Coronary Heart Disease
Conditions
Keywords
Coronary Heart Disease, Ischaemic Heart Disease, Angina, Cardiac Magnetic Resonance Imaging
Brief summary
CE-MARC 2 is a randomised controlled trial to determine diagnosis and patient management in patients presenting to outpatient clinics with suspected stable angina. Cardiac Magnetic Resonance Imaging (at 3Tesla) will be evaluated prospectively against current best clinical practice (defined by international guidelines). The study hypothesis is that 3Tesla CMR-guided management of patients with suspected stable angina is superior to current clinical practice based on 1) the principles of the National Institutes for Clinical Excellence (NICE) CG95 guidelines (2010); 2) SPECT AHA appropriateness criteria, in terms of avoiding study-defined unnecessary invasive coronary angiography.
Detailed description
The study is a randomized controlled trial of non-invasive imaging to determine diagnosis and management of patients presenting with suspected stable angina. Despite the widespread availability of non-invasive imaging and guideline-enshrined use of optimal medical therapy (OMT), patients with suspected coronary heart disease (CHD) often end up having invasive coronary angiography early in their disease course. Currently \>50% of elective invasive coronary angiograms performed in the UK and US do not lead on to a revascularisation procedure (data from 2008-09 UK Hospital Episode Statistics; American College of Cardiology National Cardiovascular Data Registry (Patel MR, et al., N Engl J Med 2010;362:886-95)). The UK NICE guidelines for the management of chest pain of recent onset (CG95; 2010) could increase this proportion even further. This is inefficient for patients and also of healthcare resources. More widespread use of non-invasive functional imaging could reduce the rates of unnecessary angiography. We have shown in the CE-MARC study (Lancet 2012) that cardiovascular magnetic resonance (CMR) at 1.5Tesla has a higher diagnostic accuracy for the detection of CHD than single-photon emission computed tomography (SPECT). CE-MARC 2 will be a three-way randomised controlled trial of patient management in 1200 patients with known or suspected CHD, comparing 3Tesla CMR to SPECT-guided care or NICE guidelines-based management. The primary endpoint will be the reduction of unnecessary invasive angiography (defined by invasive FFR) at 12 months - identified by our expert patients as an important 'patient focused' clinical outcome measure. The secondary objectives will include: 1) assessment of safety of a CMR-guided management strategy 2) cost effectiveness analysis of these strategies.
Interventions
OTHER3T CMR
3Tesla Cardiac Magnetic Resonance Imaging
OTHERSPECT
SPECT: Single Photon Emission Computed Tomography
OTHERCT calcium score
CT calcium score
CT coronary angiography
OTHERX-Ray coronary angiography
X-Ray coronary angiography
Sponsors
University of Leicester
University of Glasgow
British Heart Foundation
University of Leeds
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient ≥30yrs * Patient has suspected stable angina (CHD) that requires further investigation * Has a defined risk of 10-90% (according to NICE guidelines CG95; 2010) * Suitable for revascularisation if required * Given informed written consent
Exclusion criteria
* Non-anginal chest pain * Clinically unstable * Previous MI or biomarker positive ACS * Previous revascularisation with coronary artery bypass surgery or PCI * Contraindication to CMR imaging (pacemaker, intra-orbital debris, intra-auricular implants, intracranial clips, severe claustrophobia) * Contraindication to adenosine infusion (regular adenosine antagonist medication, significant reversible airways disease, second or third degree atrio-ventricular heart block, sino-atrial disease) * Known adverse reaction to Adenosine or Gadolinium contrast agent * Obesity (where body girth exceeds scanner diameter) * Pregnancy or breast feeding * Inability to give informed consent * Known chronic renal failure (eGFR \<30mL/min/1.73m2)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Unnecessary Invasive Coronary Angiography | 12 months | * A negative FFR and positive non-invasive test (either 3T CMR or SPECT/CCT) * A negative FFR in a high pre-test risk (61-90%) patient that proceeds directly to invasive angiography in the NICE guidelines-based strategy arm * A negative FFR and a negative non-invasive test (either 3T CMR or SPECT/CCT) (i.e. a True Negative strategy result in which the imaging result was 'not believed' by the treating cardiologist) * An inconclusive non-invasive test result (either 3T CMR or SPECT/CCT) in which angiography had to be performed to make the diagnosis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiovascular Event (MACE) | at 12 months | MACE is defined as one of the following: * Death due to cardiovascular cause (including type 3 MI) † * Myocardial infarction† * Unplanned revascularisation * Hospital admission for cardiovascular cause \[ACS Troponin -ve, spontaneous myocardial infarction (Type 1)†, Myocardial infarction secondary to ischaemic imbalance (Type 2) †, Myocardial Infarction related to stent thrombosis (Type 4b) †, Arrhythmia, Stroke, Heart failure\]. † As defined by the third universal definition of myocardial infarction. |
