Early Cardiac Magnetic Resonance Imaging in Suspected Non-ST-Elevation Myocardial Infarction
Early Cardiac Magnetic Resonance Imaging in Suspected Non-ST-Elevation Myocardial Infarction
Background and rationale: Evaluating patients with acute chest pain, elevated high-sensitive
 cardiac troponin (hs-cTn) levels and non-diagnostic electrocardiogram (ECG), i.e. suspected
 non-ST elevation myocardial infarction (MI), is a daily challenge. Although contemporary
 hs-cTn assay-based algorithms have greatly facilitated clinical decision-making, still
 one-quarter of patients is categorized as 'observe' group and in whom a diagnosis initially
 remains unknown. Although routinely treated as acute (MI) with referral to invasive coronary
 angiography (ICA), up to one-third does not have obstructive coronary artery disease (CAD).
 Follow-up cardiac magnetic resonance imaging (CMR) has been shown to be a very useful
 diagnostic tool in this setting but is not part of routine clinical care in every patient.

 Objectives: To investigate in patients with suspected non-ST elevation MI meeting the
 'observe' criteria and who are scheduled for ICA: 1) the prevalence of coronary artery
 disease as well as non-coronary artery disease related and extra-cardiac diseases by adding
 CMR early in the diagnostic pathway, and 2) the number of major adverse cardiac events (MACE)
 and a composite of MACE and major (non-cardiac) adverse events after 30 days and one year.
 These objectives allow an accurate estimate of the number of potentially avoidable ICA in the
 future and whether early CMR could be a safe gatekeeper for inappropriate ICA.

 Study population and design: In this prospective, observational two-center study in The
 Netherlands (MUMC+ and VieCuri Medical Center), 87 consecutive patients with acute chest
 pain, non-diagnostic ECG and hs-cTn levels meeting the observe criteria and scheduled for
 ICA, will be investigated. Patients will undergo a comprehensive CMR examination prior to ICA
 and will be followed-up at one month and one year. After completion of follow-up, an
 independent clinical diagnosis committee will adjudicate a final diagnosis: at discharge and
 after one year. The final diagnosis at discharge will be adjudicated twice: once with and
 once without considering the results of CMR. For the diagnosis at one-year, all clinical
 variables and CMR results will be considered. MACE and complications will be scored after 30
 days and one year.

 Main study parameters/endpoints: The primary endpoint is the prevalence of coronary artery
 disease as well as non-coronary artery disease related and extra-cardiac diseases. The
 secondary (safety) endpoint is the number of major adverse cardiac events (MACE) and a
 composite of MACE and major (non-cardiac) adverse events after 30 days and one year.

 Nature and extent of the burden and risks associated with participation, benefit and group
 relatedness:

 CMR is an accepted and safe imaging modality in patients with (suspected) non-ST-elevation
 myocardial infarction.
1. OBJECTIVES 1.1 Primary Objective To investigate the prevalence of coronary artery
 disease as well as non-coronary artery disease related and extra-cardiac diseases in
 patients presenting with acute chest pain, a non-diagnostic ECG and elevated hs-cTn
 levels meeting the 'observe' criteria by using CMR early in the diagnostic pathway and
 at least prior to intended invasive coronary angiography.

 1.2 Secondary Objective

 To investigate in patients presenting with acute chest pain, a non-diagnostic ECG and
 elevated hs-cTn levels meeting the 'observe' criteria and who are scheduled for ICA:

 -  The number of MACE and a composite of MACE and major (non-cardiac) adverse events
 after 30 days and one year.

 -  The diagnostic accuracy of CMR for the diagnosis of obstructive CAD (i.e. stenosis
 ≥70%)

