Angina After PCI: a Systems Medicine Study (CorMicA-PCI)

Angina After PCI: a Systems Medicine Cohort Study

Angina may persist or recur in patients treated by coronary angioplasty. The angioplasty involves a balloon treatment to open a blocked heart blood vessel and usually a stent (thin metal tube) is placed. Stents do not always improve symptoms and may make symptoms worse. Sometimes a drug-eluting-balloon is used instead of a stent.

This balloon coats the inside of the blood vessel to prevent re-narrowing. Research is needed to clarify the causes of ongoing angina and its impact on patients and the NHS, and to identify which patients will or will not benefit from a stent (hence avoiding over-treatment in the future).

We plan a 5-year UK-wide multicenter study involving up to 600 patients with angina undergoing coronary angioplasty (with or without a stent). They will initially have a heart MRI scan. We will assess what might influence the recurrence of angina in the year after the angioplasty procedure. We will measure small blood vessel function in the heart and the amount of plaque persisting after PCI.

Patients who report angina after coronary angioplasty usually have a second invasive angiogram. Instead, we will invite patients to have a heart MRI scan allowing us to also assess whether this scan might be more useful than a repeat angiogram in guiding clinical care. We will collaborate with life scientists, mathematicians, statisticians, and health economists to better understand causes and health economic implications of angina arising after coronary angioplasty procedures.

Study Overview

• Status: Enrolling by invitation
• Conditions: Angina (Stable); Ischemic Heart Disease (IHD)
• Intervention / Treatment: Diagnostic test: Cardiovascular magnetic resonance imaging; Diagnostic test: Coronary physiology

Detailed Description

Background: Prior studies indicate that potentially one in three patients may experience angina within 12 months of undergoing percutaneous coronary intervention (PCI).

Hypothesis: 1) Diffuse coronary atherosclerosis and/or microvascular dysfunction impair myocardial blood flow (MBF) leading to angina post-PCI.

Design: A 5-year interdisciplinary program with 3 scientific work-packages (WPs): 1) Clinical, 2) Systems medicine, and 3) Health Economics.

WP1) Cohort study In 4 or more centers in the United Kingdom, 600 patients with angina will undergo stress/rest perfusion cardiovascular magnetic resonance (CMR) imaging with inline pixel-mapping of MBF (ml/min/g) and then coronary physiology measured during PCI. Patient reported outcome measures will be collected routinely during follow-up to 12 months.

Primary outcome: Adjudicated, residual angina (Seattle Angina Questionnaire Angina Frequency (SAQ-7-AF) score <90).

Nested case-control study: stress perfusion CMR (MBF culprit artery territory, primary outcome) in approximately 200 patients reporting residual angina and 50 consecutive asymptomatic controls (all post-PCI). Clinically indicated coronary angiography including physiology tests (change from baseline measurement) and acetylcholine testing will be undertaken in approximately 120 patients.

WP2) Systems medicine (n=600) using biostatistics to identify multivariable baseline associates (clinical, coronary physiology, haemodynamics, circulating biomarkers (DNA, RNA, protein) of the SAQ-7-AF score (range 0 (Severe) - 100 (no angina)) post-PCI.

WP3) Health economics of NHS resource utilization and value of information (VoI) modelling to design stratified medicine trials.

Value: Identification of mechanisms to inform downstream diagnostic and therapeutic strategies for angina post-PCI.

• Study Type: Observational
• Enrollment (Estimated): 600

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB20AY
      • Royal Papworth Hospital NHS Foundation Trust
  • Dunbartonshire
    • Clydebank, Dunbartonshire, United Kingdom, G814DY
      • Golden Jubilee National Hospital
  • Lanarkshire
    • East Kilbride, Lanarkshire, United Kingdom, G75 8RG
      • University Hospital Hairmyres
  • Yorkshire
    • Leeds, Yorkshire, United Kingdom, LS13EX
      • Leeds General Infirmary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with stable angina in whom stress perfusion CMR imaging is reasonable on clinical and/or research grounds and in whom invasive management is plausible or intended will be eligible to participate.

