Diagnostic and Clinical Management of Non-Obstructive Myocardial Ischemia in Patients With Long Covid-19 Syndrome and New Onset Chest Pain (L-C INOCA)

May 25, 2026 updated by: Javier Escaned, Fundacion Investigacion Interhospitalaria Cardiovascular

Diagnostic and Clinical Management of Non-Obstructive Myocardial Ischemia in Patients With Long Covid-19 Syndrome and New Onset Chest Pain: the Long Covid-19 INOCA Trial

Long Covid-19 INOCA is an investigator-initiated, prospective, randomized, sham-controlled, single center study. Its objective is to investigate the benefits of tailored medical therapy according to the results of the coronary functional testing (CFT) against the routine standard of care and the prevalence and endotypes of ischemia with non-obstructive coronary arteries (INOCA) in patients with long covid-19 syndrome (LCS) and new onset chest pain. All LCS patient with new onset of chest pain will be enrolled. Invasive coronary angiogram and epicardial physiological assessment will be performed to exclude significant epicardial coronary artery disease. Patients without significant epicardial coronary artery disease will undergo CFT which include Acetylcholine test and Coronary microvascular function test. Patients will be randomized into 2 groups: 1) tailored treatment group guided by the results of CFT (intervention) and 2) the routine standard of care group (sham). All patients will undergo the angina symptom and the quality-of-life (QoL) assessment at baseline, 3, and 12 months using the Seattle Angina Questionnaire (SAQ). In the sham group, patients and physicians will be blinded to the results of coronary functional testing for 3 months. Treatment of INOCA will be provided in both groups. The main hypothesis of the Long-Covid INOCA study states that, in LCS patients with chest pain, treatment guided by CFT will demonstrate better angina symptom control and improvement in quality of life (QoL) comparing to the routine standard of care.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Long Covid-19 INOCA is an investigator-initiated, prospective, randomized, sham-controlled, single center study intended to compare the benefits in angina symptom and Quality of Life assessed by the Seattle Angina Questionnaire (SAQ) between tailored medical therapy guided by the results of the coronary functional testing (CFT) and the routine standard of care in patient with LCS and new onset of chest pain. Secondary objective is to investigate the prevalence and endotypes of INOCA in LCS patients with chest pain. This study will be conducted at Hospital Clínico San Carlos, Madrid, Spain.

All patients with the history of SARS-CoV-2 infection, either with acute infection confirmed by PCR or antigen testing, or with past infection demonstrated by serological testing, with symptoms suggestive of LCS such as post exertional malaise, persistent fatigue, difficulty concentrating or shortness of breath who present with typical angina or angina equivalent chest pain starting after SARS-CoV2 infection will be enrolled in this study.

After obtaining patient's informed consent. patients will be randomized by simple randomization in a 1:1 ratio using a central online module to 1) tailored treatment guided by the results of CFT (intervention) or 2) the routine standard of care treatment (sham). All patients will undergo an invasive coronary angiogram as a first step. Patients with severe epicardial coronary artery stenosis define by stenosis ≥ 90% by angiogram will be excluded for further testing. Patients with intermediate coronary artery stenosis will undergo a wire-based physiological assessment of epicardial stenosis. If there is a significant epicardial coronary artery disease defined by fractional flow reserve (FFR) ≤ 0.80 or non-hyperemic pressure ratio (NPHR) ≤ 0.89, the patients will be excluded for further testing. In patients without significant epicardial coronary artery disease, coronary functional testing which include coronary microvascular dysfunction test and Acetylcholine test will be performed. Both tests will be performed in a standard fashion according to the protocol from the guidelines. The results of the CFT will be reported as follow: 1) normal coronary functional testing 2) vasomotor disorder (including both epicardial and microvascular) 3) coronary microvascular dysfunction (including both structural and functional) and 4) combined vasomotor disorder and coronary microvascular dysfunction.

