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Copeptin: a new marker in cardiology

Morawiec, Beata; Kawecki, Damian

Journal of Cardiovascular Medicine: January 2013 - Volume 14 - Issue 1 - p 19–25
doi: 10.2459/JCM.0b013e3283590d59
Narrative review

Copeptin, the C-terminal part of the prohormone of vasopressin (AVP), is released together with AVP in stoichiometric concentrations reflecting an individual's stress level. Copeptin has come to be regarded as an important marker for identifying high-risk patients and predicting outcomes in a variety of diseases. It improves the clinical value of commonly used biomarkers and the tools of risk stratification. Elevated AVP activation and higher copeptin concentrations have been previously described in acute systemic disorders. However, the field that could benefit the most from the introduction of copeptin measurements into practice is that of cardiovascular disease. Determination of copeptin level emerges as a fast and reliable method for differential diagnosis, especially in acute coronary syndromes. A particular role in the diagnosis of acute myocardial infarction (AMI) is attributed to the combination of copeptin and troponin. According to available sources, such a combination allows AMI to be ruled out with very high sensitivity and negative predictive value. Moreover, elevated copeptin levels correlate with a worse prognosis and a higher risk of adverse events after AMI, especially in patients who develop heart failure. Some authors suggest that copeptin might be valuable in defining the moment of the introduction of treatment and its monitoring in high-risk patients. The introduction of copeptin into clinical practice might also provide a benefit on a larger scale by suggesting changes in the allocation of financial resources within the health system. Although very promising, further larger trials are required in order to assess the clinical benefits of copeptin in everyday practice and patient care.

Second Department of Cardiology, Silesian Medical University of Katowice, Katowice, Poland

Correspondence to Beata Morawiec, Second Department of Cardiology, Silesian Medical University of Katowice, M. Curie-Skłodowskiej Street 10, 41-800 Zabrze, Poland Tel: +48322711010; fax: +48322711010; e-mail: beamorawiec@wp.pl

Received 18 July, 2012

Revised 1 August, 2012

Accepted 7 August, 2012

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Introduction

Vasopressin (AVP), as a hormone that mediates the endogenous stress reaction, plays an important role in several clinical settings, including cardiovascular diseases. AVP is secreted by two main pathophysiological pathways (Fig. 1) to reach the concentration characteristic of the endogenous stress response in reaction to any disturbances in homeostasis.1 The main releasing factors for AVP are hypovolemia, a decrease in osmolality and hyponatremia.2 AVP induces vasoconstriction by stimulating the V1 receptors on vascular smooth muscle cells and mediates water reabsorption by a complex mechanism following V2 receptor activation in renal collecting tubule cells.3 However, the clinical role of AVP measurements has never been introduced into practice due to technical limitations such as its ex-vivo instability, small size, interactions with platelets in the serum and short plasma half-life.4 The degree of stress axis activation can be measured using the C-terminal part of the preprohormone of vasopressin – copeptin. It is released together with AVP in stoichiometric concentrations during processing of the precursor (Fig. 2) and acts in the circulation in a manner similar to AVP with respect to osmotic and hypotensive stimuli. In contrast to AVP, copeptin is stable in the serum and plasma at room temperature and is easy to measure.5 AVP is the main hormone of the hypothalamo-pituitary–adrenal axis and together with corticotropin-releasing hormone (CRH) induces the secretion of adrenocorticotropic hormone and cortisol.6 Similarly to AVP, cortisol reflects an individual's stress level. As a fragment of provasopressin, copeptin seems to be a more sensitive marker than cortisol for estimating stress levels.7 On the basis of the cosecretion of copeptin and AVP from the hypothalamus, anterior and posterior pituitary, copeptin has come to be regarded as an important marker for identifying high-risk patients and predicting outcomes in a variety of diseases.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

This article is a review of the most recent data on the use of copeptin in different clinical contexts with focus on the clinical role of the marker in cardiovascular disease, which is the most promising field for the introduction of the new marker.

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Practical role of copeptin as a diagnostic and prognostic marker

Elevated AVP activation and higher copeptin concentrations have been previously described in systemic disorders such as septic and hemorrhagic shock,8–10 sepsis9,11–13 and systemic inflammatory response syndrome12. Copeptin seems also to be useful in isolated organic disturbances.

