COronoary Microcirculation Analysis NETwork (COMA-NET)

Assessment of Risk Factors for Coronary Circulatory and Microcirculatory Disorders, Comparison of Invasive and Non-Invasive Diagnostic Methods, and Evaluation of the Impact of Individualized Pharmacotherapy Optimization on Patients' Quality of Life

COMA.NET (Coronary Microcirculation Analysis Network) is a prospective, randomized, open-label, parallel-group clinical trial designed to determine whether endotype-guided pharmacotherapy is superior to standard care in improving quality of life in patients with ischemia with non-obstructive coronary arteries. Approximately 180-190 participants with objective ischemia will be randomized to either the control or the intervention group.

Pharmacotherapy based on the endotype established during intracoronary assessment will be introduced in the intervention arm of the study. The primary endpoint is the change in the Seattle Angina Questionnaire (SAQ) score from baseline to 3 months. Secondary endpoints include the diagnostic accuracy of transthoracic echocardiographic coronary flow velocity reserve (CFVR), the incidence of adverse events, associations between biomarkers and coronary microvascular dysfunction (CMD), and the identification of risk factors for specific CMD endotypes.

Participants will undergo invasive functional evaluation of the coronary microcirculation, measurement of echocardiographic CFVR, and analysis of selected circulating biomarkers. The study cohort will be followed up at three and six months and will include reassessment of quality of life (Seattle Angina Questionnaire, EuroQol 5-Dimensions 5-Level questionnaire, 12-item Short Form Health Survey), anxiety (Generalized Anxiety Disorder-7 score), and functional status (6-minute walk test).

The study began in October 2025. Primary completion is anticipated in October 2027, and the overall study completion date is expected in March 2028.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Echocardiography; Doppler Echocardiography; Microcirculation Resistance; Microcirculatory Status; Microcirculation; Biomarkers; Myocardial Ischemia; Microcirculatory Dysfunction
• Intervention / Treatment: Diagnostic test: Coronary microvascular function assessment; Diagnostic test: Coronary microvascular function assessment

Detailed Description

According to the European Society of Cardiology (ESC) guidelines on chronic coronary syndromes, up to 70% of patients presenting with anginal symptoms and ischemia on non-invasive tests demonstrate no significant coronary artery disease on coronary angiography (INOCA - ischemia with non-obstructive coronary arteries). The underlying pathophysiology of this condition may include functional or structural abnormalities of the coronary microcirculation.

The aforementioned ESC guidelines recommend invasive coronary functional testing as a primary diagnostic strategy in persistently symptomatic patients with ischemia with non-obstructive coronary arteries (INOCA) or angina with non-obstructive coronary arteries (ANOCA) and impaired quality of life, despite medical treatment (Class I recommendation). Identification of the specific coronary microvascular dysfunction (CMD) endotype or epicardial vasospastic angina is crucial for the introduction of optimal, targeted pharmacological therapy. Therefore, this study addresses a critical evidence gap. As a superiority trial, it aims to determine whether endotype-guided pharmacotherapy is superior to standard care in improving quality of life and relieving symptoms over a 3-month period. The primary hypothesis is that endotype-guided therapy will result in a greater improvement in the Seattle Angina Questionnaire (SAQ) score compared with standard therapy at 3 months of follow-up.

COMA.NET (Coronary Microcirculation Analysis Network) is a prospective, randomized, open-label, interventional clinical trial with a parallel-group design. The eligible sample for this study consists of adults with chronic coronary syndrome, proven myocardial ischemia, and excluded obstructive coronary disease, either by invasive coronary angiography or coronary computed tomography angiography (CCTA) (defined as no significant epicardial coronary stenosis).

The sample size was calculated using a conservative approach comparing mean change scores between groups, with a two-sided alpha level of 0.05 and 80% statistical power. Under these assumptions, approximately 160 evaluable participants are required. We anticipate an attrition rate of 15% (including loss to follow-up and incomplete questionnaire data); thus, the total planned enrollment is approximately 180-190 participants.

