Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease-2 (CE-MARC2)

• Major adverse cardiovascular event (MACE) [ Time Frame: at 12 months and at 3 years ] [ Designated as safety issue: Yes ]

  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. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  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 [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  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) [ Time Frame: 3 years ] [ Designated as safety issue: No ]

  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 [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  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.

• Major adverse cardiovascular event (MACE) [ Time Frame: at 12 months and at 3 years ] [ Designated as safety issue: Yes ]

  MACE is defined as one of the following:

  • Death due to Cardiovascular causes,
  • Myocardial infarction,
  • Unscheduled revascularisation,
  • Hospital admission for cardiovascular cause
  • Myocardial Infarction (STEMI)
  • ACS Troponin +ve (i.e. NSTEMI)
  • ACS Troponin -ve
  • Arrhythmia
  • Stroke
  • Heart failure
• False Negative and True Positive rates for each strategy. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  False Negative (i.e. negative non-invasive test and positive FFR (≤0.80) and True Positive (i.e. positive non-invasive test and positive FFR (≤0.80)) rates for each strategy.
• Cost effectiveness analysis [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  Cost effectiveness analysis
• Health-related quality-of-life measures (SAQ-UK; SF12; EQ-5D) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  Health-related quality-of-life measures (SAQ-UK; SF12; EQ-5D)
• Complications [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  Complications - investigational or procedural related only

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.

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.

• Other: 3T CMR
  3Tesla Cardiac Magnetic Resonance Imaging
• Other: SPECT
  SPECT: Single Photon Emission Computed Tomography
• Other: CT calcium score
  CT calcium score
• Other: CT coronary angiography
  CT coronary angiography
• Other: X-Ray coronary angiography
  X-Ray coronary angiography

• Active Comparator: 3T CMR-guided management
  Patient to be managed according to the results of 3T CMR imaging
  Interventions:

  • Other: 3T CMR
  • Other: X-Ray coronary angiography
• Active Comparator: SPECT-guided management
  Patients to be managed according to the results of SPECT
  Interventions:

  • Other: SPECT
  • Other: X-Ray coronary angiography
• Active Comparator: 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

  Interventions:

  • Other: SPECT
  • Other: CT calcium score
  • Other: CT coronary angiography
  • Other: X-Ray coronary angiography

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)

• University of Leicester
• University of Glasgow
• British Heart Foundation