Copeptin (C-terminal pro Arginine-Vasopressin) is an Independent Long-Term Prognostic Marker in Heart Failure with Reduced Ejection Fraction

doi:10.1016/j.hlc.2014.10.008

Heart, Lung and Circulation

Volume 24, Issue 4, April 2015, Pages 359-367

https://doi.org/10.1016/j.hlc.2014.10.008 Get rights and content

Background

The level of copeptin, a stable fragment of pro-arginine-vasopressin (AVP), correlates with disease severity. It is an established, short-term prognostic marker for patients with heart failure with reduced ejection fraction (HFREF). We aimed to examine the association between copeptin and long-term mortality. We also studied the clinical usefulness of copeptin as a prognostic biomarker by analysing the improvement of net reclassification.

Methods

Copeptin concentrations were measured in a cohort of 195 consecutive patients with HFREF. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was recorded after five-year follow-up.

Results

One hundred and ten patients died during the five-year follow-up (five-year mortality rate: 0.56). Univariate analysis identified copeptin (HR 2.168 [95% CI 1.740-2.700]) as a predictor of mortality. The final, multivariable Cox survival model identified a number of independent predictors of death. These included higher NHYA functional class, previous MI, at least one hospitalisation for worsening HF (within the two years before inclusion into the study), elevated blood urea nitrogen, NT-proBNP-, and copeptin levels, as well as increased red blood cell distribution width, and decreased GFR. The addition of copeptin alone to the baseline predictive model (NT-proBNP only) resulted in a minor (8.21%) improvement, whereas the final, multivariable model showed a significant increase in net reclassification (10.26%, p = 0.015).

Conclusions

These data indicate that copeptin is an independent long-term prognostic marker in HFREF, with possible clinical relevance for multimarker risk prediction algorithms.

Section snippets

Background

Neurohormonal activation plays a major role in chronic heart failure (CHF). Natriuretic peptides have been investigated far and wide in CHF, and B-type natriuretic peptide (BNP) has become an established diagnostic and prognostic marker [1]. However, other endocrine mechanisms such as the vasopressin system were also investigated in heart failure. Vasopressin, an antidiuretic and vasoconstrictor hormone is produced in the supraoptic and paraventricular nuclei of the hypothalamus. It is secreted

Patients

This paper describes the post-hoc analysis of a prospectively collected cohort study conducted at the 3^rd Department of Internal Medicine, Semmelweis University (Budapest, Hungary). The study was implemented in compliance with the Helsinki Declaration, and its protocol was approved by the Scientific and Research Ethics Committee of the Medical Research Council, Hungary.

Inclusion criteria: Consecutive patients with clinical signs of CHF, referred for transthoracic echocardiography between

Characteristics of the Patient Population

Baseline clinical and laboratory characteristics of the cohort are shown in Table 1. Males predominated the study population (74.4%) with a median age of 69.5 years. The median of left ventricular ejection fraction (LVEF) was 34% (all values were less than 45%), and the subjects’ baseline status corresponded to New York Heart Association (NYHA) functional classes I to IV. The aetiology of heart failure was ischaemic heart disease in 57.9% of the patients. Concomitant diseases included

Discussion

In this study, we examined the long-term (five-year) prognostic value of copeptin in predicting death in patients with HFREF. Our most important finding is the strong and independent five-year prognostic role of copeptin in HFREF. In the stepwise, multivariable Cox survival model, both copeptin and NT-proBNP were independent predictors of death, even when further adjusted for clinical risk factors. ROC curve analysis is not the best statistical method for comparing the prognostic values of

Conclusion

In this long-term, prospective cohort study conducted in heart failure patients with reduced ejection fraction, we confirmed the independent prognostic value of copeptin for all-cause mortality. A minor, but significant increase in integrated discrimination and net reclassification for copeptin and certain clinical variables was also observed, as compared to NT-proBNP.

Limitations

This was a single-centre study in a population of elderly people with several co-morbidities. Furthermore, the moderate size of the study cohort did not allow for the identification of rare therapeutic modalities as possible predictors of death. Finally, although our study did not establish copeptin as a new, robust biomarker in HF, our data may lend further support to a role for the arginine-vasopressin system in the pathogenesis and treatment of HF. However, this assumption will have to be

Acknowledgement

This work was supported by the National Research Fund (NF72689 Z Prohászka). No other extramural funding was obtained. The authors are solely responsible for the design and conduct of this study, for all study analyses, as well as for the drafting and editing of the manuscript, and for the final content of the submitted paper. We are grateful to our patients for their participation in this study. We acknowledge the skillful technical assistance of Holeczky Rudolfné, Szigeti Antalné, Korponai

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Cited by (38)