All patients will receive the medications for treatment of INOCA at an out-patient clinic. In intervention group, patient and physician will receive the CFT's results and medications will be prescribed according to patient's type of INOCA and follow with the recommendations in the EAPCI Consensus Document on INOCA and ESC Guidelines. In sham group, patient and physician will be blinded from the CFT's results for 3 months and medications will be prescribed according to physician's decision during this period. After 3 months, the CFT's result will be given to all patients and the treatment will follow with the recommendations from the guideline. Angina symptom and Quality of life in both groups will be assessed by the Seattle Questionnaire of Angina (SAQ), Duke Activity Status Index (DASI) and Euro-Quality of life 5D (EQ-5D) at baseline and each follow up which will occur at 3, and 12 months.

Study Type

Interventional

Enrollment (Estimated)

108

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
    • Madrid
      • Madrid, Madrid, Spain, 28005
        • Hospital Clinico San Carlos

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

- All patients with the history of SARS-CoV-2 infection, either with acute infection confirmed by PCR or antigen testing, or with past infection demonstrated by serological testing, with symptoms suggestive of LCS such as post exertional malaise, persistent fatigue, difficulty concentrating or shortness of breath who present with typical angina or angina equivalent chest pain starting after SARS-CoV2 infection

Exclusion Criteria:

  • Previously been diagnosed with coronary artery disease
  • Severe left ventricular systolic dysfunction (LVEF) < 30%
  • Any moderate to severe concomitant structural heart disease (e.g. moderate to severe valvular heart abnormalities, severe left ventricular hypertrophy)
  • Severely reduced renal function (glomerular filtration rate < 30 ml/min/1.73m2)
  • Contraindications to the administration of Adenosine or Acetylcholine
  • A life expectancy of less than 2 years

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Intervention
Treatment of INOCA guided by the results of the coronary functional testing during the entire follow up period (12 months)
Diagnostic test: Coronary functional test
CFT will be reported as follow: 1) normal coronary functional testing 2) vasomotor disorder (including both epicardial and microvascular) 3) coronary microvascular dysfunction (including both structural and functional) and 4) combined vasomotor disorder and coronary microvascular dysfunction.
Sham Comparator: Sham
Treatment of INOCA by the routine standard of care for the first 3 months and guided by the results of the coronary functional testing during the rest of the follow up period (9 months)
Diagnostic test: Coronary functional test
CFT will be reported as follow: 1) normal coronary functional testing 2) vasomotor disorder (including both epicardial and microvascular) 3) coronary microvascular dysfunction (including both structural and functional) and 4) combined vasomotor disorder and coronary microvascular dysfunction.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The changes in angina symptom and quality of life assessed by Seattle Questionnaire of Angina score in the treatment guided group comparing to the standard of care group
Time Frame: From the date of enrollment to the end of follow up period at 12 months
The Seattle Angina Questionnaire (SAQ) measures 5 dimensions of coronary artery disease (physical limit, stability, frequency, satisfaction, disease perception) on a 0-100 scale, where higher scores indicate better health status. Scores are interpreted as: 0-24 (Poor), 25-49 (Fair), 50-74 (Good), 75-100 (Excellent).
From the date of enrollment to the end of follow up period at 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The prevalence and type of INOCA in LCS patients with chest pain
Time Frame: From the date of enrollment to the last follow up period at 12 months
INOCA can be diagnosed by Functional coronary testing if there is an evidence of vasomotor disorder (Epicardial or microvascular) from acetylcholine test and/or coronary microvascular dysfunction defined by coronary flow reserve less than 2.5 during hyperemia.
From the date of enrollment to the last follow up period at 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fundacion Investigacion Interhospitalaria Cardiovascular

Collaborators

Instituto de Salud Carlos III

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 2, 2021

Primary Completion (Actual)

April 30, 2025

Study Completion (Estimated)

June 30, 2026

Study Registration Dates

First Submitted

April 28, 2026

First Submitted That Met QC Criteria

April 28, 2026

First Posted (Actual)

April 30, 2026

Study Record Updates

Last Update Posted (Actual)

May 28, 2026

Last Update Submitted That Met QC Criteria

May 25, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PI21/01481

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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