 2. STUDY DESIGN This prospective, two-center observational study will be performed in
 Maastricht University Medical Center (MUMC+) and VieCuri Medical Center, Venlo, The
 Netherlands. Patients visiting the cardiac ED with acute chest pain, a non-diagnostic
 ECG and hs-cTn levels meeting the 'observe' criteria and who are scheduled for ICA are
 eligible. After written informed consent, patients will be included. They will be
 treated according to current guidelines and undergo a comprehensive CMR investigation as
 soon as possible after inclusion but at least prior to an intended ICA (taking into
 account the guideline requirement of performing ICA <72 hours after admission). Early
 CMR will not interfere with routine clinical care and was previously shown to be
 feasible.(16) The interventional cardiologists and treating physicians will be blinded
 for the CMR results since this is not part of current clinical practice. All CMR studies
 will be analyzed in MUMC+ (i.e. core lab) as soon as possible after ICA is performed.
 Only incidental extra-cardiac findings that may significantly change clinical management
 will be reported to the treating physician (i.e. malignancy, massive pulmonary embolism,
 acute aortic dissection, etc.). Also, when a clinical diagnosis remains unknown after
 ICA and only if clinicians explicitly request to perform additional CMR as a clinical
 routine, the results of the early CMR will be provided. Patients will be followed at
 least after 30 days and one-year and normal clinical variables, final diagnosis, total
 number of ICA and outcome (MACE and major (non-cardiac) adverse events) will be
 collected in each patient. After all patients have completed their one-year follow-up,
 an independent final diagnosis committee will adjudicate a final diagnosis. This
 committee will adjudicate a final diagnosis: 1) after the index discharge, and 2) after
 one year. The final diagnosis at discharge will be adjudicated twice by the committee:
 once with and once without considering the results of CMR. For the adjudicated final
 diagnosis at one-year, all clinical variables including the results of CMR will be
 considered.

 3 STUDY POPULATION

 3.1 Population Patients presenting to the cardiac ED with acute chest pain, a non-diagnostic
 ERCG, elevated hs-cTn levels meeting the 'observe' criteria and who are admitted and
 scheduled for an ICA, will be eligible to participate in this study.

 In MUMC+, approximately 4000 patients visit the cardiac ED every year of whom half present
 with acute chest pain.(25) After excluding 15% of patients with ST-Elevation Myocardial
 Infarction (STEMI), 1700 patients with acute chest pain need further evaluation.
 Approximately one-quarter (n=425) meet the 'observe' criteria.(8) Although a rather
 conservative estimate, based on pilot data and previous study results (25), the investigators
 expect that at least 20% of patients (n=90) will be eligible or willing to participate in a
 similar research trial per center. Because the number of cardiac ED visits in VieCuri Medical
 Center is comparable to MUMC+, it is expected that all 87 patients can be included within one
 year after start of the study.

 The study will be performed according to Good Clinical Practice (GCP) guidelines and the data
 will be analyzed and reported in accordance with the CONSORT (Consolidated Standard of
 Reporting Trials) guidelines. Prior to inclusion, patients will be asked to give written
 informed consent.

 3.2 Inclusion criteria

 -  Acute onset (>1 hour) chest pain (or angina pectoris equivalent) suspected of
 non-ST-elevation myocardial infarction (NSTEMI)

 -  Hospital admission and scheduling for ICA

 -  Hs-cTn levels meeting the 'observe' criteria

 -  Age between 18 years - 85 years old

 -  Written informed consent 3.3 Exclusion criteria

 -  Refractory angina or on-going severe ischemia requiring immediate ICA

 -  Patients requiring ICA < 24 hours after admission (see previous bullet)

 -  Hemodynamic instability and/or cardiogenic shock (mean arterial pressure <60 mmHg)

 -  Heart failure (Killip Class ≥ III) requiring intravenously medication (nitroglycerine,
 diuretics, etc.)

 -  ST-Elevation Myocardial Infarction (ST-elevation in 2 contiguous leads: ≥0.2mV in men or
 ≥0.15 mV in women in leads V2-V3 and/or ≥0.1 mV in other leads or new left bundle branch
 block)

 -  Symptoms highly suggestive of non-cardiac origin at presentation (as judged by the
 cardiac ED physician/cardiologist)

 -  Symptoms highly suggestive of AAD, PE, or acute peri-myocarditis

 -  Inability to organize ICA and CMR <72 hours after admission (especially for patients
 admitted on Friday evenings/nights (logistic restrictions).

