Clinical trial NCT03477890: Coronary Microvascular Function and CT Coronary Angiography (CorCTCA)
Official title: Angina in Patients Without Obstructive Coronary Disease As Revealed by CT Coronary Angiography (Cor-CTCA): an Observational Cohort Study Involving Coronary Function Tests and a Nested Randomised Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Angina, Stable
Angina Pectoris, Variant
Microvascular Angina
Lead sponsor: NHS National Waiting Times Centre Board
Sponsor class: OTHER
Collaborators: name: University of Glasgow
name: British Heart Foundation
name: Chief Scientist Office of the Scottish Government
name: NHS Greater Clyde and Glasgow
First posted: 2018-03-27
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, parallel group, prospective
Primary purpose: DIAGNOSTIC

Brief summary: Angina in patients without obstructive coronary artery disease (CAD) is a clinical conundrum and patient management is heterogeneous. Hypothesis: Abnormal coronary function is common and clinically relevant in this population. Design: An observational cohort study and nested randomised controlled diagnostic strategy trial. Methods: 250 patients with known or suspected angina informed by validated questionnaires but without obstructive CAD (\<70% stenosis) in an artery \>=2.5 mm or structural heart disease, as revealed by CT coronary angiography (CTCA), will be invited to undergo coronary function testing (FFR, CFR, IMR; intra-coronary ACh) during invasive angiography. Patients will be randomised following angiography but before testing coronary function to disclosure of the coronary function test results or not. Treatment decisions by the attending cardiologist will be recorded before and after disclosure of results. Outcomes: Primary: The between-group difference in the reclassification rate of the initial diagnosis using logistic regression, adjusted for baseline factors associated with the likelihood of reclassification of the initial diagnosis. Secondary: Prevalence of microvascular or vasospastic angina; health status reflected by the EuroQol group 5-Dimensions (EQ-5D), Seattle Angina Questionnaire, Illness perception, treatment satisfaction questionnaires and functional status questionnaires; angina medication and adherence. Value: This research will provide new insights into the conundrum of angina in patients without obstructive CAD or structural heart disease.

Detailed description: According to information provided by the British Heart Foundation, there are approximately 2.3 million men and women living with angina in the United Kingdom (UK). In 2014, there were \~247,363 coronary angiograms performed, mostly for the investigation of known or suspected angina, but only about half of the patients have obstructive coronary artery disease (CAD) identified by the angiogram. Considering CT coronary angiography (CTCA), \<=1 in 4 patients referred to the Chest Pain Clinic with chest pain of suspected cardiac origin have obstructive CAD identified by the CTCA scan. The explanation for the cause(s) of the chest pain are often unclear, which can be frustrating to patients and clinicians. Small vessel disease, i.e. microvascular or vasospastic angina may be one explanation.

Anatomical imaging of the coronary arteries non-invasively by CTCA or invasively is an insensitive approach for the assessment of coronary function, and even visual assessment of the angiogram for obstructive CAD by invasive angiography or CTCA, may sometimes lead to mis-diagnosis and sub-optimal outcomes. Novel adjunctive tests of coronary function may have incremental diagnostic value to further inform medical decisions. Taken together, the literature and practice guidelines suggest a clinical problem of unmet need, with the potential for benefits to patients and healthcare providers if the diagnostic management can be improved. Our proposal addresses the evidence gap, by exploiting advances in diagnostic tests to gather information on the prevalence of microvascular and vasospastic disorders in patients with angina in whom obstructive CAD has been ruled out. By implementing a diagnostic management strategy in the context of a randomised, blinded, controlled trial, the investigators aim to determine whether use of coronary function tests in relevant patients might be beneficial.

Angina in patients without obstructive CAD and insights from contemporary clinical trials: The Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME-2), Scottish COmputed Tomography of the HEART (SCOT-HEART), Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), and Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC 2) 2 trials focused on the diagnosis and treatment of angina due to obstructive CAD. Paradoxically, the findings in these trials have diagnosed considerable numbers of patients with angina without obstructive CAD. In FAME-2, of 1220 patients with stable CAD, 332 (27%) had non-flow limiting (FFR\>0.80) CAD. The distribution of the Canadian Cardiovascular Society angina classes was similar between the randomised patients and those in the registry (p=0.64), as was the prevalence of silent ischaemia (16%; p=0.96). The registry patients were treated with medical therapy and the MACE rate was 9% at 2 years.

In SCOT-HEART, of 4146 patients with suspected angina assessed at the Chest Pain Clinic, 2450 (59%) had confirmed angina (typical or atypical), yet considering the prevalence of obstructive CAD as revealed by CTCA (\>70% stenosis in ≥1 major branches or 50% in the left main stem), just 25% had obstructive CAD. In the PROMISE trial, 10,003 participants (n=8939 (89.4%) with typical or atypical angina) were randomised to a strategy of initial anatomical testing with CTCA or to a strategy of functional testing (exercise ECG or stress imaging). Using similar diagnostic criteria as in SCOT-HEART, only 517 (10.7%) of the 4996 participants in the CTCA group had a 'positive' result. No further data were provided to explain the aetiology of the angina in the patients without obstructive CAD.

