angina). Thus, a diagnosis may be ruled-in or ruled-out based on the test results. Microvascular disease will be characterised as structural (abnormal IMR) and/or functional (abnormal CFR, RRR). Primary outcome: Between-group difference in Seattle Angina Questionnaire (SAQ) scores at 6 months; Secondary: Reclassification of the treatment decision; certainty of the diagnosis; health status (EQ-5D, Illness Perception, Treatment Satisfaction & Patient Health questionnaires); angina medication and adherence; health economics; reference clinical decisions as evaluated by an independent expert panel of clinicians. Follow-up will continue in the longer term, including through electronic health record linkage.

Value: To our knowledge, the study is the first to assess the clinical value of invasive management guided by routine use of adjunctive tests of coronary function in appropriately selected patients. The study will provide new insights into disease mechanisms and provide pilot data to inform the rationale and design of a larger clinical trial. The CMR substudy will provide information on the diagnostic utility of quantitative non-invasive imaging methods in this patient population. Should our hypotheses be confirmed, the research will bring new knowledge with potential benefits to patients and healthcare providers.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 151
• Est. completion date: November 6, 2019
• Est. primary completion date: July 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

A clinically-indicated plan for invasive coronary angiography. Symptoms of angina or angina-equivalent (according to the Rose- and Seattle Angina questionnaires).

Exclusion Criteria:

A non-coronary indication for invasive angiography e.g. valve disease During the angiogram:

obstructive disease evident in a main coronary artery (diameter >2.5 mm), i.e. a coronary stenosis>50% or a fractional flow reserve (FFR) =0.80 Lack of informed consent.

Related Conditions & MeSH terms

• Angina Pectoris
• Angina, Stable
• Coronary Circulation
• Coronary Disease
• Coronary Syndrome
• Coronary Vasospasm
• Microvascular Angina

Intervention

Diagnostic Test:
• Stratified medicine involving a diagnostic intervention
Adjunctive tests of coronary artery function at the time of invasive coronary angiography. Diagnostic groups: stable coronary syndromes in patients with no-obstructive coronary artery disease including the following sub-groups (coronary artery vasospasm, microvascular spasm, impaired vasorelaxation due to (1) endothelial dysfunction and/or (2) non-endothelial dysfunction, or unaffected (normal test results). Medical management is linked to contemporary clinical guidelines for the management of patients with stable coronary artery disease (European Society of Cardiology (2013)).

Locations

Country	Name	City	State
United Kingdom	Golden Jubilee National Hospital	Clydebank	Dunbartonshire
United Kingdom	Hairmyres Hospital	East Kilbride	Lanarkshire

Sponsors (2)

Lead Sponsor	Collaborator
NHS National Waiting Times Centre Board	British Heart Foundation

Country where clinical trial is conducted

United Kingdom, 

References & Publications (26)

Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade. Circulation. 2017 Mar 14;135(11):1075-1092. doi: 10.1161/CIRCULATIONAHA.116.024534. Review. — View Citation

Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Bairey Merz CN; Coronary Vasomotion Disorders International Study Group (COVADIS). International standardization of diagnostic criteria for vasospastic angina. Eur Heart J. 2017 Sep 1;38(33):2565-2568. doi: 10.1093/eurheartj/ehv351. — View Citation

Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Bairey Merz CN; Coronary Vasomotion Disorders International Study Group (COVADIS). The Who, What, Why, When, How and Where of Vasospastic Angina. Circ J. 2016;80(2):289-98. doi: 10.1253/circj.CJ-15-1202. Epub 2015 Dec 18. Review. — View Citation

Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007 Feb 22;356(8):830-40. Review. — View Citation

Cannon RO 3rd, Bonow RO, Bacharach SL, Green MV, Rosing DR, Leon MB, Watson RM, Epstein SE. Left ventricular dysfunction in patients with angina pectoris, normal epicardial coronary arteries, and abnormal vasodilator reserve. Circulation. 1985 Feb;71(2):218-26. — View Citation

Cannon RO 3rd, Leon MB, Watson RM, Rosing DR, Epstein SE. Chest pain and "normal" coronary arteries--role of small coronary arteries. Am J Cardiol. 1985 Jan 25;55(3):50B-60B. — View Citation