AVP is an important hormone in water and electrolyte metabolism. Copeptin might be useful in the diagnosis of disturbances such as diabetes insipidus and any water homeostasis disorders, as well as in the identification of posterior pituitary insufficiency after pituitary surgery.14

With regard to the central nervous system, copeptin levels are correlated with functional outcomes and death in patients with ischemic stroke.11,15,16 Copeptin is founded to be the first factor enforcing the predictive value of the National Institute of Health stroke scale (NIHSS) score15 and, together with NIHSS score, contributes to the area under the curve for the prediction of functional outcome and mortality in patients with ischemic stroke17. Copeptin levels in traumatic brain injury correlate with trauma severity, but not with osmoregulation mechanisms.18 Copeptin levels displayed a positive correlation with hematoma volume and a negative correlation with the Glasgow Coma Scale (GCS).19 According to previous authors, copeptin could become a useful tool in risk stratification and the therapeutic decision-making process in the treatment of an acute phase of intracerebral hemorrhage.19,20 In the same setting, copeptin is a predictor of 1-month mortality, but there is no improvement in the risk stratification with the GCS.20

Patients suffering from severe lower respiratory tract diseases benefit from copeptin measurements as well. Copeptin and the Pneumonia Severity Index were independent risk factors for community-acquired pneumonia.21 The multivariable analysis in patients with acute-phase chronic obstructive pulmonary disease showed that copeptin levels were independent predictors of clinical failure during long-term follow-up, independently of age, common risk factors, hypoxemia and pulmonary dysfunction.22 There is no correlation between copeptin and decreased Vo2 in patients with chronic lung diseases,23 which suggests that copeptin could serve as a marker for acute diseases.

Copeptin was reported to reach higher concentrations in renal dysfunction,24 higher osmolality states,25 hyponatremia26 and cases of inappropriate antidiuretic hormone hypersecretion (SIADH). Copeptin levels correlated with urine sodium levels27 and were, therefore, proposed for use as a differential diagnostic tool for SIADH and cerebral salt–water syndrome.28–30

Major surgery will trigger the endogenous stress axis, which is followed by hormone release. Copeptin levels tended to be higher after cardiac surgery.11 They mirror heart and renal function after heart transplantation, but not after kidney transplantation,31 and might be valuable factors for the postoperative evaluation of outcome and fluid therapy monitoring.32 Copeptin levels also tended to rise in umbilical blood samples after child delivery and in the context of acidosis in newborns.33

A broad spectrum of clinical cases involves stress axis activation and causes an elevation in copeptin concentrations. However, the field that could benefit the most from the introduction of copeptin measurements into practice is that of cardiovascular disease.34–36 According to available sources, copeptin can be a diagnostic and prognostic tool especially for the management of acute myocardial infarction (AMI) and heart failure.

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Acute myocardial infarction

One of the most promising sectors for the introduction of copeptin as a diagnostic marker seems to be acute coronary syndromes (ACSs). Although the first announcement of the potential role of AVP in AMI was published in 1986,37 copeptin efficacy in AMI was established in 2007.38 Many patients admitted to the emergency department (ED) with chest pain turn out not to have AMI.39 Currently, the process for the exclusion of AMI is time and cost consuming. Serial blood sampling, the ‘grey zone’ for troponin elevation, limited value of ECG in AMI exclusion39–41 result in the need for an extended monitoring period before discharge. A fast and reliable method for differential diagnosis must be established.

A particular role in the diagnosis of AMI is attributed to the combination of copeptin and troponin.42–47 The Leicester Acute Myocardial Infarction Peptide (LAMP) Study proved the usefulness of a combination of a copeptin level less than 14 pmol/l and a troponin level less than 0.01 μg/l to rule out AMI, with a negative predictive value (NPV) of 99.7% and high sensitivity (98.8%).38 On the basis of those outcomes, the National Academy of Clinical Biochemistry listed copeptin among potential cardiac markers in 2007.48 In 2010, copeptin was named one of the promising markers in early AMI diagnostics.49 Similar outcomes to those reported in the LAMP study were published for non-ST-elevation myocardial infarction (NSTEMI).47

With regard to the practicality of copeptin measurements, the results from a trial performed in the ED of a general hospital should be mentioned. One-third of patients with suspected AMI were discharged with the exclusion of ACS based on negative copeptin and highly sensitive troponin (hs-troponin) measurements with sensitivity and an NPV of 100%.46 Similar results have been reported recently.50,51 Some authors find that copeptin measurement is helpful in patients with pre-existing coronary artery disease (CAD).51 Copeptin significantly improves the diagnostic accuracy in this group if used in combination with fourth-generation cardiac troponin (cTnT) but only trended to be superior over hs-troponin alone.52

Less impressive outcomes were reported for low-risk to intermediate-risk patients with acute chest pain: copeptin did not add any diagnostic value to the use of hs-troponin.53 Copeptin reaches higher concentrations in AMI than in unstable angina and is comparable in unstable angina and other causes of chest pain of either cardiac or noncardiac origin.42

