Characterising disease mechanisms in coronary microvascular disease
| ISRCTN | ISRCTN94728379 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN94728379 |
| IRAS number | 288132 |
| Secondary identifying numbers | CPMS 47795, IRAS 288132 |
- Submission date
- 22/01/2021
- Registration date
- 28/01/2021
- Last edited
- 19/02/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English Summary
Current plain English summary as of 22/05/2023:
Background and study aims
Angina is the term used to describe chest pain that is caused by an imbalance between the supply and demand of blood to the heart muscle. The coronary circulation supplies the heart muscle with its blood supply and is made up of large arteries (visible on a special x-ray test called an angiogram) and small arteries (the microvasculature, not visible on an angiogram). Up to 30% of patients with angina have no detectable narrowings in their large arteries but have disease of the small arteries; this is known as coronary microvascular disease (CMD). CMD is associated with poor quality of life, adverse clinical outcomes and an increased cost to the healthcare and social system. It is now possible to assess the small arteries using special techniques during an angiogram. Using these techniques, our group has shown that there may be two distinct subtypes of CMD. Patients with either subtype suffer from an inability to dilate their small arteries in response to stress; this leads to a supply:demand mismatch, leading to angina. However, they have distinct differences in their disease mechanisms and may respond in a disparate manner to different anti-anginal therapy. In this study, we will test the utility of disease characterisation in predicting response to common antianginal therapy in patients with angina and small vessel disease; therefore, assessing the clinical translation of our catheter lab based measurements.
Who can participate?
All adult patients attending for diagnostic coronary angiography for stable angina at St. Thomas’ Hospital who are found to have unobstructed coronary arteries.
What does the study involve?
The protocol will consist of four visits. On the day of the first visit, patients will be requested to undergo a treadmill exercise tolerance test (ETT). We will insert a venous cannula into one of the veins in their arms, through which we will withdraw a small sample of blood to be analysed before and 2 hours after the ETT. The blood tests will be analysed to look for markers of reduced blood supply to the heart before and after exercise. During their visit, patients will be requested to fill out a questionnaire pertaining to their angina symptom burden and quality of life. Their pedometer data will be noted. Patients will then be given a commonly used anti-anginal agent (either amlodipine or ranolazine) and requested to take the medication for four weeks. After 4 weeks, patients will be requested to return for the second visit. They will undergo a repeat ETT, pre-exertion and post-exertion (2 hours post-exertion) blood tests and are requested to fill out a questionnaire as before. Their pedometer data will be noted. They will be given the other commonly used anti-anginal agent (if they were given amlodipine for the first 4 weeks, then they will be given ranolazine, and vice versa) and requested to take the medication for four weeks (after a 1-week washout period). After 4 weeks of taking the medication, they will be requested to return for the third visit. Patients will undergo the final ETT, pre-exertion and post-exertion (2 hours post-exertion) blood tests and requested to fill out a questionnaire as before. Their pedometer data will be noted. Finally, patients will be requested to stop the study medication and return for a final visit 4 weeks later. This will mark the end of the study.
What are the possible benefits and risks of participating?
Benefits: The coronary angiogram with small blood vessel assessment will help provide clarity into patients' diagnosis, which may allow for a more targeted therapeutic approach. The treadmill test and pedometer analysis provide useful information about patients' exercise capacity, and the blood tests may give information on whether there is evidence of reduced blood supply to the heart during exertion.
Risks: Radiation exposure: The placing of the special angioplasty wire for research measurements will lengthen the screening time by up to 5 minutes with resultant small
additional ionizing radiation exposure to form images of your body.
Where is the study run from?
St. Thomas’ Hospital (UK)
When is the study starting and how long is it expected to run for?