| Positive Angiogram (by FFR) Rate for Each Strategy. | 12 months | The Positive Angiogram rate will be determined from the proportion of patients in the relevant population who undergo an angiogram within 12 months of randomisation which yields a positive finding by FFR (or QCA where no FFR reading is undertaken) |
| Cost Effectiveness Analysis | 3 years | To assess the long term cost-effectiveness of the alternate diagnostic testing strategies, information from the trial will be used to update the economic model developed as part of the original CE-MARC trial. The model will use information from the trial, including on resource use, costs, HRQoL and other clinical outcomes (e.g. on unnecessary tests and MACE events), together with epidemiological, clinical and economic data from other sources to calculate costs and quality-adjusted life-years (QALYs) for patients. The economic analysis will use methods consistent with those recommended by the National Institute for Health and Clinical Excellence (NICE). Given the potential difference between diagnostic strategies in terms of mortality, the modelling will adopt a lifetime time horizon to capture any difference. |
| Health-related Quality-of-life Measures (SAQ-UK; SF12; EQ-5D) | 3 years | Health-related quality-of-life (HRQoL) will be measured at baseline (in clinic), 6 months, 12 months, 2yrs and 3yrs (by post), using the following validated questionnaires: * Seattle Angina Questionnaire (SAQ) - UK version * SF12v2 * EuroQol (EQ-5D) |
| Complications | 3 years | Complications - investigational or procedural related only. All complications from all study procedures/investigations will be recorded and reported if they result in an extended length of stay or specific treatment. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 3T CMR-guided Management Patient to be managed according to the results of 3T CMR imaging
3T CMR: 3Tesla Cardiac Magnetic Resonance Imaging
X-Ray coronary angiography: X-Ray coronary angiography
Patients with suspected angina pectoris were eligible if they were 30 years or older, had a CHD pretest likelihood of 10% to 90%, and suitable for revascularization. Exclusion criteria included nonanginal chest pain, a normal MPS or cardiac computed tomography (CCT) result within the previous 2 years, being clinically unstable, previous myocardial infarction, previous coronary revascularization, and contraindication to any study noninvasive imaging test . | 481 |
| SPECT-guided Management Patients to be managed according to the results of SPECT
SPECT: SPECT: Single Photon Emission Computed Tomography
X-Ray coronary angiography: X-Ray coronary angiography
Patients with suspected angina pectoris were eligible if they were 30 years or older, had a CHD pretest likelihood of 10% to 90%, and suitable for revascularization. Exclusion criteria included nonanginal chest pain, a normal MPS or cardiac computed tomography (CCT) result within the previous 2 years, being clinically unstable, previous myocardial infarction, previous coronary revascularization, and contraindication to any study noninvasive imaging test . | 481 |
| NICE-guidelines Based Management Patients will be receive NICE-guidelines based management and will receive the imaging strategy specified by NICE according to their pre-test likelihood of having CHD.
10-29% - CT calcium score +/- CT coronary angiography; 30-60% - SPECT; 61-90% - X-Ray coronary angiography
SPECT: SPECT: Single Photon Emission Computed Tomography
CT calcium score: CT calcium score
Patients with suspected angina pectoris were eligible if they were 30 years or older, had a CHD pretest likelihood of 10% to 90%, and suitable for revascularization. Exclusion criteria included nonanginal chest pain, a normal MPS or cardiac computed tomography (CCT) result within the previous 2 years, being clinically unstable, previous myocardial infarction, previous coronary revascularization, and contraindication to any study noninvasive imaging test .