 -  Life threatening arrhythmias prior to or during presentation (sustained ventricular
 tachycardia, repetitive non-sustained ventricular tachycardia, ventricular fibrillation,
 sinoatrial or atrio-ventricular block)

 -  Atrial fibrillation with persistent ventricular rate ≥100 beats per minute (bpm) after
 treatment

 -  Ongoing tachycardia (≥100/bpm)

 -  Angina pectoris secondary to anemia (<5.6 mmol/L), untreated hyperthyroidism, or severe
 hypertension (>200/110 mmHg)

 -  More than mild aortic and mitral valve calcification or stenosis by latest
 echocardiography

 -  Recent revascularization or ACUTE MI (<6 months)

 -  Known CAD not suitable for further interventions (PCI or CABG)

 -  Pregnancy

 -  Breast feeding women

 -  Life expectancy <1 year (malignancy, etc.)

 -  Refusal of data storage until 15 years after end of study

 -  Participation in another investigational study that has not reached its primary endpoint

 -  Contraindications to CMR:

 ODIN-protocol: "Uitvoering van MRI-onderzoek bij patiënten met een cardiaal implanteerbaar
 elektronisch device (CIED), waaronder een pacemaker en ICD"; ODIN-protocol: "Voorbereiding
 klinische patiënten voor MRI-onderzoek"

 -  Metallic implant (vascular clip, neuro-stimulator, cochlear implant)

 -  Pacemaker or implantable cardiac defibrillator (ICD)

 -  Claustrophobia

 -  Body weight >130 kg or body habitus that does not fit into the gantry

 -  Renal failure (estimated Glomerular Filtration Rate (eGFR) ≤30 mL/min/1,73m2) / chronic
 renal failure stage 4-5

 -  Known severe allergy to gadolinium contrast agents (patient with mild allergy is
 eligible for inclusion when pre-medication according to hospital guidelines can be
 administered)

 • Contraindications to adenosine:

 -  High degree atrio-ventricular block (2nd or 3rd degree)

 -  Severe bronchial asthma

 -  Chronic obstructive pulmonary disease GOLD >=III

 -  Concomitant use of Dipyridamole (Persantin)

 -  Long QT syndrome (congenital)

 3.4 Patient inclusion process Eligible patients need to have acute chest pain (or angina
 pectoris equivalent) for at least one hour, a non-diagnostic ECG and hs-cTn levels meeting
 the 'observe' criteria and need to be admitted and scheduled for ICA. The physician working
 on the cardiac ED will screen patients. When eligible, patients will be informed about the
 study and asked for oral permission to be approached by a member of the research team. Two
 hours after written information is given, the patient is asked to participate. After written
 informed consent, the patient is included in the study.

 3.5 Sample size calculation This is an observational study primarily aiming to investigate
 the prevalence of non-coronary artery and extra-cardiac diseases in patients presenting with
 acute chest pain, non-diagnostic ECG and elevated hs-cTn levels meeting the 'observe'
 criteria (i.e. patients with suspected NSTEMI) and who are scheduled for ICA. Knowing this
 prevalence will help to determine the number of potentially avoidable ICA in the future.

 Based on studies performed in comparable but not similar patients in the conventional
 troponin assay (non-hs-cTn) era, the investigators transpose a prevalence of at least 20%
 having non-obstructive CAD to the current population. This is a rather conservative
 estimation and the prevalence is expected to be even higher in the current high-sensitive
 troponin assay era. Similarly, the investigators transpose the results of additional CMR in
 patients with ST-elevation myocardial infarction and non-obstructive CAD where CMR was
 helpful providing a diagnosis in 70%. Using follow-up CMR in this setting, myocarditis can be
 diagnosed in 34%, (stress) cardiomyopathy in 15%, PE or AAD in 1%, and other diseases in 2%
 of patients. Interestingly, MI or myocardial ischemia can still be diagnosed in 20% of
 patients in the absence of obstructive CAD. CMR is expected to be normal in 25% and
 non-diagnostic in 5%.

 ICA will be considered appropriate when obstructive CAD is found at ICA and, for safety
 reasons, when CMR shows MI or myocardial ischemia despite non-obstructive CAD at follow-up
 ICA (in 20%) or when CMR is non-diagnostic (in 5%). The total proportion of appropriate ICA
 is thus expected to be 85% (i.e. patients with obstructive CAD at ICA [80% of total] + 25% of
 20% of patient with non-obstructive CAD [5% of total]).