October 2020 to January 2024
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Dr Aish Sinha, aish.1.sinha@kcl.ac.uk
Previous plain English summary:
Background and study aims
Angina is the term used to describe chest pain that is caused by an imbalance between the supply and demand of blood to the heart muscle. The coronary circulation supplies the heart muscle with its blood supply and is made up of large arteries (visible on a special x-ray test called an angiogram) and small arteries (the microvasculature, not visible on an angiogram). Up to 30% of patients with angina have no detectable narrowings in their large arteries but have disease of the small arteries; this is known as coronary microvascular disease (CMD). CMD is associated with poor quality of life, adverse clinical outcomes and an increased cost to the healthcare and social system. It is now possible to assess the small arteries using special techniques during an angiogram. Using these techniques, our group has shown that there may be two distinct subtypes of CMD. Patients with either subtype suffer from an inability to dilate their small arteries in response to stress; this leads to a supply:demand mismatch, leading to angina. However, they have distinct differences in their disease mechanisms.
In this study, we will investigate the disease mechanisms underlying the different CMD subtypes using coronary angiogram with special small vessel assessment. We will test our hypothesis of whether one of the CMD subtypes have an inability to augment their blood flow due to dysfunction of enzymes that normally lead to dilation of small arteries. We will also test the utility of our disease characterisation in predicting response to common antianginal therapy in patients with angina and small vessel disease; therefore, assessing the clinical translation of our catheter lab based measurements.
This study will provide a better understanding of the mechanisms that lead to CMD. This knowledge can be used to develop novel therapeutic targets in the future.
Who can participate?
All adult patients attending for diagnostic coronary angiography for stable angina at St. Thomas’ Hospital who are found to have unobstructed coronary arteries.
What does the study involve?
Catheter laboratory protocol: At present, as part of the normal care, patients will be scheduled to have a coronary angiogram with the possibility of pressure recordings made within narrowed arteries (using an angioplasty pressure wire) to help decide the best treatment option (options include stents, medicines, operation). If the large arteries look normal, then they will undergo measurements of the small arteries as part of standard of clinical care. Participants of this study will undergo further assessment of the small arteries in response to the infusion of a safe substance called S-methyl-L-thiocitrulline (SMTC).
Exercise protocol: The exercise protocol will consist of three visits. Four weeks prior to the first visit, patients will be given a pedometer device and requested to wear it so that their daily level of activity can be analysed. On the day of the first visit, patients will be requested to undergo a treadmill exercise tolerance test (ETT). We will insert a venous cannula in to one of the veins in their arms, through which we will withdraw a small sample of blood to be analysed before and two hours after the ETT. The blood tests will be analysed to look for markers of reduced blood supply to the heart before and after exercise. During their visit, patients will be requested to fill out a questionnaire pertaining to their angina symptom burden and quality of life. Their pedometer data will be downloaded and their device reset to factory settings and returned back to them. Patients will then be given a commonly used anti-anginal agent (either Amlodipine or Ranolazine) and requested to take the medication for four weeks. After four weeks, patients will be requested to return for the second visit. They will undergo a repeat ETT, pre-exertion and post-exertion (2 hours post-exertion) blood tests and requested to fill out a questionnaire as before. Their pedometer data will be downloaded and their device reset to factory settings and returned back to them. They will be given the other commonly used anti-anginal agent (if they were given Amlodipine for the first four weeks, then they will be given Ranolazine, and vice versa) and requested to take the medication for four weeks. After four weeks of taking the medication, they will be requested to return for the third visit. Patients will undergo the final ETT, pre-exertion and post-exertion (2 hours post-exertion) blood tests and requested to fill out a questionnaire as before. Their pedometer data will be downloaded. This will mark the end of the study.
What are the possible benefits and risks of participating?
Benefits: The coronary angiogram with small blood vessel assessment will help provide clarity into patients' diagnosis, which may allow for a more targeted therapeutic approach. The treadmill test and pedometer analysis provide useful information about patients' exercise capacity, and the blood tests may give information on whether there is evidence of reduced blood supply to the heart during exertion.