Association between copeptin and contrast-induced nephropathy in patients with ST-elevation myocardial infarction
2019, Revista Portuguesa de Cardiologia
The aim of this study was to investigate the predictive value of copeptin levels in the development of contrast-induced nephropathy (CIN).
A total of 274 patients diagnosed with ST-elevation myocardial infarction (STEMI) and who had undergone primary percutaneous coronary intervention were included in the study. The patients were divided into two groups according to the presence (CIN+) or absence (CIN-) of CIN. These groups were compared in terms of demographic characteristics, laboratory findings and risk factors.
Copeptin levels (10.68±6.43 vs. 7.07±05.53 pmol/l; p<0.001) and peak creatinine (1.46±1.20 vs. 1.03±0.20 mg/dl; p=0.005) were significantly higher in the CIN+ group than in the CIN- group. Female gender was significantly more prevalent in the CIN- group compared to the CIN+ group (19% vs. 8.6%; p<0.05). Copeptin level at hospital admission (OR: 2.36, p=0.005) was found to be an independent predictor for CIN development.
Copeptin level is an independent predictor of CIN development in patients with acute STEMI that can be detected rapidly and easily. This result indicates that physicians should be aware of the possibility of CIN development in patients with high copeptin levels and preventive measures should start early.
Análise do valor preditivo dos níveis de copeptina no desenvolvimento da nefropatia induzida por contraste (NIC).
Foram incluídos no estudo 274 doentes, diagnosticados com enfarte do miocárdio com elevação do segmento ST (STEMI) e submetidos a angioplastia coronária primária. Os doentes foram divididos em dois grupos de acordo com a confirmação de NIC. Estes grupos foram comparados quanto às características demográficas, achados laboratoriais e fatores de risco.
O nível de copeptina (10,68±6,43 versus 7,07±5,53; p<0,001) e o pico dos níveis de creatinina (1,46±1,20 versus 1,03±0,20; p=0,005) foram significativamente superiores nos grupos de NIC (+) quando comparados com os grupos de NIC (-). A percentagem do género feminino foi significativamente superior no grupo NIC (-) quando comparada com o grupo NIC (+) (19% versus 8,6%; p<0,05). O nível da copeptina no momento do internamento (OR: 2,36, p=0,005) foi considerado como um valor preditor independente no desenvolvimento da NIC.
O nível da copeptina é um fator preditor independente do desenvolvimento da NIC em doentes com STEMI agudo. Pode ser detetado rápida e facilmente e este resultado indica que os médicos devem ser mais cuidadosos em relação ao desenvolvimento da NIC em doentes com níveis de copeptina levados. Medidas preventivas devem ser tomadas precocemente.
Prognostic value of copeptin in patients with aneurysmal subarachnoid hemorrhage
2019, Journal of Neuroimmunology
Citation Excerpt :
Copeptin was a surrogate marker for vasopressin release and might act as a marker for stress response (Morgenthaler et al., 2006). Copeptin has been proposed as a prognostic marker in many acute illness, such as intracerebral hemorrhage (ICH) (Zhang et al., 2012; Yu et al., 2014; Zweifel et al., 2010), ischemic stroke (De Marchis et al., 2013; Tu et al., 2013), acute myocardial infarction (Lattuca et al., 2019), traumatic brain injury (Choi et al., 2017), cardio-cerebrovascular patients (Sun et al., 2015) and heart failure with reduced ejection fraction (Pozsonyi et al., 2015). Interestingly, one study reported that copeptin level was a useful, complementary tool to predict functional outcome and mortality after aSAH (Zhu et al., 2011), while Fung et al. (Fung et al., 2013) found that copeptin may indicate clinical severity of the initial bleeding and may therefore help in guiding treatment decisions in the setting of aSAH.
Recently, copeptin has been identified as a plasma prognosis marker in acute ischemic stroke and intracerebral hemorrhage (ICH). This study investigated the prognostic value of copeptin in the patients with aneurysmal subarachnoid hemorrhage(aSAH).
In this retrospective study, 243 consecutive patients were included. Upon admission, plasma copeptin levels were measured by enzyme-linked immunosorbent assay. The end points were mortality and poor functional outcome (Glasgow Outcome Scale score of 1–3) after 3 months.
In 243 patients, 112 (46.1%) were male and median age was 58 years (IQR 49–68). Median copeptin plasma levels were 21.0 pmol/l (IQR 13.2–31.2). Copeptin levels increased with increasing severity of aSAH as defined by the World Federation of Neurological Surgeons (WFNS) score. Patients with a poor outcome and nonsurvivors had significantly increased copeptin levels on admission (P < .001 both). In the multivariate analysis, for each 1 pmol/l increase of plasma concentration of copeptin, the adjusted risk of poor outcomes and mortality would be increased by and 6% (1.06 [1.02–1.10], P < .001) and 9% (1.09 [1.03–1.13], P < .001), respectively. Receiver operating characteristics to predict functional outcome and mortality demonstrated areas under the curve of copeptin of 0.74 (95% confidence interval [CI], 0.67–0.81) and 0.81 (95% CI, 0.74–0.87), which was comparable with the WFNS score(P > .05) but superior to C-reactive protein and IL-6 (P < .01).
The data shows that copeptin levels may reliably predict short-term prognosis at its onset in aSAH patients.
Copeptin in heart failure: Review and meta-analysis
2017, Clinica Chimica Acta
Citation Excerpt :
Copeptin is not a superior predictor of all-cause mortality in HF patients, as compared with NT-proBNP. Pozsonyi et al. [31] used ROC analysis to estimate prognostic accuracy of biomarkers'. In the multivariable Cox model, they selected NT-proBNP level as a reference, and found that NT-proBNP level plus copeptin resulted in an improvement of prognostic accuracy with 0.033 in c-statistics, this improvements of prognostic accuracy was marginally significant (P = 0.068).
The aim of this study was to explore the prognostic value of copeptin for predicting all-cause mortality in heart failure (HF).
PubMed, Embase and Cochrane databases were systematically searched to identify if a 2 × 2 contingency table could be constructed based on both the copeptin level and the all-cause mortality in patients diagnosed with HF. The characteristics of test performance were summarized using forest plots and summary receiver operating characteristic curves (SROC). Q-test and I² index were used to evaluate heterogeneity.
Ten prospective cohort studies comprising 4473 patients were eligible in this meta-analysis. An elevated copeptin level was associated with an increased risk of all-cause mortality in HF patients (Relative risk (RR) was 2.64 (95% CI, 2.09–3.32)). The pooled sensitivity (SEN) and specificity (SPE) of copeptin were 0.57 (95% CI, 0.50–0.63) and 0.74 (95% CI, 0.69–0.79), respectively. The positive likelihood ratio was 2.2 (95% CI, 1.90–2.60) and the negative likelihood ratio was 0.58 (95% CI, 0.52–0.66). Furthermore, the summary Diagnostic Odds Ratio (DOR) was 4.00 (95% CI, 3.00–5.00) and the AUC was 0.70 (95% CI, 0.66–0.74) similar to the AUC of NT-proBNP 0.71 (95% CI, 0.67–0.75).
