Clinical trial NCT05865600: Perfusion Estimation For Optimal Treatment Strategy in Chronic Coronary Syndrome
Official title: Perfusion Estimation for Optimal Revascularization and Medical Therapy in Chronic Coronary Syndrome - a Randomized Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Chronic Coronary Syndrome
Myocardial Ischemia
Stable Angina
Coronary Artery Disease
Keywords: Myocardial Ischemia
Angina Pectoris
Coronary Artery Disease
Coronary Angiography
Computed Tomography Angiography
Myocardial Perfusion Imaging
Lead sponsor: Gødstrup Hospital
Sponsor class: OTHER
First posted: 2023-05-19
Enrollment: 570
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All eligible patients are included in a prospective cohort with repeated questionnaires.

Patients with abnormal perfusion and clinical indication for invasive coronary angiography are randomized 1:1 in permuted blocks with random varying sizes of 4,6 and 8 to either immediate invasive coronary angiography or delayed invasive coronary angiography via a standard computerized random-number generator stratified for age ≥70 years and sex (REDcap). Proper concealment of randomization is obtained by the use of an external randomization service (Clinical Trial Unit, Dept. of Clinical Medicine, Aarhus University, Denmark).
Primary purpose: TREATMENT

Brief summary: We will establish a cohort of 570 symptomatic chronic coronary syndrome patients undergoing 15O-water PET and assess their symptoms through repeated questionnaires. Two hundred patients with abnormal perfusion will be randomized to immediate or delayed referral to invasive coronary angiography with concomitant optimization of guideline-directed medical therapy with repeated 15O-water PET and questionnaires at 3 and 6 months. The primary objective is to compare the potential benefit of early invasive coronary angiography (ICA) versus guideline directed medical therapy (GDMT) on symptomatic relief defined as freedom of angina after 3 months following a positive \[15O\]H2O cardiac PET/CT in patients with symptomatic chronic coronary syndrome.

Detailed description: BACKGROUND:

Ischemic heart disease (IHD) is highly prevalent in Western countries and an emerging disease in developing countries around the globe. While the Danish incidence rate of IHD for both females and males has been declining during the last 15 years, the prevalence has stabilized at 165,000 patients in 2018 due to enhanced survival.

Ischemic heart disease is caused by atherosclerotic plaque formation in the epicardial coronary arteries, abnormalities in the coronary microcirculation, spasms in the vessel wall, or a combination thereof. This may result in chest discomfort or dyspnoea leading to frequent primary care consultations and admissions on the suspicion of acute coronary syndrome. To emphasize the chronic nature of the disease, the European Society of Cardiology has replaced the previous nomenclature of stable coronary artery disease with chronic coronary syndrome (CCS) in their latest guidelines from 2019.

When cardiac imaging is used to diagnose and select treatment in patients with CCS, guidelines recommend non-invasive functional imaging modalities in patients with an intermediate or high clinical likelihood of IHD or in patients with prior revascularization. In patients with prior myocardial infarction or percutaneous coronary intervention, studies have found higher diagnostic accuracy of \[15O\]H2O cardiac PET/CT with measurement of absolute quantification of myocardial perfusion to diagnose obstructive coronary artery disease compared with single-photon emission computed tomography and magnetic resonance imaging. Current European guidelines recommend myocardial revascularization in addition to guideline-directed medical therapy (GDMT) in CCS patients with large areas of ischemia (≥ 10%) in the left ventricle to improve prognosis.

Since the publication of these guidelines, a large randomized trial of initial invasive versus conservative strategy in patients with moderate-severe ischemia on stress testing has been published with no observed prognostic benefit of an initial invasive strategy in these patients. However, patients assigned to an initial invasive strategy had a greater improvement in angina-related health status as compared with a conservative strategy, with larger differences observed in patients who were more symptomatic at baseline. The study is limited by the high use of stress ECG (25% of participants) which has a very low diagnostic power and the high proportion of asymptomatic participants at baseline (35%).

It is unknown whether the results of MPI with absolute quantification of myocardial perfusion can improve the selection of patients with an additional symptomatic benefit of an initial invasive strategy compared with GDMT.

METHODS:

Patients with symptomatic CCS referred for clinically indicated \[15O\]H2O cardiac PET/CT will be included in a prospective cohort and assessed with questionnaires at baseline, 3, 6, 12, 60, and 120 months. Clinical outcomes will be assessed through national registries.

