Accelerated Rule Out of Myocardial Infarction
Accelerated Rule Out of Myocardial Infarction
Every year > 50.000 people in Denmark are hospitalized with a suspected acute myocardial
 infarction (AMI). The majority has other explanations of their chest discomfort and most are
 discharged again without any initiation of treatment. Still, the suspicion dictates acute
 ambulance deployment, hospital admission to a highly specialized cardiac unit, cardiac
 surveillance and cardiac troponin blood sampling. The novel biomarker copeptin, a byproduct
 of vasopressin production, is released immediately from the pituitary gland as part of the
 hormonal response to AMI. Peak concentrations are reached within the first hour. Previous
 studies have suggested the combination of copeptin and cardiac troponin for fast and reliable
 rule out of AMI. However, the blood sampling should be performed as soon as possible after
 symptom onset, preferably already during the prehospital phase.

 We aim, in an open randomized setting, to investigate the combined measurement of prehospital
 copeptin and in-hospital high sensitive cardiac Troponin T compared to the standard rule-out
 procedure of suspected myocardial infarction. We hypothesize that the combined measurement of
 prehospital copeptin and in-hospital high sensitive troponin T:

 1. Reduces admission time by 1.5 hours in patients where AMI is ruled out

 2. Reduces the time to disposition

 3. Is non-inferior compared to the standard rule-out procedure in relation to major adverse
 cardiovascular events.

 4. Is more cost efficient compared to standard diagnostic strategy
Patients with suspected Acute Myocardial Infarction (AMI) constitute one of the largest
 patient groups in emergency medicine. The majority of these patients, however, have other
 causes than AMI, for their chest discomfort and many are discharged again without any
 initiation of treatment.(1) At present, cardiac troponin is gold standard in diagnosing AMI.
 Diagnostic levels of troponin are not reached until hours after onset of symptoms and serial
 sampling is recommended at intervals of 3-6 hours to confirm or rule-out AMI. The novel
 biomarker copeptin, a by-product of vasopressin production, is released immediately from the
 pituitary gland as part of the hormonal response to AMI. However, copeptin elevation, is not
 specific of AMI. Peak concentrations of copeptin are reached within the first hour and the
 values normalizes within 4-10 hours.(3) Previous studies have suggested the combination of
 copeptin and high-sensitive cardiac troponin T (hs-cTnT) for early and reliable rule-out of
 AMI.(2,3,6) These studies are based on copeptin measurement in blood sample acquired at
 hospital admission. However, because of the rapid release of copeptin, the blood sampling
 should be performed as early as possible after symptom onset, preferably already in the
 ambulance, whereas the analysis can be performed after arrival at the hospital because
 copeptin is stable. The PREHAB trial conducted in the Central Denmark Region, documented that
 prehospital blood sampling is performed 70 minutes earlier than first in-hospital sample.(5)
 Post-trial analysis of blood samples from the PREHAP trial has demonstrated the potential for
 early and safe rule-out of AMI using the combination of prehospital copeptin and in-hospital
 troponin analysis. AMI could potentially be safely, ruled out in approximately 40-50% of
 patients, in whom the AMI diagnosis eventually was dismissed.

 During the last 7 years, studies have evaluated the effect and validity of prehospital blood
 sample analysis. This is now standard procedure in The Central Denmark Region, Denmark.(5)
 Currently, prehospital blood sampling is carried out in two major randomized studies, aiming
 at identifying patients with myocardial infarction and heart failure (NCT01638806 and
 NCT02050282).

 Unfortunately, there is at present no point-of-care analysis equipment for copeptin
 available. Manufacturer of copeptin analysis equipment, Thermo Fischer, has informed that the
 development of point-care-care equipment is in process, but will not be available in near
 future. Therefore, we will perform in-hospital analysis of the prehospital blood samples.