Participants will be randomized in a 1:1 allocation ratio to one of two arms: the intervention group or the control group. Randomization will be performed using a simple randomization procedure based on a computer-generated randomization sequence with permuted blocks of variable size (4 and 6).

According to the study protocol, prior to hospital admission, all participants will be adequately prepared by discontinuing pharmacotherapy known to interfere with vasoreactivity (e.g., non-dihydropyridine calcium channel blockers such as verapamil and diltiazem), in accordance with appropriate washout periods.

On admission, blood and urine samples will be collected for analysis of redox and inflammatory biomarkers, including non-enzymatic antioxidants, enzymatic antioxidants, total antioxidant capacity and oxidative status, markers of oxidative damage, cytokines, chemokines, growth factors, damage-associated molecular patterns (DAMPs), and matrix metalloproteinases (MMPs 1-14) and their tissue inhibitors. All biomarker analyses will be performed using validated laboratory methods according to established protocols.

Overall quality of life (QoL) assessment will be performed using the Seattle Angina Questionnaire (SAQ), EuroQol 5-Dimensions 5-Level questionnaire (EQ-5D-5L), Generalized Anxiety Disorder-7 (GAD-7) score, 12-item Short Form Health Survey (SF-12), and Six-Minute Walk Test (6MWT) distance at baseline and follow-up.

All participants will undergo transthoracic echocardiography. Coronary flow velocity in the left anterior descending (LAD) artery will be assessed using pulsed-wave Doppler at rest and during regadenoson-induced hyperemia. Coronary flow velocity reserve (CFVR) will be calculated as the ratio of hyperemic to resting coronary flow velocity.

Subsequently, invasive diagnostics will be performed in both groups in two consecutive stages:

1. Coronary vasomotor testing: Intracoronary bolus administration of acetylcholine in increasing concentrations during coronary angiography will be used to evaluate epicardial and microvascular vasomotor function.
2. Microcirculatory function evaluation: Coronary flow reserve (CFR) and the index of microvascular resistance (IMR) will be assessed using the Coroventis CoroFlow™ Cardiovascular System, with hyperemia induced by intravenous regadenoson. CMD endotypes will be defined according to prespecified ESC criteria based on invasive coronary measurements.

Thereafter, following the examinations, patients will complete a numerical rating scale evaluating discomfort associated with the procedures.

In the intervention arm, antianginal treatment will be initiated in accordance with current ESC guidelines and tailored to specific CMD endotypes. The control group will receive standard pharmacotherapy according to current clinical practice, without endotype-specific treatment selection.

Participants initially assigned to the control group will cross over to the intervention arm at the 3-month follow-up. Following treatment revision according to the diagnosed endotype, both groups will be reassessed by telephone at 6 months from baseline using the previously described scales. Participants in the intervention arm will receive a follow-up telephone call one month after initiation of the intervention to assess clinical status, medication tolerance, adherence, and, if appropriate, to up-titrate prescribed medications.

At 3 months after the index hospitalization, participants in the intervention arm will undergo outpatient follow-up evaluation, including the SAQ, EQ-5D-5L, SF-12, 6-minute walk test, and GAD-7 score. Statistical analyses will be performed according to the intention-to-treat (ITT) and per-protocol principles.

The primary endpoint is the between-group difference in change in SAQ Summary Score at 3 months.

Secondary endpoints include:

• Comparison of treatment strategies
• Assessment of the diagnostic accuracy of echocardiographic CFVR
• Incidence of adverse events
• Associations between biomarkers and CMD
• Identification of risk factors for specific CMD endotypes The study commenced in October 2025. Participants will be recruited for approximately 21 months. The primary completion date will occur when the last enrolled patient completes follow-up (estimated October 2027). The overall study completion date, defined as completion of all study-related procedures and follow-up, is expected in March 2028.

This trial is designed to provide comprehensive data regarding the epidemiology, pathophysiological endotypes, and biomarkers of coronary vasomotor disorders in patients with INOCA. Furthermore, it will evaluate the clinical utility of invasive and non-invasive diagnostic tests and assess the impact of endotype-based pharmacotherapy on patient-related outcomes. The findings may contribute to the refinement of diagnostic algorithms and patient-centered management strategies.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Maciej A. Poludniewski, MD, PhD; Phone Number: +48 85-831-84-96; Email: maciej.poludniewski@umb.edu.pl
• Study Contact Backup: Name: Emil J. Dąbrowski, MD, PhD; Phone Number: +48 85-831-84-96; Email: emil.dabrowski@umb.edu.pl

Study Locations

• Poland
  • Bialystok, Poland, 15-276
    • Recruiting
    • University Clinical Hospital, Department of Invasive Cardiology, Internal Medicine with CICU and Catheterization Laboratory-Uniwersytecki Szpital Kliniczny w Białymstoku, Klinika Kardiologii Inwazyjnej, Chorób Wewnętrznych z OIOK i Pracownią Hemodynamiki
    • Contact: Maciej A. Poludniewski, MD, PhD; Phone Number: +48 85 831 84 96; Email: maciej.poludniewski@umb.edu.pl
    • Contact: Emil J. Dąbrowski, MD, PhD; Phone Number: +48 85 831 84 96; Email: emil.dabrowski@umb.edu.pl
    • Principal Investigator: Maciej A. Południewski, MD, PhD
    • Principal Investigator: Emil J. Dąbrowski, MD, PhD
    • Sub-Investigator: Piotr Pogorzelski, MD
    • Sub-Investigator: Michał Święczkowski, MD
    • Sub-Investigator: Michał Łuczaj, MD
    • Sub-Investigator: Maciejczyk, MD, PhD
    • Sub-Investigator: Marcin Kożuch, MD, PhD
    • Sub-Investigator: Oliwia Grunwald, MD
    • Principal Investigator: Sławomir Dobrzycki, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

a. Chronic coronary syndrome c. Anginal symptoms > CCS class I or angina equivalent d. Myocardial ischemia confirmed by non-invasive testing e. Provision of informed consent to participate in the study

Exclusion Criteria:

1. Angiographically significant coronary artery stenosis or FFR < 0.8
2. Renal insufficiency with eGFR < 30 ml/min/1.73 m²
3. Left ventricular ejection fraction < 40%
4. Hypertrophic cardiomyopathy
5. Acute coronary syndrome within < 90 days
6. Percutaneous coronary intervention (PCI) within < 90 days
7. Previous coronary artery bypass grafting (CABG)
8. Anemia < 10 g/dL or thrombocytopenia < 100,000/µL
9. Intraventricular conduction disturbances preventing ST-T segment assessment
10. Severe concomitant valvular heart disease
11. Active malignancy
12. Type 1 diabetes mellitus
13. Coronary artery anatomical abnormalities precluding assessment using PressureWire X (myocardial bridge causing > 50% luminal narrowing of the investigated vessel, severe coronary tortuosity, inability to properly cannulate coronary ostia)
14. Pregnancy
15. Heart failure ≥ NYHA class III
16. Asthma or COPD with severe irreversible airflow obstruction
17. Atrial fibrillation
18. Second- or third-degree atrioventricular block without pacemaker implantation (IPG)
19. Manifest pre-excitation on ECG or history of AVRT episodes without prior ablation of the accessory pathway