CT coronary angiography: CT coronary angiography
X-Ray coronary angiography: X-Ray coronary angiography | 240 |
| Total | 1,202 |
Baseline characteristics
| Characteristic | 3T CMR-guided Management | SPECT-guided Management | NICE-guidelines Based Management | Total |
|---|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 9.1 | 55.9 years STANDARD_DEVIATION 8.87 | 56.5 years STANDARD_DEVIATION 9.21 | 56.3 years STANDARD_DEVIATION 9.03 |
| Sex: Female, Male Female | 227 Participants | 225 Participants | 112 Participants | 564 Participants |
| Sex: Female, Male Male | 254 Participants | 256 Participants | 128 Participants | 638 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 481 | 0 / 481 | 2 / 240 |
| serious Total, serious adverse events | 15 / 481 | 15 / 481 | 6 / 240 |
Outcome results
Primary
Number of Participants With Unnecessary Invasive Coronary Angiography
* A negative FFR and positive non-invasive test (either 3T CMR or SPECT/CCT) * A negative FFR in a high pre-test risk (61-90%) patient that proceeds directly to invasive angiography in the NICE guidelines-based strategy arm * A negative FFR and a negative non-invasive test (either 3T CMR or SPECT/CCT) (i.e. a True Negative strategy result in which the imaging result was 'not believed' by the treating cardiologist) * An inconclusive non-invasive test result (either 3T CMR or SPECT/CCT) in which angiography had to be performed to make the diagnosis
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3T CMR-guided Management | Number of Participants With Unnecessary Invasive Coronary Angiography | 36 Participants |
| SPECT-guided Management | Number of Participants With Unnecessary Invasive Coronary Angiography | 34 Participants |
| NICE-guidelines Based Management | Number of Participants With Unnecessary Invasive Coronary Angiography | 69 Participants |
Secondary
Complications
Complications - investigational or procedural related only. All complications from all study procedures/investigations will be recorded and reported if they result in an extended length of stay or specific treatment.
Time frame: 3 years
Secondary
Cost Effectiveness Analysis
To assess the long term cost-effectiveness of the alternate diagnostic testing strategies, information from the trial will be used to update the economic model developed as part of the original CE-MARC trial. The model will use information from the trial, including on resource use, costs, HRQoL and other clinical outcomes (e.g. on unnecessary tests and MACE events), together with epidemiological, clinical and economic data from other sources to calculate costs and quality-adjusted life-years (QALYs) for patients. The economic analysis will use methods consistent with those recommended by the National Institute for Health and Clinical Excellence (NICE). Given the potential difference between diagnostic strategies in terms of mortality, the modelling will adopt a lifetime time horizon to capture any difference.
Time frame: 3 years
Secondary
Health-related Quality-of-life Measures (SAQ-UK; SF12; EQ-5D)
Health-related quality-of-life (HRQoL) will be measured at baseline (in clinic), 6 months, 12 months, 2yrs and 3yrs (by post), using the following validated questionnaires: * Seattle Angina Questionnaire (SAQ) - UK version * SF12v2 * EuroQol (EQ-5D)
Time frame: 3 years
Secondary
Major Adverse Cardiovascular Event (MACE)
MACE is defined as one of the following: * Death due to cardiovascular cause (including type 3 MI) † * Myocardial infarction† * Unplanned revascularisation * Hospital admission for cardiovascular cause \[ACS Troponin -ve, spontaneous myocardial infarction (Type 1)†, Myocardial infarction secondary to ischaemic imbalance (Type 2) †, Myocardial Infarction related to stent thrombosis (Type 4b) †, Arrhythmia, Stroke, Heart failure\]. † As defined by the third universal definition of myocardial infarction.
Time frame: at 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3T CMR-guided Management | Major Adverse Cardiovascular Event (MACE) | 20 Participants |
| SPECT-guided Management | Major Adverse Cardiovascular Event (MACE) | 17 Participants |
| NICE-guidelines Based Management | Major Adverse Cardiovascular Event (MACE) | 4 Participants |
Secondary
Positive Angiogram (by FFR) Rate for Each Strategy.
The Positive Angiogram rate will be determined from the proportion of patients in the relevant population who undergo an angiogram within 12 months of randomisation which yields a positive finding by FFR (or QCA where no FFR reading is undertaken)
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3T CMR-guided Management | Positive Angiogram (by FFR) Rate for Each Strategy. | 47 Participants |
| SPECT-guided Management | Positive Angiogram (by FFR) Rate for Each Strategy. | 42 Participants |
| NICE-guidelines Based Management | Positive Angiogram (by FFR) Rate for Each Strategy. | 29 Participants |