Elevated levels of copeptin are associated with all-cause mortality in HF patients. The predictive value of copeptin is comparable with NT-proBNP for all-cause mortality in HF patients. Further studies are warranted to explore the prognostic value of copeptin in conjunction with other biomarkers and to determine an optimal cut-off level.
Novel Biomarkers of Heart Failure
2017, Advances in Clinical Chemistry
Although substantial improvements have been made in majority of cardiac disorders, heart failure (HF) remains a major health problem, with both increasing incidence and prevalence over the past decades. For that reason, the number of potential biomarkers that could contribute to diagnosis and treatment of HF patients is, almost exponentially, increasing over the recent years. The biomarkers that are, at the moment, more or less ready for use in everyday clinical practice, reflect different pathophysiological processes present in HF.
In this review, seven groups of biomarkers associated to myocardial stretch (mid-regional proatrial natriuretic peptide, MR-proANP), myocyte injury (high-sensitive troponins, hs-cTn; heart-type fatty acid-binding protein, H-FABP; glutathione transferase P1, GSTP1), matrix remodeling (galectin-3; soluble isoform of suppression of tumorigenicity 2, sST2), inflammation (growth differentiation factor-15, GDF-15), renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL; kidney injury molecule-1, KIM-1), neurohumoral activation (adrenomedullin, MR-proADM; copeptin), and oxidative stress (ceruloplasmin; myeloperoxidase, MPO; 8-hydroxy-2′-deoxyguanosine, 8-OHdG; thioredoxin 1, Trx1) in HF will be overviewed.
It is important to note that clinical value of individual biomarkers within the single time points in both diagnosis and outcome prediction in HF is limited. Hence, the future of biomarker application in HF lies in the multimarker panel strategy, which would include specific combination of biomarkers that reflect different pathophysiological processes underlying HF.
The role of postictal laboratory blood analyses in the diagnosis and prognosis of seizures
2017, Seizure
Citation Excerpt :
In ACS, copeptin indicates the presence of myocardial ischemia [151]. As a general stress marker, copeptin displayed mild elevations in perinatal infant stress and in healthy students who were experiencing psychological stress before taking exams [152–174]. In a multicenter, prospective ER study of 389 patients, copeptin levels were found to be elevated after seizures occurred, but they were unable to predict complications such as seizure recurrence, mortality and hospitalizations [175].
Epileptic seizures (ES) lead to alterations in the blood laboratory values and reflect changes in different organ systems. Here, we review the diagnostic and prognostic value of various blood laboratory values within the context of epilepsy.
Narrative review and literature search on PubMed using the term, “seizure” and various laboratory values.
Laboratory markers can help clinicians determine whether an unwitnessed event was more likely to be epileptic or non-epileptic. Prolactin testing helps differentiate ES from psychogenic non-epileptic seizures (PNES) in adults and adolescents, and is associated with high specificity and moderate sensitivity. Elevations in the creatine kinase (CK) levels are common after generalized tonic-clonic seizures (GTCS) and display high specificity and moderate sensitivity. Metabolic markers such as ammonia and lactate may have diagnostic potential for postictal blood tests.
Analyzing blood postictally is important for identifying the cause of the symptomatic seizures due to endocrine, metabolic, toxic or infectious etiologies.
Finally, laboratory analyses are used for identifying patients who are at risk for developing rare, threatening complications such as rhabdomyolysis, acute renal failure (ARF) or cardiomyopathy.
Presently, no postictal laboratory values can definitively prove or rule out the diagnosis of an epileptic seizure. For seizures with unknown causes, simple blood tests can be a valuable aid for quickly defining the etiology, particularly with certain metabolic and toxic encephalopathies. For this reason, CK, electrolytes, creatinine, liver and renal function tests should be measured on at least one occasion. Further research is needed in order to identify new biomarkers that improve the diagnosis and prognosis of seizures and seizure-related complications.
Elevated copeptin is a prognostic factor for mortality even in patients with renal dysfunction
2016, International Journal of Cardiology
Citation Excerpt :
Also in hemodialysis patients with diabetes mellitus, increased copeptin levels show an increased risk for all-cause mortality [23]. Some studies used cutoff copeptin levels which even differ between these studies [7,24] and others analyzed continuous copeptin values [23,25]. In order to use copeptin as a valuable biomarker and predictor in every day practice, uniform cutoff values need to be defined in future prospective trials.
Copeptin has turned out to give valuable prognostic information for future cardiovascular events. However, since its plasma concentration directly depends on renal function, the value of copeptin as a predictor for outcome also in patients with chronic kidney disease (CKD) is unknown.
In this single-center substudy of the German Coronary Artery Disease–REnal Failure (CAD-REF) registry, 301 patients with an angiographically diagnosed stenosis ≥ 50% in at least one major coronary vessel were included. Estimated glomerular filtration rate (eGFR) was determined using the MDRD formula and patients were classified according to their CKD stage. Copeptin concentrations were measured before initial angiography. Follow-up was performed at 180 days, study endpoint was all-cause mortality.
Of the 301 included patients, 35 (11.6%) patients had no CKD, 113 (37.5%) had CKD stage 1 or 2, 117 (38.9%) had CKD stage 3, and 36 (12.0%) had CKD stage 4 or 5. Copeptin was elevated (≥ 14 pmol/L) in 81 (26.9%) patients and normal (< 14 pmol/L) in 220 (73.1%) patients. Copeptin values significantly increased with decreasing eGFR (p < 0.001) and were strongly correlated with creatinine values (r = 0.567, p < 0.001). During 180 days of follow-up, 15 patients (5.0%) died, 10 of them with elevated copeptin values. Multivariate Cox regression analysis showed that copeptin was the sole predictor for mortality (HRR 5.317 (95% CI 1.653–17.098), p = 0.005), independent of serum creatinine.
Elevated copeptin can be used as a valuable prognostic factor for intermediate-term mortality in patients with both coronary artery and renal disease.