Risks: Radiation exposure: The placing of the special angioplasty wire for research measurements will lengthen the screening time by up to 5 minutes with resultant small additional ionizing radiation exposure to form images of your body.
Where is the study run from?
St. Thomas’ Hospital (UK)
When is the study starting and how long is it expected to run for?
October 2020 to January 2024
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Dr Aish Sinha, aish.1.sinha@kcl.ac.uk
Contact information
Scientific
The Rayne Institute
St. Thomas' Hospital
Westminster Bridge Road
London
SE1 7EH
United Kingdom
| Phone | +44 (0)7828295640 |
|---|---|
| Aish.1.sinha@kcl.ac.uk |
Scientific
St. Thomas' Hospital
Westminster Bridge Road
London
SE1 7EH
United Kingdom
| Phone | +44 (0)2071881048 |
|---|---|
| divaka.perera@kcl.ac.uk |
Study information
| Study design | Prospective randomised phenotype-blinded crossover trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Characterising disease mechanisms in patients with coronary microvascular disease |
| Study acronym | ChaMP-CMD |
| Study hypothesis | Current study hypothesis as of 22/05/2023: 1a. Patients with angina with non-obstructive coronary arteries (ANOCA) and coronary microvascular disease (CMD, defined by a CFR <2.5) will have a greater improvement in their exercise capacity in response to Amlodipine, compared to patients with ANOCA and normal microvascular function (controls, defined by a CFR ≥2.5). 1b. Patients with ANOCA and coronary microvascular disease (CMD, defined by a CFR<2.5) will have a greater improvement in their exercise capacity in response to ranolazine, compared to patients with ANOCA and normal microvascular function (controls, defined by a CFR ≥2.5). 2a. Endotyping CMD will allow the selection of more specific therapies than identifying CMD alone. It is hypothesised that patients with functional coronary microvascular disease (fCMD, defined by a CFR <2.5 and hMR <2.5 mmHg/cm/s) will have a greater improvement in their exercise capacity in response to ranolazine compared to amlodipine. 2b. Patients with structural coronary microvascular disease (sCMD, defined by a CFR <2.5 and hMR ≥2.5 mmHg/cm/s) will have a greater improvement in their exercise capacity in response to amlodipine compared to ranolazine. Previous study hypothesis: 1. Resting coronary blood flow (CBF) in patients with functional coronary microvascular disease (CMD) is elevated due to an upregulation of neuronal nitric oxide synthase (NOS). Intracoronary S-methyl-l-thiocitrulline (SMTC), an nNOS inhibitor, will attenuate the resting CBF in these patients by 16% or more compared to patients with structural CMD 2. Our novel disease characterisation will predict clinical response to commonly used antianginal therapy. Ranolazine and Amlodipine will improve exercise duration by 30 seconds or more, compared to baseline, in patients with functional and structural CMD, respectively, as compared to exercise duration in the other subtype. |
| Ethics approval(s) | Approved 17/12/2020, London - Bromley Research Ethics Committee (Health Research Authority, Skipton House, 80 London Road, London, SE1 6LH, UK; +44 (0)207 104 8063; bromley.rec@hra.nhs.uk), ref: 20/LO/1294 |
| Condition | Coronary microvascular disease |
| Intervention | Current interventions as of 22/05/2023: Patients will be recruited from the catheter laboratory protocol or if they have already had invasive coronary physiology assessment previously. On their first visit of the exercise protocol, patients will undergo treadmill exercise tolerance test (ETT), venepuncture for blood sampling before and after the ETT, complete a validated angina questionnaire (Seattle Angina Questionnaire [SAQ]) and have their pedometer data analysed. Patients will then be requested to take 4 weeks of either amlodipine or ranolazine. After 4 weeks, patients will return for the second exercise protocol visit and undergo the same investigations as above (ETT, pre-exertion and post-exertion blood sampling, angina questionnaire and pedometer data analysis). After this, patients will be requested to cross over to the other drug (either amlodipine or ranolazine) for 4 weeks (after 1 week washout period). After 4 weeks, patients will return for the third exercise protocol visit to have the same assessments carried out as before. Patients will then be requested to stop their study medications and return for the final visit 4 weeks later. This will mark the end of the exercise protocol and the study. Previous interventions: Our study has two protocols. The catheter lab protocol aims to characterise disease mechanisms in the subtypes of CMD and the exercise protocol aims to test the utility of our novel disease characterisation in predicting response to commonly prescribed anti-anginal therapy. Catheter Lab Protocol (as part of routine care with additional research measurements) (visit #1): The catheter lab protocol will involve consenting patients already listed for a coronary angiogram (invasive procedure commonly used to assess the arteries supplying the heart using contrast dye and special xrays). Patients who are found to have visually normal or borderline coronary artery disease will undergo further testing in the form of pressure wire testing. A special wire, termed the Combowire, will be placed in the left anterior descending (LAD) vessel to allow simultaneous pressure and flow measurements, without further manipulation during the protocol. Measurements will be taken following infusions of each of the following substances: adenosine, acetylcholine and S-methyl-Lthiocitrulline (SMTC). The measures of pressure and flow will allow calculation of fractional flow reserve (FFR), coronary flow reserve (CFR), hyperaemic microvascular resistance (hMR) and acetylcholine flow reserve (AChFR). FFR measures the significance of large vessel narrowing, with a value of <0.80 typically suggesting functionally significant disease in the large arteries; this group will not be included in the research protocol and will be treated as per the current clinical guidelines. In patients with an FFR≥0.80, CFR≤2.5 is a means of identifying patients with small vessel disease. Patients with CFR≤2.5 will be subdivided into two subtypes according to their hMR. The differential blood flow response to SMTC between the two subtypes will be assessed. These measurements will all take place in one setting. It is important to mention that measurements of FFR, CFR, hMR and AChFR form part of standard of care for patients with angina and unobstructed large arteries. The research component here is the infusion of SMTC and the measurements made in response to it. Exercise protocol (visit #2-4): For the exercise protocol, patients will be recruited from the catheter laboratory protocol or if they have already been characterised with CMD previously. Patients will be issued with a pedometer four weeks prior to their first visit of the exercise protocol and requested to wear it. On their first visit of the exercise protocol, patients will undergo treadmill exercise tolerance test (ETT), venepuncture for blood sampling before and after the ETT, complete a validated angina questionnaire (Seattle Angina Questionnaire, SAQ) and have their pedometer data analysed. Patients will then be requested to take 4 weeks of either Amlodipine or Ranolazine, which are both commonly used empirical anti-anginal drugs in patients with CMD. After four weeks, patients will return for the second exercise protocol visit and undergo the same investigations as above (ETT, pre-exertion and post-exertion blood sampling, angina questionnaire and pedometer data analysis). After this, patients will be requested to crossover to the other drug (either Amlodipine or Ranolazine) for four weeks. After four weeks, patients will return for the third exercise protocol visit to have the same assessments carried out as before. This will mark the end of the exercise protocol and the study. Patients who have already been characterised with CMD in the catheter laboratory previously can participate in the exercise protocol without having to repeat a coronary angiogram. These patients will receive a separate patient information sheet and consent form. Both of these are attached with the application. We may utilise data from clinically indicated cardiac MRI scans for research purposes. |
| Intervention type | Other |
| Primary outcome measure | Current primary outcome measure as of 22/05/2023: Change in exercise time (in seconds) compared with baseline, measured using an exercise treadmill test at visit 2, visit 3 and visit 4 Previous primary outcome measure: 1. Coronary blood flow will be measured during the coronary angiogram on visit 1 2. Exercise ability will be measured as exercise duration on a treadmill on visits 3 and 4 |