Corcoran D, Ford TJ, Hsu LY, Chiribiri A, Orchard V, Mangion K, McEntegart M, Rocchiccioli P, Watkins S, Good R, Brooksbank K, Padmanabhan S, Sattar N, McConnachie A, Oldroyd KG, Touyz RM, Arai A, Berry C. Rationale and design of the Coronary Microvascula — View Citation

Cox ID, Salomone O, Brown SJ, Hann C, Kaski JC. Serum endothelin levels and pain perception in patients with cardiac syndrome X and in healthy controls. Am J Cardiol. 1997 Sep 1;80(5):637-40. — View Citation

Crea F, Bairey Merz CN, Beltrame JF, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Camici PG; Coronary Vasomotion Disorders International Study Group (COVADIS). The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift. Eur Heart J. 2017 Feb 14;38(7):473-477. doi: 10.1093/eurheartj/ehw461. Erratum in: Eur Heart J. 2016 Dec 24;:. — View Citation

Elliott PM, Krzyzowska-Dickinson K, Calvino R, Hann C, Kaski JC. Effect of oral aminophylline in patients with angina and normal coronary arteriograms (cardiac syndrome X). Heart. 1997 Jun;77(6):523-6. — View Citation

Ford TJ, Berry C. Angina: contemporary diagnosis and management. Heart. 2020 Mar;106(5):387-398. doi: 10.1136/heartjnl-2018-314661. Epub 2020 Feb 12. — View Citation

Ford TJ, Berry C. How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease: Lessons from the British Heart Foundation CorMicA Trial. Interv Cardiol. 2019 May 21;14(2):76-82. doi: 10.15420/icr.2019.04.R1. eCollection 2019 May. Review. — View Citation

Ford TJ, Corcoran D, Berry C. Coronary artery disease: physiology and prognosis. Eur Heart J. 2017 Jul 1;38(25):1990-1992. doi: 10.1093/eurheartj/ehx226. — View Citation

Ford TJ, Corcoran D, Padmanabhan S, Aman A, Rocchiccioli P, Good R, McEntegart M, Maguire JJ, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sattar N, Hsu LY, Arai AE, Oldroyd KG, Touyz RM, Davenport AP, Berry — View Citation

Ford TJ, Rocchiccioli P, Good R, McEntegart M, Eteiba H, Watkins S, Shaukat A, Lindsay M, Robertson K, Hood S, Yii E, Sidik N, Harvey A, Montezano AC, Beattie E, Haddow L, Oldroyd KG, Touyz RM, Berry C. Systemic microvascular dysfunction in microvascular — View Citation

Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sidik N, McCartney P, Corcoran D, Collison D, Rush C, McConnachie A, Touyz RM, Oldroyd KG, Berry C. Strat — View Citation

Ford TJ, Stanley B, Sidik N, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, McCartney P, Corcoran D, Collison D, Rush C, Sattar N, McConnachie A, Touyz RM, Oldroyd KG, Berr — View Citation

Ford TJ, Yii E, Sidik N, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, McCartney P, Corcoran D, Collison D, Rush C, Stanley B, McConnachie A, Sattar N, Touyz RM, Oldroyd KG, Berr — View Citation

Kaski JC, Elliott PM, Salomone O, Dickinson K, Gordon D, Hann C, Holt DW. Concentration of circulating plasma endothelin in patients with angina and normal coronary angiograms. Br Heart J. 1995 Dec;74(6):620-4. — View Citation

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

Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC. Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging. 2013 Jun;6(6):660-7. doi: 10.1016/j.jcmg.2012.12.011. Epub 2013 May 1. — View Citation

Rosano GM, Collins P, Kaski JC, Lindsay DC, Sarrel PM, Poole-Wilson PA. Syndrome X in women is associated with oestrogen deficiency. Eur Heart J. 1995 May;16(5):610-4. — View Citation

Sax FL, Cannon RO 3rd, Hanson C, Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina. Evidence of a generalized disorder of vascular function? N Engl J Med. 1987 Nov 26;317(22):1366-70. Erratum in: N Engl J Med 1987 Dec 24;317(26):1674. — View Citation

Sidik NP, McEntegart M, Roditi G, Ford TJ, McDermott M, Morrow A, Byrne J, Adams J, Hargreaves A, Oldroyd KG, Stobo D, Wu O, Messow CM, McConnachie A, Berry C. Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Function and CT Coronary Angiogram (CorCTCA) study. Am Heart J. 2020 Mar;221:48-59. doi: 10.1016/j.ahj.2019.11.015. Epub 2019 Dec 2. — View Citation

