Effect of the Biomarker Copeptin in Managing Patients With Suspected Acute Coronary Syndrome (ACS)

Study Overview
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Brief Summary
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Acute chest pain is commonly known to be the classic symptom of acute myocardial infarction. Of the many patients which visit the Emergency Department because of chest pain, less than half do actually suffer from an acute myocardial infarction or acute myocardial ischemia. In some patients the acute myocardial infarction can be diagnosed at admission, either because of typical changes in their ECG (STEMI, ST-elevation myocardial infarction)or because of increased levels of the laboratory value Troponin in their blood (NSTEMI, Non-ST-elevation myocardial infarction). Troponin is currently the most important marker to diagnose acute myocardial infarction. Unfortunately a lot of patients with suspected acute coronary syndrome do not show any ECG or Troponin changes. These patients pose a major problem in emergency medicine as they need to precautionally be admitted to a chest pain unit and to be started on medical treatment until a second Troponin test after 6-9 hours is available. In this study, we investigate the biomarker Copeptin. Copeptin has shown excellent results in diagnostic clinical trials assessing its use in various acute diseases. There are three important trials showing an excellent negative predictive value of Copeptin in combination with Troponin in patients with suspected acute coronary syndrome (Reichlin et al., JACC, 2009; Keller et al. JACC, 2010, Giannitsis et al. Clin Chem 2011). This trial compares two processes of managing patients with suspected acute coronary syndrome (ACS), the standard process according to current guidelines and the experimental process integrating copeptin as a rule-out marker for acute myocardial infarction into management decisions. Main Hypothesis: Patients with suspected ACS who test negative for Troponin and negative for Copeptin at their initial presentation to the ED can safely be discharged (interventional process). They will not experience more major cardiac adverse events than patients who were managed by standard practise (control process)within 30 days after admission. The Investigators want to test Copeptin in patients with suspected acute coronary syndrome in whom the ECG is unspecific and the initial Troponin test is negative. Further patient care will be based on the Copeptin result. Patients with a negative Copeptin will be discharged into the ambulant care of resident cardiologists.Copeptin positive patients will be managed according to standard guidelines for the management of patients with ACS.

Detailed Description
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The management of patients with suspected Non-ST elevation acute coronary syndrome (NSTEACS) can be time-consuming and expensive. Often patients need to be hospitalized for precautionary medical treatment and serial Troponin testing until further decisions can be made. Copeptin, a 39 amino acid glycopeptide, is the C-terminal portion of Pro-Vasopressin. It is co-secreted from the posterior pituitary gland together with Vasopressin and mirrors the amount of Vasopressin in the circulation. Vasopressin is primarily known as Anti-Diuretic Hormone (ADH), which acts in the kidney to regulate the body's retention of water and in high concentration causes arterial vasoconstriction. Vasopressin is, as a central hormone, also a crucial part of the hypothalamo-pituitary-adrenal axis, which responds to severe, life-threatening stress inputs; its levels reflect the body's individual stress level.Vasopressin itself has a half-life of 5-10 minutes and is therefore difficult to measure in-vivo. Copeptin is secreted stoichiometrically with Vasopressin, it remains stable for days after blood withdrawal and can therefore easily be measured. Copeptin has been studied as a diagnostic and prognostic marker since 2006. In acute myocardial infarction Copeptin levels have been shown to increase early after the onset of symptoms (0-4 hours) and start decreasing after 4-5 hours. In acute myocardial infarction (AMI) Copeptin levels increase early after the onset of symptoms. In patients with suspected ACS Copeptin levels were significantly higher in patients with AMI than in patients with other diagnoses. Copeptin in conjunction with Troponin T was particularly useful as a rule-out marker of AMI. This is a randomized controlled diagnostic trial to quantify the benefit of integrating Copeptin into the management process of patients with NSTEACS and a negative baseline Troponin I test result in the Chest Pain Unit (CPU). Patient management will depend on Copeptin rather than serial Troponin results. Patients will be randomized in either a standard group (management according to current guidelines on managing patients with ACS, Copeptin will be tested, but result will not be revealed to treating personnel) or an interventional group (Copeptin testing, further management dependent on Copeptin result). In this interventional group, patients with a negative baseline Copeptin will be discharged into the ambulant care of co-operating resident cardiologists. Patients with a positive Copeptin result will be treated as by standard care (like patients in the control group). The investigators will assess the efficacy and safety of the new process as compared to the standard process. Secondary endpoints will assess patient satisfaction and length of hospital stay. This study design will not only assess the diagnostic use but also the clinical relevance of Copeptin testing in the ED/CPU. Consecutive N-STEACS patients of the Chest Pain Unit with a negative Troponin I at admission will be invited to participate. Troponin I is tested as part of the standard management of patients with suspected acute coronary syndrome on a point of care test device (POCT). Patients who give their written informed consent will then be randomized into one of two study arms (experimental and standard management) where further management depends on their Copeptin result at admission.