Description

Inclusion Criteria:

BEFORE INVASIVE MANGEMENT

1. Angina by SAQ-7 Angina Frequency Score <90*

2. Stress CMR imaging*

   DURING INVASIVE MANAGEMENT

3. PCI (successful)
4. Coronary physiology assessment post-PCI.

Exclusion Criteria:

1. Age <=18 years
2. Acute MI within 30 days
3. Invasive management >90 days after stress CMR
4. Inability to comply with the protocol
5. Lack of written informed consent.
6. Pregnancy.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients receiving percutaneous coronary intervention; The study population will include individuals with stable angina who undergo stress perfusion cardiovascular magnetic resonance (CMR) imaging before invasive management. Eligibility will be sequentially assessed. Informed consent will initially be based on angina occurring in patients in whom there is a reasonable expectation for invasive management. Stress CMR imaging should be undertaken on either clinical grounds or for research. Potentially, 700 patients will provide written informed consent. Finally, eligibility will be reassessed during invasive management and eligibility will be confirmed when percutaneous coronary intervention is completed. The population will be defined by individuals who fulfil the eligibility criteria. The target sample size is 600 patients with complete data post-PCI. This sample size is anticipated to lead to approximately 200 participants who will report angina consistent with an Seattle Angina Questionnaire Angina Frequency score <90.

Diagnostic test: Cardiovascular magnetic resonance imaging; Observational diagnostic tests will include adenosine-stress perfusion cardiovascular magnetic resonance imaging before undergoing percutaneous coronary intervention.; Diagnostic test: Coronary physiology; Invasive coronary function tests using a diagnostic guidewire (PressureWire-X, Abbott), thermodilution, intravenous or intracoronary infusion of adenosine and intracoronary infusions of acetylcholine.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Residual angina after percutaneous coronary intervention.	Residual angina post-PCI, defined as adjudicated, angina (Seattle Angina Questionnaire Angina Frequency (SAQ-7-AF) score <90) occurring within one year of percutaneous coronary intervention.	From enrolment to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Angina	Angina severity will be assessed using the Seattle Angina Questionnaire Summary Score.	From enrolment to 12 months
Myocardial perfusion reserve	Myocardial perfusion reserve (MPR) within the distribution of the target coronary artery/ies revealed by cardiovascular magnetic resonance (CMR) imaging.	From enrolment to 12 months
Fractional flow reserve post-percutaneous coronary intervention	Fractional flow reserve after percutaneous coronary intervention, reflecting the success of the procedure.	24 hours
Coronary flow reserve after percutaneous coronary intervention	Coronary flow reserve (CFR) post-PCI. Coronary flow reserve takes account of adenosine-mediated vasodilatation of the coronary artery and microcirculation. A CFR <2.0 is abnormal, a CFR 2.0-<2.5 is impaired and a CFR>2.5 is normal.	24 hours
Index of microvascular resistance after percutaneous coronary intervention	Index of microvascular resistance (IMR) post-PCI. IMR reflects adenosine-mediated minimal microvascular resistance. An IMR >=25 is abnormal.	24 hours
Microvascular dysfunction after percutaneous coronary intervention	Microvascular dysfunction is defined as a CFR<2.5 and/or an IMR>=25 post-PCI.	24 hours
Health-related quality of life	Health-related quality of life will be assessed using the EuroQol-5D 5 Level (5L) questionnaire. EQ-5D-5L is a health status questionnaire that measures five dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression	From enrolment to 12 months
Physical function	The Duke Activity Status Index (DASI) is a self-administered questionnaire with a 12-item scale that estimates physical functional capacity, cardiorespiratory function and metabolic equivalents (METs).	From enrolment to 12 months
Illness perception	Brief Illness Perception Questionnaire (BIPQ) is a nine-item scale that measures the cognitive and emotional representations of illness.	From enrolment to 12 months
Anxiety and depression	Patient Health Questionnaire-4 (PHQ-4) is a self-reported questionnaire to assess for anxiety and depression over the last 2 weeks. Scores are rated as normal (0-2), mild (3-5), moderate (6-8), and severe (9-12). Total score ≥3 for first 2 questions suggests anxiety.	From enrolment to 12 months
Productivity loss	The Institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ) is a generic tool to measure productivity losses.	From enrolment to 12 months
Fraility	The Rockwood Clinical Frailty Scale (CFS) is a tool to summarize the overall level of fitness or frailty of an older individual.	From enrolment to 12 months
Serious adverse events	Serious adverse events (SAE) post-enrolment will be assessed using electronic health records without the need for participant contact. The SAE of interest are pre-specified in the protocol. Where e-health records are not an option, then an annual contact with the participant should be undertaken to assess for SAE. The final visit is defined as when the last participant has completed 12 months follow-up. The minimum duration of follow-up will be 12 months and the maximum duration of follow-up is anticipated to be up to 48 months. Longer term follow-up to 20 years will be undertaken using electronic health record linkage.	From enrolment to 12 months
Low density lipoprotein	Abnormal lipid metabolism, and hyperlipidemia, mediate atherogenesis. The circulating concentrations of low density lipoprotein, a proatherogenic lipid, will be assessed.	From enrolment to 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammation	Systemic inflammation may underlie the pathogenesis of resistant angina. Systemic inflammation will be assessed by measurement of the circulating concentration of C-reactive protein.	From enrolment to 12 months
Glycemic status	Glycemic status may underlie the pathogenesis of resistant angina. Cardiometabolic status will be assessed by measurement of the circulating concentration of glycated hemoglobin (HbA1c), a metabolic biomarker.	From enrolment to 12 months
Myocardial injury	The circulating concentration of troponin, measured using a high sensitivity assay, reflects ischemic myocardial injury or infarction.	From enrolment to 12 months
Lipoprotein(a)	Abnormal lipid metabolism, and hyperlipidemia, mediate atherogenesis. The circulating concentrations of lipoprotein(a), a proatherogenic lipid, will be assessed.	From enrolment to 12 months
Microvascular dysfunction (acetylcholine test population)	Microvascular dysfunction is defined as a composite outcome including the occurence of CFR<2.5 and/or an IMR>=25 and/or microvascular spasm (acetylcholine). Since acetylcholine-mediated microvascular spasm may reflect microvascular dysfunction, in the subpopulation also undergoing acetylcholine coronary reactivity testing, the microvascular dysfunction outcome measure will include the response to acetylcholine (yes/no), and CFR<2.5 and/or IMR>=25.	24 hours
Microvascular blood flow	The ratio of stress subendocardial myocardial blood flow / stress subepicardial myocardial blood flow. Myocardial blood flow is estimated as ml/min/g myocardial tissue on the American Heart Association model of myocardial segments.	From enrolment to 12 months
Impaired myocardial blood flow	Extent of impaired hyperemic myocardial blood flow (MBF, ml/min/g), defined as the ordinal number of segments with impaired peak hyperemic myocardial blood flow according to consensus-based, reference thresholds (PMID: 30772231). A regional perfusion defect is defined as myocardial blood flow <2.0 ml/min/g in one or more segments. If the perfusion defect is global (rather than regional) and suspected as being due to microvascular disease, then the MBF threshold is <2.25 ml/min/g.	From enrolment to 12 months
Coronary vasomotor dysfunction in response to intracoronary infusion of acetylcholine	Coronary vasomotor dysfunction in response to intracoronary infusion of acetylcholine. Vasomotor dysfunction is defined as coronary artery spasm and/or microvascular spasm according to contemporary diagnostic criteria (PMID: 39210710).	From enrolment to 12 months
Myocardial blood flow (hyperaemic, global)	Hyperemic myocardial blood flow (MBF, ml/min/g) in all segments.	From enrolment to 12 months