Most recently, the CE-MARC 2 trial compared diagnostic strategies in patients referred to the Chest Pain Clinic with a pre-test likelihood of CAD of 10% to 90%. All (n=1202) of the participants had a history of angina, with 401 (33.4%) having typical angina. Only a minority of participants had a positive non-invasive test (12.4% in the CMR group, 18.2% in the myocardial perfusion scintigraphy (MPS) group and 13.4% in the NICE Guideline group). Invasive coronary angiography was performed within 12 months of randomisation in 265 (22%) patients. The primary outcome of unnecessary angiography (defined as an FFR\>0.8 or quantitative coronary analysis showing no stenosis ≥70% in 1 view or ≥50% in 2 orthogonal views in all coronary vessels ≥2.5 mm diameter), occurred in 139 subjects (12%): 7.5% in the CMR group, 7.1% in the MPS group and 28.8% of participants in the NICE guidelines group. CEMARC 2 was a pragmatic trial and since invasive angiography was not performed in all of the subjects, the causes of the angina in patients with 'negative' non-invasive imaging tests were unclear. Finally, the ISCHEMIA trial investigators have observed that some of the participants enrolled with moderate-severe myocardial ischemia on stress testing (% left ventricular (LV) mass) do not have obstructive CAD. The Changes in Ischemia and Angina over One year among ISCHEMIA trial screen failures with no obstructive coronary artery disease on coronary CT angiography (CIAO-ISCHEMIA) study has been instigated to investigate these patients in greater detail.

In the SCOT-HEART trial, symptoms and quality of life assessed at baseline and 6 months improved less in patients assigned to the CTCA-guided strategy as compared to standard care. This analysis refuted the hypothesis that symptoms and quality of life would improve with a CTCA-guided strategy and it conflicts with the NICE-95 guideline recommendations. Patients in the CTCA group with a change in diagnosis confirming obstructive CAD or excluding CAD had the greatest improvement in symptoms. By contrast, patients with non-obstructive CAD had the least improvement in symptoms. There could be several reasons to explain this finding. Firstly, patient satisfaction may be greater with a definitive diagnosis and treatment plan i.e. 1) normal coronaries - stop treatment, 2) obstructive CAD - percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG), while a result of intermediate CAD with no change in treatment may result in lower patient satisfaction. Secondly, a false negative CTCA result may have occurred in some patients with flow limiting CAD (since objective assessments of flow limiting CAD and/or ischaemia were not performed). Finally, some patients with non-obstructive CAD may have had microvascular disease. Since clinicians may have stopped angina treatment in patients without obstructive CAD, the symptoms of patients who had microvascular angina (and a negative CTCA scan) may have deteriorated.

The design of our study includes a multicentre, observational study involving novel diagnostic tests of coronary function in order to provide information on the prevalence of microvascular and/or vasospastic disease in patients with angina but non obstructive CAD as revealed by CTCA. The CTCA protocol will be undertaken according optimal standards i.e. heart rate control with beta-blocker medication, administration of sublingual nitrate before the CTCA scan, etc. The clinical relevance of additional tests of coronary function will be assessed through a nested randomised strategy trial of management (diagnosis and treatment) guided by the coronary function test results versus standard care guided by angiography. The possibility of occasional CAD misclassification by CTCA (i.e. false negative, obstructive CAD) will also be assessed. Follow-up will include assessments of health, well-being and treatment satisfaction. The wider adoption of anatomical imaging with CTCA as a first-line diagnostic test for the assessment of stable chest pain (NICE-95 guideline update, November 2016), supports the rationale for this research.

Eligibility criteria: Inclusion Criteria:

1. Symptoms of angina or angina-equivalent informed by the Rose Angina questionnaire.
2. Intermediate or no obstructive coronary disease i.e. no coronary stenosis \>70% in an artery \>2.5 mm, as revealed by CT coronary angiography.

Exclusion Criteria:

1. A health problem that would explain the angina, e.g. anaemia, moderate-severe aortic stenosis, hypertrophic obstructive cardiomyopathy
2. Obstructive disease evident in a coronary artery (diameter \>2.5 mm), i.e. \>50 - 70% circumferential plaque extending for ≥2 coronary segments, or a stenosis\>70% as revealed by CT coronary angiography
3. Lack of informed consent.

   Exclusion from randomisation in the catheter laboratory:
4. Flow-limiting coronary disease defined by a fractional flow reserve (FFR) ≤0.80 in an artery\>2.5 mm.