 To accurately estimate this proportion of appropriate ICA the investigators aim to include a
 sample large enough so that the total width of the 95% confidence interval does not exceed
 15%, and thus the maximum margin of error (i.e., the half-width of the confidence interval)
 does not exceed 7.5%. Assuming a proportion of 85%, the investigators need to include at
 least 87 patients.

 4 TREATMENT OF SUBJECTS Patients will be treated according to current international
 guidelines and local practice. CMR will be performed as soon as possible prior to ICA (taking
 into account the requirement of ICA <72 hours after admission) and does not interfere with
 routine clinical care.
Inclusion Criteria:

 -  Acute onset (>1 hour) chest pain (or angina pectoris equivalent) suspected of
 non-ST-elevation myocardial infarction (NSTEMI)

 -  Hospital admission and scheduling for ICA

 -  Hs-cTn levels meeting the 'observe' criteria (figure 2, p17)

 -  Age between 18 years - 85 years old

 -  Written informed consent

 Exclusion Criteria:

 -  Refractory angina or on-going severe ischemia requiring immediate ICA

 -  Patients requiring ICA < 24 hours after admission (see previous bullet)

 -  Hemodynamic instability and/or cardiogenic shock (mean arterial pressure <60 mmHg)

 -  Heart failure (Killip Class ≥ III) requiring intravenously medication (nitroglycerine,
 diuretics, etc.)

 -  ST-Elevation Myocardial Infarction (ST-elevation in 2 contiguous leads: ≥0.2mV in men
 or ≥0.15 mV in women in leads V2-V3 and/or ≥0.1 mV in other leads or new left bundle
 branch block)

 -  Symptoms highly suggestive of non-cardiac origin at presentation (as judged by the
 cardiac ED physician/cardiologist)

 -  Symptoms highly suggestive of AAD, PE, or acute peri-myocarditis

 -  Inability to organize ICA and CMR <72 hours after admission (especially for patients
 admitted on Friday evenings/nights (logistic restrictions).

 -  Life threatening arrhythmias prior to or during presentation (sustained ventricular
 tachycardia, repetitive non-sustained ventricular tachycardia, ventricular
 fibrillation, sinoatrial or atrio-ventricular block)

 -  Atrial fibrillation with persistent ventricular rate ≥100 beats per minute (bpm) after
 treatment

 -  Ongoing tachycardia (≥100/bpm)

 -  Angina pectoris secondary to anemia (<5.6 mmol/L), untreated hyperthyroidism, or
 severe hypertension (>200/110 mmHg)

 -  More than mild aortic and mitral valve calcification or stenosis by latest
 echocardiography

 -  Recent revascularization or ACUTE MI (<6 months)

 -  Known CAD not suitable for further interventions (PCI or CABG)

 -  Pregnancy

 -  Breast feeding women

 -  Life expectancy <1 year (malignancy, etc.)

 -  Refusal of data storage until 15 years after end of study

 -  Participation in another investigational study that has not reached its primary
 endpoint

 -  Contraindications to CMR:

 ODIN-protocol: "Uitvoering van MRI-onderzoek bij patiënten met een cardiaal implanteerbaar
 elektronisch device (CIED), waaronder een pacemaker en ICD"; ODIN-protocol: "Voorbereiding
 klinische patiënten voor MRI-onderzoek"

 -  Metallic implant (vascular clip, neuro-stimulator, cochlear implant)

 -  Pacemaker or implantable cardiac defibrillator (ICD)

 -  Claustrophobia

 -  Body weight >130 kg or body habitus that does not fit into the gantry

 -  Renal failure (estimated Glomerular Filtration Rate (eGFR) ≤30 mL/min/1,73m2) /
 chronic renal failure stage 4-5

 -  Known severe allergy to gadolinium contrast agents (patient with mild allergy is
 eligible for inclusion when pre-medication according to hospital guidelines can be
 administered)

 • Contraindications to adenosine:

 -  High degree atrio-ventricular block (2nd or 3rd degree)

 -  Severe bronchial asthma

 -  Chronic obstructive pulmonary disease GOLD >=III

 -  Concomitant use of Dipyridamole (Persantin®)

 -  Long QT syndrome (congenital)