Copeptin for Risk Stratification in Non-traumatic Headache in the Emergency Setting - The CoHead Study
Copeptin for Risk Stratification in Non-traumatic Headache in the Emergency Setting - The CoHead Study
Headache is a common symptom, and patients often seek medical attention at emergency
 departments due to headaches.

 The aim of the CoHead Study is to find out if it is possible by measuring copeptin, a marker
 of stress in the blood, to find out which patients have simple headaches and which patients
 have dangerous headaches that are the symptom of an underlying disease and need further
 investigation and treatment.

 Copeptin is a marker for physical stress and has been tested in patients with stroke, heart
 attack and pneumonia. In all these illnesses, the patients with the most serious forms had
 the highest levels of copeptin, while the ones with only mild presentation or no affection at
 all had the lowest levels of copeptin.

 The investigators expect to show the same in patients with headaches.
Background: In the emergency setting, non-traumatic headache (NTH) is in 80% a benign
 symptom, but serious causes have to be ruled out.

 Copeptin, as a surrogate marker for antidiuretic hormone (ADH), is a marker for the
 individual stress level, even more subtle than cortisol. As a prognostic stress hormone it
 holds promise as a prognostic point of care tool in the risk stratification of different
 acute illnesses such as acute myocardial infarction, respiratory tract infections and
 cerebrovascular events, among others.

 Objective: To evaluate copeptin as a marker for risk stratification in NTH. Design:
 Prospective multicenter observational cohort study with a derivation set and a validation
 set.

 Location Setting: Emergency Department (ED) and Medical Policlinic (MUP; walk-in clinic) and
 Neurologic Clinic (NC) of the University Hospital of Basel. ED and NC of the Cantonal
 Hospital of Aarau.

 Intervention: Patients presenting to the ED or the MUP or the NC with NTH are recruited
 during a 1-year-period. After informed consent is given by the patient, baseline data will be
 assessed including medical history, clinical items (i.e. neurological status, vital
 parameters, blood pressure, BMI) and routine laboratory items. Patients will be evaluated
 using a validated standardized diagnostic tool and questionnaire. CT scans and other
 diagnostics, such as lumbar puncture, MRI, etc., will be ordered upon request of the treating
 physician. All diagnostic procedures, results, diagnosis made by the treating physicians and
 initiated therapy will be recorded. Copeptin will be measured on admission by batch analysis
 by blinded laboratory staff upon completion of the study.

 After 3 months, all patients will be followed-up by a structured telephone interview to
 assess the final diagnosis and outcome (i.e. MIDAS-Questionnaire). The final diagnosis will
 be made by two independent physicians according to ICHDII-criteria and verified by a
 board-certified neurologist, all blinded to copeptin levels. Thereby, primary and secondary
 headache entities will be classified according to ICHD.

 Endpoints: The primary endpoint of this study is serious secondary NTH as opposed to benign,
 self-limiting NTH. Serious secondary NTH will be defined as a composite endpoint including
 different secondary NTH causes and entities as listed in the International Classification of
 Headache Disorders (ICHD)-II-Criteria.

 The secondary endpoint will be clinical outcome of patients; thereby we will look at
 all-cause mortality within the 3-month follow-up period and at morbidity measured by the
 MIDAS-questionnaire.

 Study hypothesis: We hypothesize that copeptin will serve as a point of care tool to
 discriminate benign headache from potentially serious secondary headaches (e.g.
 subarachnoidal hemorrhage (SAH) or cerebral aneurysm, intracranial bleeding (ICB), brain
 tumor, vasculitis, meningitis) which require prompt hospitalisation and intervention. Based
 on copeptin values measured in other acute diseases, we assume a critical range between 5 and
 20 pmol/l. The lower copeptin cutoff point of ≤ 5 pmol/l will have a sensitivity of ≥ 97% for
 ruling out serious secondary headache, and the higher cutoff point of ≥ 20 pmol/l will have a
 specificity of 90% to confirm serious NTH.

 Analysis: Based on data of two previous years, we aim to recruit 600 - 800 patients within
 one year at the sites of Basel and Aarau, respectively, of which 10-20% will present with
 serious secondary NTH. We will calculate 95% confidence intervals of sensitivity of copeptin
 of <10% and perform multivariable logistic regression analysis to assess the independent and
 additive utility of copeptin compared with other risk scores and outcome predictors. The
 first 50% of patients will be used as derivation set and the second 50% as the validation
 set, based on the timely inclusion of patients.

 Significance: If copeptin as a biomarker safely rules out serious secondary causes of NTH, it
 will represent a tool for an optimized allocation of health care resources.
Inclusion Criteria:

 -  headache at the time of screening

 -  Patients must be able to give informed consent

 Exclusion Criteria:

 -  less than 18 years of age

 -  preceding (head) trauma