Primary outcomes:
measure: Final diagnosis
timeFrame: Day 1
Secondary outcomes:
measure: Occurrence of abnormal coronary function in a major epicardial coronary artery
timeFrame: Day 1
measure: Presence of an obstructive or flow-limiting stenosis in a major coronary artery.
timeFrame: Day 1
measure: Procedure-related serious adverse events
timeFrame: Day 1
measure: Prevalence of endotypes
timeFrame: Day 1
measure: Cardiovascular risk
timeFrame: Day 1
measure: Anxiety and depression
timeFrame: Through study completion, 3 years
measure: Treatment satisfaction
timeFrame: Through study completion, 3 years
measure: Illness perception
timeFrame: Through study completion, 3 years
measure: Health status EQ-5D
timeFrame: Through study completion, 3 years
measure: Health status (Seattle Angina Score)
timeFrame: Through study completion, 3 years
measure: Functional status
timeFrame: Through study completion, 3 years
measure: Health economics
timeFrame: 36 months
measure: Serum troponin concentration
timeFrame: Through study completion, 3 years
measure: Physical activity
timeFrame: Through study completion, 3 years
measure: Plasma endothelin-1
timeFrame: Through study completion, 3 years
Other outcomes:
Locations:
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital
state: Dunbartonshire
city: Larbert
country: United Kingdom
facility: Forth Valley Royal Hospital
state: Forth Valley
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
state: Strathclyde
Study officials:
affiliation: University of Glasgow
name: Katriona Brooksbank, PhD
role: STUDY_DIRECTOR
References:
citation: Sidik NP, Stanley B, Sykes R, Morrow AJ, Bradley CP, McDermott M, Ford TJ, Roditi G, Hargreaves A, Stobo D, Adams J, Byrne J, Mahrous A, Young R, Carrick D, McGeoch R, Corcoran D, Lang NN, Heggie R, Wu O, McEntegart MB, McConnachie A, Berry C. Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial. Circulation. 2024 Jan 2;149(1):7-23. doi: 10.1161/CIRCULATIONAHA.123.064751. Epub 2023 Oct 5.
citation: Berry C. Stable Coronary Syndromes: The Case for Consolidating the Nomenclature of Stable Ischemic Heart Disease. Circulation. 2017 Aug 1;136(5):437-439. doi: 10.1161/CIRCULATIONAHA.117.028991. No abstract available.
citation: 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.
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. No abstract available.
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.
citation: SCOT-HEART investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet. 2015 Jun 13;385(9985):2383-91. doi: 10.1016/S0140-6736(15)60291-4. Epub 2015 Mar 15.
citation: Greenwood JP, Ripley DP, Berry C, McCann GP, Plein S, Bucciarelli-Ducci C, Dall'Armellina E, Prasad A, Bijsterveld P, Foley JR, Mangion K, Sculpher M, Walker S, Everett CC, Cairns DA, Sharples LD, Brown JM; CE-MARC 2 Investigators. Effect of Care Guided by Cardiovascular Magnetic Resonance, Myocardial Perfusion Scintigraphy, or NICE Guidelines on Subsequent Unnecessary Angiography Rates: The CE-MARC 2 Randomized Clinical Trial. JAMA. 2016 Sep 13;316(10):1051-60. doi: 10.1001/jama.2016.12680.
citation: De Bruyne B, Fearon WF, Pijls NH, Barbato E, Tonino P, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T, Oldroyd K, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Limacher A, Nuesch E, Juni P; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014 Sep 25;371(13):1208-17. doi: 10.1056/NEJMoa1408758. Epub 2014 Sep 1.
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.
citation: Ong P, Athanasiadis A, Sechtem U. Patterns of coronary vasomotor responses to intracoronary acetylcholine provocation. Heart. 2013 Sep;99(17):1288-95. doi: 10.1136/heartjnl-2012-302042. Epub 2013 Feb 26. No abstract available.
citation: Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B, Cole J, Dolor RJ, Fordyce CB, Huang M, Khan MA, Kosinski AS, Krucoff MW, Malhotra V, Picard MH, Udelson JE, Velazquez EJ, Yow E, Cooper LS, Lee KL; PROMISE Investigators. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015 Apr 2;372(14):1291-300. doi: 10.1056/NEJMoa1415516. Epub 2015 Mar 14.
citation: Ford TJ, Corcoran D, Berry C. Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need. Heart. 2018 Feb;104(4):284-292. doi: 10.1136/heartjnl-2017-311446. Epub 2017 Oct 13.
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.
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, Berry C. Ischemia and No Obstructive Coronary Artery Disease: Prevalence and Correlates of Coronary Vasomotion Disorders. Circ Cardiovasc Interv. 2019 Dec;12(12):e008126. doi: 10.1161/CIRCINTERVENTIONS.119.008126. Epub 2019 Dec 13.
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, Berry C. 1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CorMicA). JACC Cardiovasc Interv. 2020 Jan 13;13(1):33-45. doi: 10.1016/j.jcin.2019.11.001. Epub 2019 Nov 11.
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. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol. 2018 Dec 11;72(23 Pt A):2841-2855. doi: 10.1016/j.jacc.2018.09.006. Epub 2018 Sep 25.
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. No abstract available.