Clinical trial NCT02666326: Accelerated Rule Out of Myocardial Infarction
Official title: Accelerated Rule-Out of Acute Myocardial Infarction, Using Copeptin and High Sensitive Troponin T - the AROMI Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Myocardial Infarction
Keywords: Acute Coronary Syndrome
Prehospital emergency care
Biological markers
Copeptin
Troponin
Rule-out
Point-of-Care systems
Infarction
Cardiovascular Diseases
Heart Diseases
Ischemia
Myocardial Ischemia
copeptins
Troponin T
Diagnostic Techniques (Cardiovascular)
High sensitivity troponin
Lead sponsor: Aarhus University Hospital Skejby
Sponsor class: OTHER
First posted: 2016-01-28
Enrollment: 4516
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: 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

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Duration of hospital stay
timeFrame: Up to three months from randomization
measure: Combined MACE
timeFrame: Within time from randomization to 30 days after randomization
Secondary outcomes:
measure: Time to disposition
timeFrame: Within 24 h of randomization
measure: Combined MACE
timeFrame: Within index admission, within time from discharge to 30, 90, and 365 days after randomization, and within time from randomization to 90 and 365 days after randomization
measure: All-cause mortality
timeFrame: Within index admission and within 30, 90 and 365 days of randomization
measure: Survived, cardiac arrest
timeFrame: Within index admission and within 30, 90 and 365 days of randomization
measure: Confirmed diagnosis of ACS or readmission with ACS
timeFrame: Within index admission and within 30, 90 and 365 days of randomization
measure: Non-scheduled coronary intervention
timeFrame: Within index admission and within 30, 90 and 365 days of randomization
measure: Life-threatening arrhythmias
timeFrame: Within index admission and within 30, 90 and 365 days of randomization
Other outcomes:
measure: Cost efficiency
timeFrame: Within index admission, and 1 year after randomization
measure: Risk factors and patient experiences
timeFrame: Within index admission, and 1 year after randomization
measure: Myocardial injury
timeFrame: Within index admission
Locations:
city: Viborg
country: Denmark
facility: Department of Cardiology, Viborg Regional Hospital
state: Central Denmark Region
city: Aarhus
country: Denmark
facility: Department of Cardiology, Aarhus University Hospital
city: Horsens
country: Denmark
facility: Department of Internal Medicine, Horsens Regional Hospital
Study officials:
affiliation: Aarhus University Hospital Skejby
name: Carsten Stengaard, MD, PhD
role: STUDY_CHAIR
affiliation: Viborg Regional Hospital
name: Hanne M Soendergaard, MD, PhD
role: STUDY_CHAIR
affiliation: Aarhus University Hospital Skejby
name: Christian J Terkelsen, MD, DmSc, Associate prof.
role: STUDY_CHAIR
affiliation: Regionshospitalet Horsens
name: Karen K Dodt, MD, PhD
role: STUDY_CHAIR
References:
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citation: Mockel M, Searle J, Hamm C, Slagman A, Blankenberg S, Huber K, Katus H, Liebetrau C, Muller C, Muller R, Peitsmeyer P, von Recum J, Tajsic M, Vollert JO, Giannitsis E. Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study. Eur Heart J. 2015 Feb 7;36(6):369-76. doi: 10.1093/eurheartj/ehu178. Epub 2014 Apr 30.
citation: Pedersen CK, Stengaard C, Sondergaard H, Dodt KK, Hjort J, Botker MT, Terkelsen CJ. A multicentre, randomized, controlled open-label trial to compare an Accelerated Rule-Out protocol using combined prehospital copeptin and in-hospital high sensitive troponin with standard rule-out in patients suspected of acute Myocardial Infarction - the AROMI trial. Trials. 2018 Dec 12;19(1):683. doi: 10.1186/s13063-018-2990-z.