Perfusion Estimation For Optimal Treatment Strategy in Chronic Coronary Syndrome (PERFORM-CCS)

Perfusion Estimation for Optimal Revascularization and Medical Therapy in Chronic Coronary Syndrome - a Randomized Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Myocardial Ischemia; Coronary Artery Disease; Stable Angina; Chronic Coronary Syndrome
• Intervention / Treatment: Other: Standard of care; Other: Optimization of guideline-directed medical therapy; Diagnostic test: Immediate referral for invasive coronary angiography; Diagnostic test: 3-months delayed referral for invasive coronary angiography

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.

• Study Type: Interventional
• Enrollment (Anticipated): 570
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jacob H Søby, MD; Phone Number: 0045 61659131; Email: jasoeb@rm.dk

Study Locations

• Denmark
  • Central Denmark Region
    • Herning, Central Denmark Region, Denmark, 7400
      • Recruiting
      • Gødstrup Hospital
      • Contact: Jacob H Søby, MD; Phone Number: 0045 61659131; Email: jasoeb@rm.dk
      • Contact: Morten Böttcher, Prof; Phone Number: 0045 25775134; Email: morboett@rm.dk

Participation Criteria

Eligibility Criteria

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

Description

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

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Cohort study; All patients with symptomatic chronic coronary syndrome undergoing clinically referred [15O]H2O cardiac PET/CT will be included in a prospective cohort with repeated symptom questionnaires and outcomes registered in national registries. A total of 570 patients are expected to be included in order to have 200 randomized patients reaching the 3-month assessment	Other: Standard of care; Standard of care
Experimental: Immediate referral to invasive coronary angiography; Patients with abnormal perfusion on [15O]H2O cardiac PET/CT and clinical indication for invasive coronary angiography randomized to immediate referral for invasive coronary angiography with concomitant optimization of guideline-directed medical therapy. Enrollment will continue until a total of 200 randomized patients reach the 3-month assessment.	Other: Optimization of guideline-directed medical therapy; Consultation every second week with optimization of guideline-directed medical therapy according to 2019 ESC guidelines on chronic coronary syndrome. Focus will be on risk-factor modification and anti-anginal medication with the treatment aim to achieve freedom from angina and dyspnea with a heart rate at rest ≤ 60 beats/min and systolic blood pressure > 100 mmHg.; Diagnostic test: Immediate referral for invasive coronary angiography; Immediate referral for invasive coronary angiography
Experimental: Delayed referral to invasive coronary angiography; Patients with abnormal perfusion on [15O]H2O cardiac PET/CT and clinical indication for invasive coronary angiography randomized to 3-months delayed referral for invasive coronary angiography with concomitant optimization of guideline-directed medical therapy. Enrollment will continue until a total of 200 randomized patients reach the 3-month assessment.	Other: Optimization of guideline-directed medical therapy; Consultation every second week with optimization of guideline-directed medical therapy according to 2019 ESC guidelines on chronic coronary syndrome. Focus will be on risk-factor modification and anti-anginal medication with the treatment aim to achieve freedom from angina and dyspnea with a heart rate at rest ≤ 60 beats/min and systolic blood pressure > 100 mmHg.; Diagnostic test: 3-months delayed referral for invasive coronary angiography; 3-months delayed referral for invasive coronary angiography

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic relief	Seattle Angina Questionnaire-7 angina frequency score = 100 (0-100 with higher scores indicating less frequent angina)	After 3 months following a positive [15O]H2O cardiac PET/CT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Walking capacity	Meters walked in six-minute walking test	3 and 6 months after randomization
Angina frequency	Seattle Angina Questionnaire-7 angina frequency score (0-100 with higher scores indicating less frequent angina)	3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
Physical limitation	Seattle Angina Questionnaire-7 physical limitation score (0-100 with higher scores indicating less physical limitation)	3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
Quality of life-score	Seattle Angina Questionnaire-7 quality of life score (0-100 with higher scores indicating better quality of life)	3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
Health status	Seattle Angina Questionnaire-7 summary score (0-100 where 0 denotes the lowest reportable health status and 100 the highest)	3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
Dyspnea	Rose Dyspnea Scale. Scores range from 0 to 4, where 0 indicates no dyspnea with activity and 4 indicates significant limitations due to dyspnea	3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
Work Ischemic Symptom score	Work Ischemic Symptom score summary score. The scoring system is currently under development.	3, 6, 12, 60, and 120 months after randomization or index [15O]H2O cardiac PET/CT
Hyperemic myocardial blood flow	Global and territorial hyperemic myocardial blood flow (ml/g/min) of perfusable myocardium on [15O]H2O cardiac PET/CT.	3 and 6 months after randomization
Myocardial flow reserve	Global and territorial myocardial flow reserve (unitless measure) on [15O]H2O cardiac PET/CT.	3 and 6 months after randomization
Coronary flow capacity	Coronary flow capacity incorporates hyperemic myocardial blood flow and myocardial flow reserve into a 5-point ordinal scale ranging from myocardial steal indicating very poor coronary flow capacity to normal coronary flow capacity. All data is derived from [15O]H2O cardiac PET/CT.	3 and 6 months after randomization
Coronary revascularization	Percutaneous coronary intervention and/or coronary artery bypass grafting	3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
Coronary revascularization	Percutaneous coronary intervention and/or coronary artery bypass grafting	10 years after randomization or index [15O]H2O cardiac PET/CT
Myocardial infarction	All myocardial infarctions	3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
Myocardial infarction	All myocardial infarctions	10 years after randomization or index [15O]H2O cardiac PET/CT
All-cause mortality	All deaths	3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
All-cause mortality	All deaths	10 years after randomization or index [15O]H2O cardiac PET/CT
Cardiovascular mortality	All cardiovascular deaths	3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
Cardiovascular mortality	All cardiovascular deaths	10 years after randomization or index [15O]H2O cardiac PET/CT
Unstable angina	Unstable angina	3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
Unstable angina	Unstable angina	10 years after randomization or index [15O]H2O cardiac PET/CT
Unplanned hospitalization	Any hospitalization requiring overnight stay not electively planned	3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
Unplanned hospitalization	Any hospitalization requiring overnight stay not electively planned	10 years after randomization or index [15O]H2O cardiac PET/CT
De novo heart failure	New diagnosis of heart failure	3 and 6 months after randomization or index [15O]H2O cardiac PET/CT
De novo heart failure	New diagnosis of heart failure	10 years after randomization or index [15O]H2O cardiac PET/CT
Use of CCTA, MPI, and ICA	Use of coronary CT angiography, myocardial perfusion imaging and invasive coronary angiography	10 years after randomization or index [15O]H2O cardiac PET/CT

Collaborators and Investigators

• Sponsor: Gødstrup Hospital
• Investigators: Principal Investigator: Morten Böttcher, Prof, University Clinic for Cardiovascular Research, Dept. of Cardiology, Gødstrup Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): September 1, 2025

Study Registration Dates

• First Submitted: May 2, 2023
• First Submitted That Met QC Criteria: May 9, 2023
• First Posted (Actual): May 19, 2023

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 23, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Coronary Artery Disease; Myocardial Perfusion Imaging; Myocardial Ischemia; Coronary Angiography; Angina Pectoris; Computed Tomography Angiography
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Disease; Chest Pain; Angina Pectoris; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Syndrome; Ischemia; Angina, Stable
• Other Study ID Numbers: 1-10-72-185-22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be readily available due to Danish legislation. Data can be shared upon reasonable request if a research protocol is submitted to the investigators and approval for data sharing is obtained via Danish authorities.

Drug and device information, study documents

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