| Secondary outcome measures | Current secondary outcome measures as of 22/05/2023: Change in angina-specific quality of life compared with baseline, measured using the Seattle Angina Questionnaire (SAQ) Summary Score at visit 2, visit 3 and visit 4 Previous secondary outcome measures: Measured at visits 3 and 4: 1. Health-related quality of life measured using The Seattle Angina Questionnaire 2. Step count measured on a pedometer 3. Cardiac biomarkers (high sensitivity troponin T) measured using blood test |
| Overall study start date | 03/10/2020 |
| Overall study end date | 03/01/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 74; UK Sample Size: 74 |
| Total final enrolment | 87 |
| Participant inclusion criteria | 1. All adult patients attending for diagnostic coronary angiography for stable angina at St. Thomas’ Hospital who are found to have unobstructed coronary arteries (epicardial coronary artery stenosis < 30% and/or pressure wire negative stenosis). 2. Tertiary referrals for invasive microvascular assessment of patients with angina and established unobstructed coronary arteries. |
| Participant exclusion criteria | Current exclusion criteria as of 22/05/2023: 1. Patients who are unable or unwilling to consent 2. Contraindications to adenosine 3. Contraindications to amlodipine and/or ranolazine 4. Patients who are already taking the study medications for clinical reasons and are unable to stop them 5. Presence of more than moderate valve disease 6. Previous percutaneous coronary intervention or bypass surgery 7. Known structural heart disease (e.g. cardiomyopathy or congenital heart disease) 8. Pregnant or breastfeeding females 9. Patients who are unable to exercise on a treadmill or those who can exercise for >540 seconds in the absence of any revealed cardiac symptoms on baseline exercise test Previous exclusion criteria: 1. Patients who are unable or unwilling to consent 2. Contraindications to adenosine or acetylcholine (for the catheter laboratory protocol), or amlodipine or ranolazine (for the exercise protocol) 3. Presence of more than moderate valve disease 4. Previous stenting or bypass surgery 5. Heart failure with reduced ejection fraction (LVEF< 50%), cardiomyopathy or congenital heart disease 6. Pregnant or breastfeeding females 7. Patients who are unable to exercise on a treadmill or those who have a good exercise capacity at baseline (>540seconds in men and >480seconds in women) will be excluded from the exercise protocol |
| Recruitment start date | 16/03/2021 |
| Recruitment end date | 16/09/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Sponsor information
University/education
Room 5.31
James Clerk Maxwell Building
London
United Kingdom
United Kingdom
| Phone | +44 (0)20 7848 3224 |
|---|---|
| reza.razavi@kcl.ac.uk | |
| Website | http://www.kcl.ac.uk/index.aspx |
"ROR" |
https://ror.org/0220mzb33 |
Hospital/treatment centre
R&D Department, 16th Floor Tower Wing
Great Maze Pond Road
London
SE1 9RT
England
United Kingdom
| Phone | +44 (0)2071887188 |
|---|---|
| R&D@gstt.nhs.uk | |
| Website | http://www.guysandstthomas.nhs.uk/Home.aspx |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/01/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | All data generated or analysed during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 6.0 | 29/09/2022 | 22/05/2023 | No | No |
| Statistical Analysis Plan | version 1.0 | 26/03/2023 | 22/05/2023 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 02/01/2024 | 19/02/2025 | Yes | No |
Additional files
Editorial Notes
19/02/2025: Publication reference and total final enrolment added.
31/10/2023: Publication reference added.
22/05/2023: The following changes were made to the study record:
1. The study hypothesis, interventions, primary and secondary outcome measures, exclusion criteria and plain English summary were updated.
2. The study acronym was changed from ChaMP to ChaMP-CMD.
3. The study design was changed from 'Interventional non-randomized' to 'Prospective randomised phenotype-blinded crossover trial'.
4. The target number of participants was changed from 78 to 74.
5. Protocol and statistical analysis plan uploaded.
22/01/2021: Trial’s existence confirmed by National Institute for Health Research (NIHR).