 Overall aim of this protocol is to demonstrate the combination of troponin T and copeptin as
 a safe and effective biomarker for rule-out of AMI. In a randomized setting, we will compare
 the combination of prehospital copeptin and in hospital hs-cTnT, to the standard diagnostic
 procedure in patients with suspected AMI, evaluating rule-out potential and potential for
 reduction of the length of stay at the hospital. The diagnostic effects of measuring
 copeptin/ hs-cTnT in prehospital vs in-hospital blood samples will be evaluated. Moreover an
 other diagnostic rule-out strategy, using hs-cTNT at admission and 1 hour after admission,
 will be evaluated in retrospective analysis of blood samples acquired from patients in the
 conventional diagnostics arm of the study.

 Primary purposes of the AROMI trial:

 1. To evaluate if early discharge, based in the combined biomarker analysis is associated
 to duration of hospital stay. Will be evaluated in interim analysis after rule out of
 AMI(discharged within 12 hours) in 900 patients (300 patients in each site)

 2. To evaluate if early discharge, based in the combined biomarker analysis is associated
 to major adverse cardiac events (MACE) during index admission, after discharge, within
 30, 90, and 365 days of randomization (separately or in combination). No interim
 evaluation of MACE.

 Secondary purposes of the AROMI trial:

 1. To evaluate if early discharge, based in the combined biomarker analysis is associated
 to time to decision of discharge or continued hospitalization. Will be evaluated in
 interim analysis after rule out of AMI(discharged within 12 hours) in 900 patients (300
 patients in each site)

 2. To evaluate if early discharge, based in the combined biomarker analysis is
 cost-effective regarding satisfaction and safety from a patients perspective.

 3. To evaluate if early discharge, based in the combined biomarker analysis is
 cost-effective from a public perspective, regarding staff resources, costs of hospital
 stay, adherence to the labour market, and use of other healthcare services, Cost benefit
 analysis(CBA).

 4. To evaluate if early discharge, based on the hs-cTnT analysis at arrival and 1 hour
 after arrival at hospital is associated to duration of hospital stay.

 5. To evaluate if early discharge, based on the hs-cTnT analysis at arrival and 1 hour
 after arrival at hospital is associated to MACE(major adverse cardiac event) during
 index admission, after discharge, within 30, 90, and 365 days of randomization
 (separately or in combination).

 6. To evaluate the diagnostic properties (including sensitivity, specificity, negative
 predictive value, and positive predictive value) of the accelerated rule out algorithm
 using copeptin and high sensitivity troponin. Will be evaluated in interim analysis
 after rule out of AMI(discharged within 12 hours) in 900 patients (300 patients in each
 site). Will be evaluated in the total cohort (since both prehospital and inhospital
 copeptin and high sensitivity troponin is available in all patients) and randomization
 will not be revealed during this evaluation.

 7. To evaluate the prognostic value of the accelerated rule out algorithm using copeptin
 and high sensitivity troponin. Will be evaluated in interim analysis after rule out of
 AMI(discharged within 12 hours) in 900 patients (300 patients in each site). Will be
 evaluated in the total cohort (since both prehospital and inhospital copeptin and high
 sensitivity troponin is available in all patients) and randomization will not be
 revealed during this evaluation.
Inclusion Criteria:

 -  Patients which, after telemedical triage, are admitted to a cardiac department in
 suspicions of myocardial infarction

 -  A peripheral venous catheter has been inserted prehospitally and blood has drawn from
 it, before flushing it.

 Exclusion Criteria:

 -  Age below 18 years

 -  Patients in which an informed concent can not be obtained (psychiatric disease,
 dementia, under influence of drugs etc.),

 -  Suspected STEMI and referral to Primary percutaneous coronary intervention (PPCI),
 referral to a highly specialized cardiac department for another cardiac reason (e.g
 ventricular tachycardia, ventricular fibrillation, 3° Atrio-ventricular block.)

 -  Known central Diabetes insipidus

 -  Other diagnosis as obvious reason for symptoms at time of admittance (e.g. a new
 diagnosis of supraventricular tachycardia, pulmonary embolism, aortic dissection) AND
 no suspicions of ACS