In patients with stable CAD, copeptin is a marker of less prognostic value. In patients with stable CAD and preserved left ventricular ejection fraction, novel biomarkers of cardiovascular stress – midregional proatrial natriuretic peptide (MR-proANP), midregional proadrenomodulin (MR-proADM) and C-terminal proendothelin-1 (CT-proTE-1), but not copeptin – were identified as those that may help indicate patients who are at higher cardiovascular risk.54 It was found that a progressive increase in levels of natriuretic peptides [N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP)] correspond with atherosclerosis stages, irrespective of the underlying myocardial disease.55 Further studies on NT-proANP proved the marker, as well as the presence of its gene variant, to be the prognostic marker of cardiovascular events at follow-up in patients with stable CAD.56,57

The latest European Society of Cardiology (ESC) guidelines call attention to the rising need for the fast introduction of an invasive strategy in ST-elevation myocardial infarction (STEMI) and high-risk NSTEMI.58 The pattern of troponin release is known to peak within the first 6 h after the onset of symptoms.59,60 Copeptin reaches maximal concentrations significantly sooner after the onset of chest pain (4–6 h) and reaches a plateau, which lasts for 3–5 days.38,61,62 Although the diagnosis of STEMI is relevantly easy based on ECG, the ECG changes in NSTEMI are not as clear. Higher copeptin levels correlate with ECG changes which might facilitate the identification of patients at higher risk.42 The clinical role of copeptin in high-risk NSTEMI patients is still being discussed; however, copeptin levels are proven to correlate with NSTEMI diagnosis and subsequent risk,62 aggravating the outcome of the Global Registry of Acute Coronary Events scale.63 The rapid diagnosis of high-risk ACS with copeptin might accelerate a decision regarding the interventional approach and demands further research.

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Heart failure

AVP activation is a response to water and sodium disorders. A high level of AVP after AMI is the cause of left ventricle dysfunction and leads to the development of heart failure. Thus, elevated copeptin levels correlate with a worse prognosis and a higher risk of adverse events, especially in the heart failure group.38,64 These data allow for conclusions regarding the diagnostic and prognostic role of copeptin in heart failure.38,65,66

AVP levels are higher in patients suffering from chronic heart failure and correlate with the stage of the disease.67 An understanding of the neurohormonal axis AVP–copeptin, renin–angiotensin and sympathetic systems might elucidate the pathogenesis in cardiovascular disorders and potentially influence new therapeutic options. Many further studies are needed to assess whether there is any relevant copeptin cutoff defining the indication for the introduction of treatment in high-risk patients depending on their personal level of neurohormonal axis activation (with the specific AVP V2-receptor antagonists – vaptans)68–70 in order to avoid AMI complications, especially heart failure.67 It remains to be determined whether copeptin level will play a role in treatment monitoring and its intensification as a response to copeptin level changes. According to previous studies, tolvaptan, an oral AVP antagonist, decreased heart failure symptoms with no influence on mortality.1,71 The response to the therapy with tolvaptan was not better in patients with AVP levels that were already elevated.71 Those outcomes could be limited by the instability and rapid metabolism of circulating AVP.4 Copeptin might be more clinically relevant as a stable marker that precisely mirrors AVP response. Moreover, copeptin concentrations are not influenced by exogenous AVP analogs, which makes copeptin an adequate marker in patients with heart failure treated in this way.72

Equivalent outcomes for 1-year mortality prediction in acute decompensated heart failure were observed for copeptin, MR-proANP, MR-proADM and brain natriuretic peptide (BNP).35 Copeptin has been previously described as a marker of the early response to acute heart failure treatment that can be used in a risk and mortality assessment.73 In this setting, the use of copeptin in combination with BNP and NT-proBNP provides more clinical benefit than each peptide alone.36,73,74

Copeptin is elevated after myocardial infarction, especially in patients who died or were readmitted with heart failure. The marker was an independent predictor of death and heart failure at 60 days38 and was associated with left ventricle dysfunction during the early post-AMI phase as well as the left ventricle remodeling stage after AMI.64 However, there are a few studies that have questioned the suitability of copeptin in heart failure and atrial fibrillation75 and in the identification of myocardial ischemia.76

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Cutoffs for copeptin

The median value of copeptin in healthy individuals was 4.2 pmol/l (range 1–13.8 pmol/l)5 and 4.3 pmol/l for men and 3.2 pmol/l for women.77 Copeptin levels are influenced by estimated glomerular filtration rate, Killip class and NT-proBNP level, as well as a history of diabetes mellitus or heart failure.38 No differences were found regarding sex,38,63,72 age, AMI location, prior AMI or hypertension.38,63 Higher copeptin levels were measured in STEMI than in NSTEMI patients.38,63 Other authors found that copeptin levels are influenced by renal function,78 age,72,77 BNP,78 exercise5 and sex.5,72,76,77 Still other authors suggest that only sex and renal function should be used to interpret copeptin values.