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Endotype-Guided Treatment Group; Participants undergo invasive and non-invasive assessment of coronary microvascular function to determine the INOCA endotype. The invasive assessment includes intracoronary acetylcholine provocation testing followed by guidewire-based measurement of coronary flow reserve and index of microvascular resistance during pharmacologically induced hyperemia. Non-invasive assessment includes echocardiographic coronary flow velocity reserve measurement in the left anterior descending artery. Based on the identified endotype of coronary microvascular dysfunction, participants receive guideline-directed pharmacotherapy targeted to the underlying mechanism in accordance with contemporary European Society of Cardiology recommendations. Follow-up assessments include quality-of-life questionnaires, functional capacity testing, and laboratory evaluation.	Diagnostic test: Coronary microvascular function assessment; Comprehensive invasive and non-invasive evaluation of coronary microvascular function used to determine microvascular dysfunction endotype and guide treatment selection.; Other Names: Endotype-guided management; Diagnostic test: Coronary microvascular function assessment; Comprehensive invasive and non-invasive evaluation of coronary microvascular function used to determine microvascular dysfunction endotype without endotype-guided management.; Other Names: Physician-guided standard care
Active Comparator: Standard Care Group; Participants undergo the same invasive and non-invasive assessment of coronary microvascular function. Pharmacotherapy is determined by the treating physician according to standard clinical practice, without protocol-mandated endotype-guided treatment selection.	Diagnostic test: Coronary microvascular function assessment; Comprehensive invasive and non-invasive evaluation of coronary microvascular function used to determine microvascular dysfunction endotype and guide treatment selection.; Other Names: Endotype-guided management; Diagnostic test: Coronary microvascular function assessment; Comprehensive invasive and non-invasive evaluation of coronary microvascular function used to determine microvascular dysfunction endotype without endotype-guided management.; Other Names: Physician-guided standard care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effectiveness of endotype-guided pharmacotherapy for coronary microvascular dysfunction	Comparison of the effectiveness of targeted pharmacotherapy tailored to the specific endotype of coronary microvascular dysfunction versus standard guideline-based pharmacotherapy. Assessment of changes in angina-related health status over time between study groups using the Seattle Angina Questionnaire (SAQ) ranging from 0 to 100, with higher scores indicating better health status and less angina-related limitations.	Assessed at baseline and at 3 months follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic value of selected blood and urinary biomarkers	Assessment whether selected biochemical markers measured in blood and urine are associated with the presence and severity of coronary microvascular dysfunction and whether they provide incremental prognostic information.	12 months
Diagnostic value of echocardiographic coronary velocity flow reserve (CFVR) assessment	Assessment of the diagnostic performance of echocardiographically measured coronary flow velocity reserve in detecting coronary microvascular dysfunction, compared with invasive coronary function testing as the reference standard.	12 months
Six-Minute Walk Test (6MWT) distance	Assessment of changes in functional exercise capacity over time before and after targeted pharmacotherapy.	Assessed at baseline and after 3 months
12-item Short Form health survey (SF-12) score	Assessment of changes in health-related quality of life reflecting physical and mental health status, ranging from 0 to 100, with higher scores indicating better health status, evaluated before and after targeted pharmacotherapy.	Assessed at baseline, after 3 and 6 months
Generalized Anxiety Disorder-7 (GAD-7) score	Assessment of changes in anxiety severity, ranging from 0 to 21, with higher scores indicating greater anxiety severity, evaluated before and after targeted pharmacotherapy.	Assessed at baseline, after 3 and 6 months
EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) index score	Assessment of changes in health-related quality of life including mobility, self-care, usual activities, pain/discomfort and anxiety/depression, ranging from -0.590 to 1.000 (based on values set for Polish population), with higher scores value indicating better health status, evaluated before and after targeted pharmacotherapy.	Assessed at baseline, after 3 and 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk factors for specific endotypes of coronary microvascular dysfunction	To identify clinical, demographic, and biochemical factors associated with the occurrence of individual endotypes of coronary microvascular dysfunction.	12 months
Prevalence of coronary microvascular dysfunction endotypes in the Polish population	Determination of the frequency of individual endotypes of coronary microvascular dysfunction in the studied Polish population and to describe their clinical characteristics.	12 months
Adverse events	Assessment of the incidence and severity of adverse events occurring during the study period, including those related to diagnostic procedures and pharmacotherapy.	3 months

Collaborators and Investigators

• Sponsor: Medical University of Bialystok
• Investigators: Principal Investigator: Sławomir Dobrzycki, MD, PhD, Medical University of Bialystok; Study Chair: Maciej A. Południewski, MD, PhD, Medical University of Bialystok; Study Chair: Emil J. Dąbrowski, MD, PhD, Medical University of Białystok

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: March 23, 2026
• First Submitted That Met QC Criteria: March 23, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: INOCA; ANOCA; coronary microcirculation; angina with non-obstructive coronary arteries; coma.net; coma-net; ischemia with non-obstructive coronary arteries
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia
• Other Study ID Numbers: APK.002.133.2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No