Official Title
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The Effect of Integrating the Biomarker Copeptin Into the Process of Managing Patients With Suspected ACS

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Behavioral: Discharge home


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Typical chest pain (with or without ECG-changes, but no ST-elevation)suggestive of unstable angina or non-ST-elevated myocardial infarction (NSTEMI) Troponin negative at admission according to the current clinical practice Patient willing and able to give written informed consent Exclusion Criteria: Patients with ST-elevation myocardial infarction (STEMI) Continuing chest pain or recurrent episodes of chest pain under therapy High-risk patients with suspected ACS who need to be hospitalized for reasons independent of their initial troponin result Patients who need to be hospitalized for other medical reasons Patients in need of urgent life-saving interventions Patients under 18 years of age Patients with a life expectancy < 6 months Patients with any condition that leads the treating physician to not consider the patient eligible for the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Copeptin<br>Patients who test negative for Copeptin at admission will be considered low-risk and will be discharged home without further interventions. To secure the patients safety they will be transferred into our co-operating network of resident cardiologists using the software Praxis-connect i.e. these patients will be discharged with an electronically booked appointment to see a cardiologist preferably the next day (but latest within the next three days). In case of any findings suggestive of acute coronary syndrome or worsening of the patient's condition, the patient will immediately be re-admitted to our Emergency Room. Patients who test positive for Copeptin will be treated as by standard practise. | Behavioral: Discharge home<br>* Patients who test negative for Copeptin at admission will be considered low-risk and will be discharged home. To secure the patients safety they will be transferred into our co-operating network of resident cardiologists preferably the next day (but latest within the next three days). In case of any findings suggestive of acute coronary syndrome or worsening of the patient's condition, the patient will immediately be re-admitted to our Emergency Room.<br>|
| No Intervention: Standard<br>Patients will be managed as by standard practice abiding current guidelines for the management of patients with suspected ACS.The copeptin result will not be available for the treating physician. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of major adverse cardiac events (MACE) within 30 days Copeptin vs. Control arm. | Rate of MACE (all- cause death or survived sudden cardiac arrest, myocardial infarction, re-hospitalisation for acute coronary syndrome, acute unplanned PCI, coronary artery bypass grafting (CABG) and documented life-threatening arrhythmias (VF, VT, AV-block III)) within 30 days Copeptin vs. Control arm (non-inferiority). | 30 days after discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients in whom coronary angiography (CA) is performed Copeptin vs. Control arm. | Efficacy endpoint Rate of Patients in whom CA is performed Rate of Patients with PCI after Index CA Rate of Patients with CABG after Index CA | within 30 days after discharge | 
| Rate of ALL major adverse cardiac events (MACE) | Rate of ALL MACE at 90 days all- cause death or survived sudden cardiac arrest myocardial infarction re-hospitalisation for acute coronary syndrome acute unplanned PCI coronary artery bypass grafting (CABG) documented life-threatening arrhythmias (VF, VT, AV-block III) | 90 days after discharge | 
| Patient satisfaction regarding management within the ED/CPU | Patient satisfaction regarding management before discharge from ED/CPU | no specific time frame, before discharge | 
| Length of hospital stay | Duration of hospital stay Length of stay at the Emergency Room Length of hospital stay in the CPU Length of stay in an intensive care unit (ICU) Total length of hospital stay in hours including time as an inpatient on other wards | within 30 days after discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Copeptin, Troponin, Acute Coronary Syndrome, Rule-out of acute myocardial infarction, Emergency Medicine