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A multimarker approach

There is still insufficient evidence to establish the routine testing of novel biomarkers such as copeptin in isolation.79 The gold standard in the diagnosis of myocardial ischemia is troponin, which is typically used according to the AMI diagnosis guidelines.80 A single copeptin assessment is useless in the diagnosis of myocardial ischemia, unless measured within the first 4–6 h from the onset of chest pain.42 Levels of copeptin were elevated after exercise regardless of the occurrence of ischemia.76 Although troponin alone is in common use as a biomarker for the diagnosis of ACS and prognosis estimation in CAD,81,82 the benefits of a multimarker model are currently discussed widely in the context of cardiovascular disease. The use of troponin, BNP and C-reactive protein in NSTEMI has been described previously.83 The multimarker strategy integrates different pathways and allows the researcher to acquire complementary information. Levels of both markers, troponin and copeptin, rise in several clinical situations, with varying patterns of release and in response to different stimuli. The combination of both markers seems to be of great diagnostic value in acute myocardial ischemia, with troponin as the marker for ischemia and copeptin as the marker of the endogenous stress response.42–45 Measuring copeptin and troponin shortly after the onset of chest pain allows for the exclusion of myocardial infarction already at the time of presentation, with a sensitivity of 98.8% and a NPV of 99.7%.42 Similar results were observed for time intervals 0–12 h from the onset of chest pain.44 A promising field for copeptin is the zone of mild troponin elevation, which is still a decision-making challenge for physicians.52 A review of the literature concerning new markers in patients presenting with chest pain and suspected for ACS and published from 2004 to 2010 has been performed. Thirty-seven different markers were evaluated to check their clinical value in combination with troponin. Only five of them, including copeptin, yielded clinical benefits in this setting.79 Copeptin was described as the most efficient marker for enhancing the diagnostic value of troponin.7,8,38,82,84 This correlation (troponin and copeptin) is more efficient than any other in the group of approved cardiovascular markers [troponin, NT-proBNP, creatine kinase-MB enzyme (CK-MB) and myoglobin].44

Another potential combination is copeptin and natriuretic peptides. The combination of NT-proBNP or BNP with copeptin is still being discussed. Some studies have shown the related predictive value in heart failure outcome,36,73,78 especially in patients with elevated NT-proBNP after AMI.38 Serial monitoring of MR-proANP and copeptin combined with cTnT was found to have a potential role in detecting the highest-risk outpatients with heart failure.85 On the contrary, no advantage of joint copeptin and natriuretic peptide assessment over copeptin alone has been found with respect to risk and mortality stratification in patients with acute heart failure.74

A parallel discussion involves marker measurements at different time points and the use of single versus repeated measurements. As long as time intervals depend on the release pattern, and therefore can be easily specified, the ability to perform serial measurements is questionable for economic reasons. Based on, so far, referential studies42 a single measurement of copeptin (in a panel of markers) seems to be sufficient for diagnostic procedures. The measurements of copeptin during follow-up appear to have additional predictive value in risk assessment and high-risk population identification, as suggested in large clinical studies.36,38,78,86 The most recent data did not confirm a predictive role of copeptin beyond the first hours after admission.79 The balance between costs and clinical benefit requires further evaluation.38,78

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The costs

The costs of routine copeptin measurements and the lack of sufficient clinical data argue against the introduction of copeptin into a multimarker model for the diagnosis of myocardial ischemia. However, the common use of such a panel (copeptin and troponin) could potentially reduce the costs generated by the prolonged monitoring of a patient requiring serial blood sampling in emergency departments or inadequate hospitalization.42,43 Those additional costs generated by diagnostic uncertainty after the first troponin measurement in patients with suspected ACS were estimated to be more than US$1 billion annually in the United States.87,88 With an NPV at the level of 98.4% for joint copeptin and troponin measurements, two-thirds of patients with chest pain could be discharged after the exclusion of AMI and without further diagnostic procedures.42

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Summary

The prognostic value of copeptin has been reported for sepsis, shock, AMI, stroke, acute pulmonary disorders and other acute diseases. It reflects the severity of the disease and can be used to identify patients at high risk for adverse events. Regarding the multifunctional potential of copeptin, the results will need to be interpreted in a clinical setting. When used in combination with routine markers, copeptin provides more specific diagnostic information, especially when used in cardiovascular patients. This information facilitates prognosis stratification, might influence the introduction and subsequent monitoring of treatment and allows the provision of optimal individual patient care. The introduction of copeptin into clinical practice might provide a benefit on a larger scale by suggesting changes in the allocation of financial resources within the health system. These are the conclusions proposed by many previous studies and analyses. However, the majority of these reports indicate the need for further larger, randomized trials are required in order to assess the clinical benefits of copeptin use in everyday practice and patient care.

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Keywords:

acute coronary syndrome; copeptin; marker

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