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Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Ltd. All rights reserved.

Original ArticleCopeptin (C-terminal pro Arginine-Vasopressin) is an Independent Long-Term Prognostic Marker in Heart Failure with Reduced Ejection Fraction

Background

Methods

Results

Conclusions

Section snippets

Background

Patients

Characteristics of the Patient Population

Discussion

Conclusion

Limitations

Acknowledgement

Am J Med.

J Am Coll Cardiol.

Am Heart J.

Cell Stress Chaperones.

J Card Fail.

Am J Med.

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC

Eur Heart J.

Dynamic processing of neuropeptides: sequential conformation shaping of neurohypophysial preprohormones during intraneuronal secretory transport

J Mol Neurosci.

Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure

Eur J Clin Invest.

Complementary role of copeptin and high-sensitivity troponin in predicting outcome in patients with stable chronic heart failure

Eur J Heart Fail.

Increased 90-day mortality in patients with acute heart failure with elevated copeptin: secondary results from the Biomarkers in Acute Heart Failure (BACH) study

Circ Heart Fail.

The role of copeptin as a diagnostic and prognostic biomarker for risk stratification in the emergency department

BMC Med.

The stress hormone copeptin: a new prognostic biomarker in acute illness

Swiss Med Wkly.

Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis

Clin Sci (Lond).

Original Article
Copeptin (C-terminal pro Arginine-Vasopressin) is an Independent Long-Term Prognostic Marker in Heart Failure with Reduced Ejection Fraction