Elevated Copeptin Levels in Acute Headache May Signify More Serious Etiology

gloved hand holding blood test in lab
gloved hand holding blood test in lab
Although it requires further validation, copeptin may serve as a novel biomarker to help rule out serious secondary headache.

Elevated copeptin levels may signify more serious underlying causes of headaches presenting in the emergency department, and may be a promising biomarker for risk stratification, according to a study published in the Journal of Headache and Pain.1 High copeptin levels consistently correlated with headaches secondary to potentially life-threatening conditions requiring immediate intervention.

Copeptin is a stress hormone activated by the hypothalamic-pituitary-adrenal system, along with vasopressin and cortisol. As a precursor protein to vasopressin and a critical regulator of water homeostasis and osmoregulation that is difficult to measure because of its pulsating nature, copeptin provides a reliable and sensitive surrogate marker for elevated vasopressin release.2-3 Copeptin levels have been used in a number of serious disease states as a prognostic indicator for myocardial infarction or ischemic stroke, which suggests it might also be effective in distinguishing serious acute headache from benign headache.4-6

The current study evaluated 3-month outcomes in 391 patients (146 men/245 women; median age, 41 years) admitted to 2 Swiss tertiary care hospitals between October 2010 and March 2013 for acute nontraumatic headache complaints. Copeptin levels were measured from blood samples drawn on admission. At discharge, 56.0% of patients were diagnosed with primary headache (n=219) compared with 44.0% (n=172) with secondary headache, of which 19.2% (n=75) were serious.

At a median 99-day follow-up, 2 patients had died and 7 were lost to follow-up. Those remaining in the cohort who were diagnosed with serious headaches were ultimately diagnosed with subarachnoidal hemorrhage (n=8), sinus vein thrombosis (n=7), intracranial hemorrhage (n=10), viral meningitis (n=7), cerebral tumor (n=6), and cerebral ischemia (n=6). Copeptin levels were highest among patients with the most serious headaches compared with all others (area under the curve, 0.70; 95% CI, 0.63-0.76).

In univariate analysis along with other predictors (age >50 years: odds ratiou [OR], 2.83 [95% CI, 1.69-4.74; P <.0001]; abnormal neurological exam: OR 3.50 [95% CI, 1.99-6.14; P <.0001]; and thunderclap onset of symptoms: OR, 4.23 [95% CI, 2.38-7.52; P <.0001]), copeptin had an OR of 2.03 (95% CI, 1.52-2.70; P <.0001) for serious secondary headache, which remained independently associated with copeptin after adjustment for other risks (OR, 1.74; 95% CI, 1.26-2.39; P =.001). In multivariate analysis compared with fibrinogen and leukocytes, copeptin was the only value to remain associated with serious secondary headache. Although copeptin was not directly associated with mortality or hospitalization, levels were higher in the 2 patients who died than in the survivors.

Notably, sensitivity of copeptin was only 64.4% at the predefined cutoff level of 5.0 pmol/L to rule out serious secondary headache. Lowering the cutoff threshold to 2.5 pmol/L increased sensitivity to 91.8%. Specificity of 95.3% to rule in serious secondary headache was found at the cutoff of 20 pmol/L predefined by the study authors.

The authors concluded that copeptin was not “an ideal marker to identify patients in need of hospitalization” because of the other medical and nonmedical factors involved in that decision. However, they said copeptin “may be a promising novel blood biomarker that should be further validated to rule out serious secondary headache in the emergency department.”


  1. Blum CA, Winzeler B, Nigro N, et al. Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study. J Headache Pain. 2017;18:21. doi: 10.1186/s10194-017-0733-2
  2. Nickel CH, Bingisser R, Morgenthaler NG. The role of copeptin as a diagnostic and prognostic biomarker for risk stratification in the emergency department. BMC Med. 2012;10:7. doi: 10.1186/1741-7015-10-7
  3. Katan M, Morgenthaler N, Widmer et al. Copeptin, a stable peptide derived from the vasopressin precursor, correlates with the individual stress level. Neuro Endocrinol Lett. 2008;29:341-346.
  4. Katan M, Christ-Crain M. The stress hormone copeptin: a new prognostic biomarker in acute illness. Swiss Med Wkly. 2010;24:140:w13101. doi: 10.4414/smw.2010.13101
  5. Reichlin T, Hochholzer W, Stelzig C, et al. Incremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Coll Cardiol. 2009;54:60-68. doi: 10.1016/j.jacc.2009.01.076
  6. Katan M, Fluri F, Morgenthaler NG, et al. Copeptin: a novel, independent prognostic marker in patients with ischemic stroke. Ann Neurol. 2009;66:799-808. doi: 10.1002/ana.21783