Collaborators and Investigators

• Sponsor: NHS National Waiting Times Centre Board
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Abbott Medical Devices; British Heart Foundation; CoreAalst BV; Robertson Centre for Biostatistics - University of Glasgow
• Investigators: Principal Investigator: Colin Berry, BSc MBChB PhD, University of Glasgow

Publications and helpful links

General Publications

• Crea F, Bairey Merz CN, Beltrame JF, Berry C, Camici PG, Kaski JC, Ong P, Pepine CJ, Sechtem U, Shimokawa H. Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization. Eur Heart J. 2019 Aug 1;40(29):2455-2462. doi: 10.1093/eurheartj/ehy857.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: December 24, 2024
• First Submitted That Met QC Criteria: February 28, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 28, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: coronary artery disease; Angina; cohort study; Percutaneous coronary intervention; Coronary physiology; Health-related quality of life; Health economics; Clinical outcomes; Microvascular angina; Cardiovascular magnetic resonance imaging; Systems medicine
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Vascular Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Chest Pain; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Angina Pectoris
• Other Study ID Numbers: 24/CARD/08

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be shared with bone fide research collaborators upon reasonable request with the agreement of the sponsor and chief investigator
• IPD Sharing Time Frame: After the completion of the study
• IPD Sharing Access Criteria: Bone fide research collaborators by contacting the chief investigator.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No