Copeptin as a Marker of Outcome After Cardiac Arrest

A Sub-Study of the TTM Trial

Joachim Düring; Martin Annborn; Tobias Cronberg; Josef Dankiewicz; Yvan Devaux; Christian Hassager; Janneke Horn; Jesper Kjaergaard; Michael Kuiper; Homa Rafi Nikoukhah; Pascal Stammet; Johan Undén; Michael Jaeger Wanscher; Matt Wise; Hans Friberg; Niklas Nielsen


Crit Care. 2020;24(185) 

In This Article

Abstract and Introduction


Background: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest.

Methods: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score.

Results: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06–1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01–1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02–1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12–0.27], p < 0.001.

Conclusion: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure.

Trial registration: Clinical Trials, NCT01020916. Registered November 26, 2009.


Hypoxic ischemic encephalopathy (HIE) is the major determinant of outcome after out-of-hospital cardiac arrest (OHCA).[1] Existing prognostication models are targeted at neurologic functional outcome. Death is biphasic after OHCA with early death (1–3 days) to a large degree related to circulatory failure, while later death (> 3 days) is mainly related to withdrawal of life-sustaining therapy (WLST) due to assumed severe HIE.[2] Patients with a presumed high risk of circulatory-related death may therefore benefit from extended hemodynamic monitoring and support. This is particularly relevant for patients without signs of severe HIE and a potential good long-term outcome. A risk stratification model addressing this topic has recently been presented but did not include the use of biomarkers.[3]

Arginine vasopressin (AVP) is a peptide hormone released from the posterior pituitary gland that increases solute-free water reabsorption in the renal tubules and systemic vascular resistance by constricting selected arterioles. Elevated AVP levels have been shown to correlate with shock[4] and cardiovascular failure.[5–7] Measurement of AVP is challenging because of its short half-life, but it can be replaced by measurement of copeptin (also known as CT-proAVP), the C-terminal proteolytic product of the pre-pro-hormone of AVP. Copeptin has shown to be a reliable surrogate biomarker of vasopressin,[8] and levels are significantly increased at hospital admission in patients with acute coronary syndrome.[9] Also, high copeptin levels are associated with risk of death in patients with cardiovascular failure[10,11] while low levels have been implemented in clinical practice to rule out non-ST-segment acute myocardial infarction.[9,12] Furthermore, copeptin has been suggested as a promising prognostic biomarker after OHCA.[13–16] It is unknown whether the prognostic capabilities of AVP/copeptin are related to cardiovascular failure alone or if copeptin is merely a marker of disease severity. The aim of this exploratory study was to investigate the relationship between early copeptin levels, circulatory failure, and mortality in the setting of OHCA. We hypothesized that (1) early copeptin levels are associated with early mortality and (2) copeptin levels are associated with circulatory failure.