Williams MC, Hunter A, Shah A, Assi V, Lewis S, Mangion K, Berry C, Boon NA, Clark E, Flather M, Forbes J, McLean S, Roditi G, van Beek EJ, Timmis AD, Newby DE; Scottish COmputed Tomography of the HEART (SCOT-HEART) Trial Investigators. Symptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trial. Heart. 2017 Jul;103(13):995-1001. doi: 10.1136/heartjnl-2016-310129. Epub 2017 Feb 28. — View Citation

Zhang Y, Jeffrey S, Barley J, Hann C, Carter N, Kaski JC. Angiotensin-converting enzyme insertion/deletion polymorphism in angina pectoris with normal coronary arteriograms. Am J Cardiol. 1996 Apr 15;77(10):877-9. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Health status (Seattle Angina Score)	Health status and symptoms will be assessed at baseline and again at 6 months using the Seattle Angina Questionnaire. The primary outcome is the within-subject change in SAQ score at 6 months from baseline.	6 months
Secondary	Feasibility of the stratified medicine approach defined by protocol compliance as measured by deviations from the protocol.	Feasibility will be assessed in terms of enrolment rates and protocol compliance relating to enrolment, cross-over, integrity of blinding, adherence with therapy during follow-up, and compliance with follow up assessments	Through study completion, 3 years
Secondary	Procedure-related serious adverse events	Safety as reflected by the occurrence of procedure-related serious adverse events	Day 1 (index coronary angiogram procedure)
Secondary	Prevalence of endotypes	Diagnosis of endotypes (disease strata): obstructive CAD, coronary vasospastic angina, microvascular angina, endothelial dysfunction (no angina), normal (non-cardiac, normal coronary function results, no angina).	Day 1
Secondary	Diagnostic utility of the diagnostic intervention	Impact of disclosure of the coronary function test results on the diagnosis and certainty of the diagnosis (diagnostic utility)	Day 1
Secondary	Clinical utility of the stratified approach	Impact of disclosure of the coronary function test results on medical decisions (including treatment and investigations), and to compare these decisions against a medical decisions formed by an independent panel of experts (reference dataset)	Day 1
Secondary	Cardiovascular risk factors	Assess the relationships between cardiovascular risk factors, reflected by validated risk scores (e.g. ASSIGN, JBS3), and parameters of coronary function, in medically managed patients.	Day 1
Secondary	Anxiety and depression	Assess the participants' self-reported levels of anxiety and depression using the Patient Health Questionnaire-4 (PHQ-4)	Through study completion, 3 years
Secondary	Treatment satisfaction	Assess the participants' self-reported levels of treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM)	Through study completion, 3 years
Secondary	Illness perception	Assess the participants' perception of their illness using the brief Illness Perception Questionnaire	Through study completion, 3 years
Secondary	Health status EQ5D	Assess the participants' general health status and self reported quality of life using the EQ5D questionnaire.	Through study completion, 3 years
Secondary	Health status (Seattle Angina Score)	Health status and symptoms will be assessed at baseline and again at 6 months, 12 months and close-out using the Seattle Angina Questionnaire. The secondary outcome is the within-subject change in SAQ score over time.	Through study completion, 3 years
Secondary	Biomarkers	Assess associations between circulating molecules that are implicated in the pathophysiology of disorders of coronary function.	36 months
Secondary	Health economics	Assess resource utilisation including primary and secondary care costs for tests, procedures and out-patient visits, and medicines, between the randomised groups	36 months
Secondary	Myocardial perfusion	Assess the diagnostic accuracy of stress perfusion magnetic resonance imaging for identification of endotypes based on reference tests of coronary function.	42 days
Secondary	Incidental findings	Detection of clinically significant (actionable) incidental findings using magnetic resonance imaging. The incidental findings may be cardiac or non-cardiac.	42 days
Secondary	Myocardial tissue characterisation	Detection of myocardial pathology using multiparametric CMR	42 days

External Links

•   British Heart Foundation
•   British Heart Foundation Centre of Research Excellence, University of Glasgow
•   Cardiology and Imaging Group, University of Glasgow
•   Cardiology Department, Golden Jubilee National Hospital