Patients with abnormal perfusion and a clinical indication for ICA will undergo coronary CT angiography and a six-minute walking test. Hereafter, they will be randomized 1:1 to immediate referral to ICA or 3 months delayed referral to ICA. Both groups will undergo optimization of GDMT with consultations every two weeks.

At 3 and 6 months, both groups will undergo repeated questionnaires, \[15O\]H2O cardiac PET/CT and a six-minute walking test.

Enrollment in the cohort study and randomized trial will continue until 200 randomized patients have reached the 3 months assessment.

Eligibility criteria: Inclusion Criteria:

1. Age \> 18 years
2. Willing to participate and able to understand, read and sign the informed consent document before the planned procedure
3. Known ischemic heart disease defined as one of the following

   1. Previous myocardial infarction, percutaneous coronary intervention or coronary artery bypass grafting
   2. Previous coronary computed tomography angiography or invasive coronary angiography documenting atherosclerosis.
4. Undergoing clinically indicated \[15O\]H2O cardiac PET/CT due to chest discomfort or dyspnea as angina equivalent

   Additional inclusion criteria for randomized trial:
5. Initial \[15O\]H2O cardiac PET/CT with abnormal perfusion defined as all of the following

   1. Hyperemic myocardial blood flow (hMBF) ≤2.3 mL/min/g in at least two adjacent myocardial segments
   2. Relative hMBF ≤ 65% in at least two adjacent segments as compared with the mean hMBF of the two adjacent segments with the highest mean hMBF
   3. Tissue perfusion defect extent ≥ 5% based on indices of relative hypoperfusion
6. Clinical indication for invasive coronary angiography decided at a multidisciplinary conference between consultants in nuclear medicine and cardiology

Exclusion Criteria:

1. Ongoing acute coronary syndrome or acute coronary syndrome within 30 days
2. Contraindications for adenosine

   1. Severe asthma
   2. Advanced atrioventricular block without pacemaker
   3. Severe aortic stenosis
3. Patients not able to breath hold (severe COPD/asthma)
4. Pregnant women, including women who are potentially pregnant or lactating
5. Allergy to iomeron
6. Life expectancy of less than 2 years
7. Severe valvular disease
8. Reduced kidney function with an estimated glomerular filtrations rate \<40 ml/min
9. Inability to consent

   Additional exclusion criteria for randomized trial:
10. Unprotected left main coronary artery stenosis on coronary CT angiography
11. Very large perfusion defect on initial \[15O\]H2O cardiac PET/CT indicating left main coronary artery stenosis or balanced ischemia defined as tissue perfusion defect extent based on indices of absolute hMBF ≥ 20% in two or more myocardial territories supplied by coronary arteries with an Agatston calcium score ≥ 300

Primary outcomes:
measure: Symptomatic relief
timeFrame: After 3 months following a positive [15O]H2O cardiac PET/CT
Secondary outcomes:
measure: Walking capacity
timeFrame: 3 and 6 months after randomization
measure: Angina frequency
timeFrame: 3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
measure: Physical limitation
timeFrame: 3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
measure: Quality of life-score
timeFrame: 3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
measure: Health status
timeFrame: 3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
measure: Dyspnea
timeFrame: 3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
measure: Work Ischemic Symptom score
timeFrame: 3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
measure: Hyperemic myocardial blood flow
timeFrame: 3 and 6 months after randomization
measure: Myocardial flow reserve
timeFrame: 3 and 6 months after randomization
measure: Coronary flow capacity
timeFrame: 3 and 6 months after randomization
measure: Coronary revascularization
timeFrame: 3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
measure: Coronary revascularization
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
measure: Myocardial infarction
timeFrame: 3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
measure: Myocardial infarction
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
measure: All-cause mortality
timeFrame: 3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
measure: All-cause mortality
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
measure: Cardiovascular mortality
timeFrame: 3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
measure: Cardiovascular mortality
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
measure: Unstable angina
timeFrame: 3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
measure: Unstable angina
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
measure: Unplanned hospitalization
timeFrame: 3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
measure: Unplanned hospitalization
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
measure: De novo heart failure
timeFrame: 3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
measure: De novo heart failure
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
measure: Use of CCTA, MPI, and ICA
timeFrame: 10 years after randomization or index [15O]H2O cardiac PET/CT
Other outcomes:
Locations:
city: Herning
country: Denmark
facility: Gødstrup Hospital
state: Central Denmark Region
Study officials:
affiliation: University Clinic for Cardiovascular Research, Dept. of Cardiology, Gødstrup Hospital
name: Morten Böttcher, Prof
role: PRINCIPAL_INVESTIGATOR
References: