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The utility of copeptin in the emergency department as a predictor of adverse outcomes in non-ST-elevation acute coronary syndrome: the COPED-PAO study
  1. Miquel Sánchez1,
  2. Pere Llorens2,
  3. Pablo Herrero3,
  4. F Javier Martín-Sanchez4,
  5. Pascual Piñera5,
  6. Òscar Miró1,
  7. on behalf of COPEP study investigators
  1. 1Emergency Department, Àrea d'Urgències, Hospital Clínic de Barcelona, Grupo de Investigación ‘Urgencias: procesos y patologias’, IDIBAPS, Barcelona, Catalonia, Spain
  2. 2Emergency Department, Servicio de Urgencias, Unidad de Corta Estancia y Hospitalización a Domicilio, Hospital General Universitario de Alicante, Alicante, Spain
  3. 3Emergency Department, Servicio de Urgencias, Hospital Central de Asturias, Oviedo, Spain
  4. 4Emergency Department, Servicio de Urgencias y Unidad de Corta Estancia, Hospital Clínico San Carlos, Madrid, Spain
  5. 5Emergency Department, Servicio de Urgencias, Hospital Reina Sofía, Murcia, Spain
  1. Correspondence to Dr Miquel Sanchez, Emergency Department, Àrea d'Urgències, Hospital Clinic, Grupo de Investigación ‘Urgencias: procesos y patologias’, IDIBAPS, Villarroel 170, Barcelona, Catalonia 08036, Spain; msanchez{at}clinic.ub.es

Abstract

Aims To test the utility of a single copeptin determination at presentation to the emergency department (ED) as a short-term prognosis marker in patients with non-ST-elevation acute coronary syndrome (NSTEACS). To compare the results with those achieved with conventional troponin.

Methods A multicentric, prospective, observational, longitudinal, cohort study involving 15 Spanish EDs. Inclusion: consecutive patients with chest pain (<12 h) finally diagnosed of NSTEACS. Measurements: copeptin and troponin at arrival. Cut-off point for copeptin: 25.9 pmol/l. Follow-up: within 2 months after ED attendance to identify 30-day adverse events. Discriminatory capacity of copeptin and troponin was compared by receiver operating characteristic (ROC) curves.

Results We included 377 patients with NSTEACS. Adverse events: 11 (2.9%) patients died, 27 (7.2%) had an adverse coronary event, 14 (3.7%) had a stroke, and 48 (12.7%) a composite endpoint. The initial copeptine value was over 25.9 pmol/l in 114 patients, and they presented a higher mortality rate (OR: 4.2, (95% CI 1.2 to 14.8); p=0.03). This association disappeared after adjusting by clinical variables or troponin level. No significant differences were found for the remaining endpoints. The area under the curve  of the ROC curve of 30-day mortality was 0.73 (95% CI 0.58 to 0.87) for copeptin, and 0.80 (95% CI 0.73 to 0.87) for troponin.

Conclusions In patients with NSTEACS, determination of copeptin at presentation to the ED is associated with risk of death during the subsequent month. This association, however, disappears after adjusting by baseline features or troponin level, so copeptin does not add complementary prognostic information over that provided by troponin.

  • acute coronary syndrome
  • emergency department

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Introduction

The risk of death and recurrent ischaemic events vary considerably across the spectrum of patients with acute coronary syndrome (ACS). Recent guidelines recommend risk stratification of all patients with non-ST-elevation  acute coronary syndrome (NSTEACS) in order to identify individuals at maximum risk of adverse outcomes who may benefit from early aggressive therapy.1 Currently, the risk of adverse outcomes can be estimated by clinical factors, signs of ischaemia in the ECG, and by circulating biomarkers of myocardial necrosis (troponin). They are all included in the Thrombolysis in Myocardial Infarction (TIMI)2 and Global Registry of Acute Coronary Events (GRACE)3 scores, which are the most commonly used methods of risk stratification.

New plasma biomarkers have emerged as potential alternatives.4,6 Copeptin, the 39-amino-acid c-terminal part of the vasopressin prohormone, is secreted stoichiometrically with arginine-vasopressin from the neurohypophysis. The determination of the plasma concentrations of copeptin has shown to be useful in patients undergoing major disorders, such as shock, pneumonia and cardiovascular diseases.7 Copeptin immediately rises after the onset of acute myocardial infarction (AMI) and rapidly decreases thereafter, showing a half-life of about 5–10 h after the onset of symptoms.8 Due to this specific release pattern, copeptin can be detected in patients with chest pain with ACS as early as the time of presentation to the emergency department (ED), the first setting where the vast majority of these patients are medically assessed.9 ,10 In conjunction with troponin, this early copeptin determination has proved to be useful for ruling out AMI when both markers are within normal ranges.8 ,11 In previous studies, copeptin has also seemed to be helpful as an independent predictor of long-term adverse outcomes in patients with ACS.12 ,18 However, the short-term prognostic value of copeptin remains unclear. Short-term prognosis of ED patients with chest pain is especially important for emergency physicians because incorrect risk stratification will presumably revert into adverse outcomes during the following days or weeks after the ED episode.19 ,20 Moreover, in these previous studies, copeptin was not obtained on arrival to the ED, when triage and risk stratification of patients with chest pain is mandatory. Instead, it was taken outside the ED and at least more than 24 h after the onset of chest pain, at which point, copeptin values could have decreased and, in turn, their clinical utility could be underestimated.

Accordingly, our study was designed to contend with these two limitations. The aim was to test the utility of a single, early copeptin determination at presentation to the ED as an early marker of mortality, adverse coronary events and ischaemic stroke in patients with NSTEACS. As a secondary aim, we compared the results obtained with copeptin with those achieved with conventional troponin determination, a well established prognostic marker in this group of patients.2 ,3

Patients and methods

Study design

The COPeptin in Emergency Department (COPED) study was a multipurpose, nationwide, prospective, observational, longitudinal, cohort study with consecutive inclusion of patients complaining of non-traumatic chest pain as the main symptom for ED consultation regardless of the suspected origin. The EDs of 28 Spanish hospitals (with low and high patient volume, public and private funding, academic and non-academic, and with and without cardiac catheterisation facilities) participated in the study. The study complied with the Declaration of Helsinki and was approved by the local ethics committee. Participation was voluntary, and written informed consent was obtained from all the patients.

Patient population

In order to reflect an unbiased, real-world population of patients attended at the ED, the COPED study included all non-traumatic chest pain patients older than 18 years who consecutively presented to the ED during the 4-month recruitment period between September and December 2010. Patients with known malignancy or severe chronic disease (renal, hepatic or cardiac failure) and severe communication problems were excluded. The COPED-PAO (prediction of adverse outcome) substudy included all patients recruited by centres selected for patient follow-up (n=15) complaining with a non-traumatic chest pain started less than 12 h before ED consultation, and in whom a final diagnosis of NSTEACS was established. Follow-up was carried out by telephone contact with the patient or close relatives. This contact was established between 31 and 60 days after ED attendance.

At presentation, all patients underwent a standard assessment in all the EDs participating in the COPED study, consisting in immediate clinical assessment with clinical history and physical examination, and a 12-lead ECG. At this point, patients were classified by the attending physician into one of these groups: ST-elevation myocardial infarction (STEMI, group 1); definitive ACS without ST-elevation (NSTEACS, group 2); probably ACS (group 3); and non-coronary chest pain (group 4), following the current European guidelines.21 Patients from groups 1 and 4 were excluded. All patients from groups 2 and 3 met criteria for continuous ECG monitoring and serial troponin determination (at least at presentation and 6–8 h later). Patients from group 3 with symptom recurrence and/or ECG changes at anytime were admitted as non-ST-elevation myocardial infarction (NSTEMI) (troponin positive) or as unstable angina (UA) (troponin negative)21. All the remaining patients were considered as having low risk of ACS and underwent a Bruce exercise stress test.22 Those with a negative result were finally classified as non-coronary chest pain, and those with positive result were admitted as UA. The diagnosis of UA was confirmed if a suspected lesion was identified by coronary angiography. Accordingly, the patients in group 3 with NSTEMI or UA along with all those in group 2 were classified as NSTEACS and included in the COPED-PAO sub-study.

Patient assessment

The investigating physician completed standardised case report forms to collect information about the patients’ characteristics, family and personal history of cardiovascular disease, cardiovascular risk factors, presenting characteristics, cardiovascular treatments and clinical outcomes during hospitalisation and at 1 month of follow-up. The timing and treatment of the patients were left to the discretion of the attending physicians, who were blinded to the copeptin results. Completed case report forms were sent to a coordinating centre, where the validity and consistency of the data were confirmed.

Troponin assay

Troponin sampling was performed at patient presentation to the ED and 8 h later. Troponin determination was performed according to the troponin assay used in each single hospital. In short, five hospitals used troponin T assay (Roche), and the 10 remaining EDs used one of the following troponin I assays (Beckman, Abott, Siemens and Roche). NSTEMI was diagnosed every time troponin determinations showed a rising and falling pattern over the 99th percentile of each single assay along with compatible clinical and electrocardiographic findings.23

Copeptin assay

Copeptin sampling was performed at patient presentation to the ED together with the first troponin determination. Copeptin was detected with a novel commercial assay in the chemiluminescence/coated-tube format (BRAHMS AG, Hennigsdorf, Germany), as described previously.10

Endpoints

As the primary endpoint, we assessed the utility of plasma copeptin levels at presentation for prediction of all-cause mortality at 30 days. As secondary endpoints, we also investigated adverse coronary events (myocardial infarction, reinfarction or the need for revascularisation), ischaemic stroke and the composite of primary and all secondary endpoints at 30 days. Clinical outcomes were obtained from hospital chart analysis during hospitalisation and telephone interviews.

Statistical analysis

Quantitative variables were expressed as mean and SD or as median and IQR when they did not fit normal distribution, and compared using the Student t test or Mann–Whitney non-parametric test, respectively. Qualitative variables were expressed as absolute values and percentages, and compared by means of the χ2 or the Fisher exact tests.

A 25.9 pmol/l cut-off point for copeptin was prefixed as proposed by Voors and coworkers in the OPTIMAAL study 14. The crude OR with a 95% CI was calculated for patients above the cut-off point with respect to the remaining patients for both, primary and secondary endpoints. The discriminatory capacity of copeptin was assessed by calculation of the area under the curve (AUC) of the receiver operating characteristic (ROC).

Statistical significance was accepted if p value was less than 0.05, 95% CI of OR excluded the value 1 or the 95% CI of AUC of the ROC excluded the value of 0.5. The analyses were performed with the SPSS 15.0 and STATA 9.0 statistical packages.

Results

Of the COPED cohort of 2044 patients, 1354 were from EDs participating in COPED-PAO substudy, with 192 patients being excluded for different reasons (see figure 1). At presentation and after the first ECG, another 57 patients were diagnosed with STEMI and were also excluded. Among the remaining 1105 patients, 728 had non-coronary chest pain and 377 had NSTEACS (183 NSTEMI and 194 UA). No patients were lost to follow-up, and thus, the 377 patients with NSTEACS were finally included and analysed. Of these, 114 had an initial copeptin value above 25.9 pmol/l, while 263 patients had values less than or equal to this value. The distribution of the basal characteristics of patients and clinical and laboratory data of patient episodes are listed in table 1.

Table 1

Baseline characteristics and clinical and laboratory data of the patients included in the COPED-PAO study

Figure 1

CONSORT diagram of patient inclusion.

Within 1 month of follow-up, the following adverse clinical events were recorded: 11 (2.9%) patients died, 27 (7.2%) had an adverse coronary event and 14 (3.7%) a stroke. Forty-eight (12.7%) patients presented the composite endpoint. Of these, four patients presented more than 1 adverse event. We found a significant association between the primary endpoint (all-cause death) and positive copeptin levels (OR: 4.2, (95% CI 1.2 to 14.8); p=0.03). However, this difference disappeared after adjustment for differences between groups (table 2).

Table 2

Crude and adjusted ORs for 30-day all-cause death for patients with increased copeptin levels (>25.9 pmol/l) respect the rest

Otherwise, no significant differences were observed between patients with copeptin values above and below 25.9 pmol/l in the secondary endpoints: OR 0.79 (95% CI 0.33 to 1.94; p=0.67) for adverse coronary events, OR 1.29 (95% CI 0.47 to 3.95; p=0.77) for ischaemic stroke and OR 1.46 (95% CI 0.77 to 2.74; p=0.24) for the composite of the primary and all secondary endpoints.

The prognostic accuracy of plasma copeptin for all-cause mortality at 1 month is shown in figure 2. The AUC of the ROC was 0.73 (95% CI 0.58 to 0.87). The best combination between sensitivity and specificity in our series was obtained for a copeptin cut-off point of 26.2 pmol/l (sensitivity 63.6%, specificity 70.8%), very close to the 25.9 pmol/l recommended in a previous study.14 Our cut-off point renders a positive predictive value of 6.1% and a negative predictive value of 98.5%. Similarly, the AUC of the ROC for troponin for all-cause mortality at 1 month was 0.80 (95% CI 0.73 to 0.87). On comparison we did not find statistical differences between the prognostic accuracy of the two biomarkers (p=0.30) (figure 2). Finally, we assessed the value of detecting a positive copeptin and/or troponin determination at ED arrival for NSTEACS patients. The incidence of all-cause mortality increased when both biomarkers were positive compared with the rest of the combinations (table 3).

Table 3

Occurrence of 30-day all-cause mortality according to the results of copeptin and troponin determination at ED arrival for patients with NSTEACS

Figure 2

Receiver operating characteristic (ROC) curve for copeptin and troponin (p value refers to comparison between both ROC curves).

Discussion

In patients with NSTEACS, we found that copeptin blood levels at presentation to the ED are associated with risk of death during the subsequent month. Nonetheless, this association disappears after adjusting by baseline features or troponin level, so copeptin does not add complementary prognostic information over that provided by troponin. No relation was established between these early copeptin levels and the risk of early adverse coronary events, ischaemic stroke, or the composite endpoint.

The risk of cardiovascular events in patients presenting with ACS is based on clinical characteristics, electrocardiographic criteria, and conventional laboratory tests. Numerous presenting characteristics are of prognostic value in patients with ACS and have become important factors in the development of clinical prediction models in large clinical trials, including those proposed by the TIMI clinical trials group2 and the GRACE investigators.3 Although cardiac troponin still remains as the preferred and most commonly used biomarker for routine differential cardiovascular diagnosis and stratification,21 ,24 it is unable to identify all patients at high risk. In recent years, clinical studies have focused on new biomarkers, which may be detected earlier than the typical markers of myocardial necrosis because of their different pathways of pathophysiologic release independent of cell necrosis.4,6 ,25 Among these biomarkers, copeptin has become one of the most promising.

The value of copeptin in the diagnosis of patients with AMI was demonstrated by two independent groups using data from large-scale populations.8 ,9 In these studies, copeptin increased the diagnosis yield of tropinin on evaluation of the two markers in combination. Based on these results, the question has been raised as to whether or not copeptin could also act as a strong predictor of risk in patients presenting with suspected ACS. Only seven previous studies have been conducted to establish the prognostic value of copeptin in patients with ACS.10,16 The main characteristics of these studies are listed in table 4.

Table 4

Summary of the main design characteristics and results of previously published studies on the prognostic value of copeptin values in patients with coronary artery disease

Although the time of follow-up differed from one study to another, all found that copeptin levels were a useful tool for the identification of patients at long-term risk of death. However, on analysis of other endpoints, the results differed and, thus, the value of copeptin as a predictor of adverse events other than mortality remains to be elucidated. Several reasons may explain such different findings. These studies varied in regard to sample size and inclusion criteria. Thus, the patients included were from different populations, such as those with stable coronary artery disease, patients with AMI, some with heart failure or diabetes, and patients with a broad range of ACS. The different studies were also conducted in different clinical settings, mostly represented by coronary care units, catheterisation laboratory, and hospitalisation wards, but never in the ED. This may explain why copeptin was determined in patients at least 24 h after chest pain onset or in those without chest pain. As copeptin has a rapid release after symptom onset and its levels decrease within the next few hours, the copeptin levels detected most likely did not correspond with the real raised values, which would also explain the different cut-off points used by the investigators in these studies. Therefore, the true clinical utility of copeptin in the initial triage in clinical assessment and risk stratification of patients with chest pain at the ED remains unclear. The present study tries to answer that question in a specific population (those with NSTEACS) and setting (the ED), at a particular time (shortly after chest pain onset and just after presentation at the ED). Under these conditions, our findings demonstrate that copetin can predict the short-term risk of death but fails to predict other adverse cardiac events during the subsequent month after the onset of chest pain. However, this prognostic value is not superior to that provided by troponin, and disappears after the adjustment for troponin level or baseline features.

Our study has some limitations that deserve to be commented. The size of the study population may limit the power of our study. Although larger studies are recommended, our data seem to be of great relevance. This is the first study to measure copeptin levels within the first hours of the onset of pain for short-term prognostic reasons. The inclusion criteria stipulated that patients were to receive information regarding the study before being asked to participate. Patients who were admitted with major clinical complications may, therefore, be under-represented. Univariate analysis showed that raised copeptin plasma concentrations measured at presentation were associated with a higher risk of death at 1 month. However, because of the relatively small number of 1-month events, a robust multivariate analysis could not be performed. The multivariate analysis attempted to adjust for classic clinical and biological risk factors, but some potential confounders could not be considered. With this cohort we could not determine whether copeptin can reliably identify patients who will benefit from aggressive management.

In conclusion, in patients with NSTEACS, our findings demonstrate a limited prognostic value of copeptin levels at presentation to the ED. They were associated with risk of death during the subsequent month, but did not add complementary prognostic information over that provided by troponin. This association disappeared after adjusting by baseline features or troponin level. No relation was established between these early copeptin levels and the risk of early adverse coronary events, ischaemic stroke, and the composite endpoint.

Acknowledgments

BRAHMS provided technical and economic support to carry out this study, but collection and interpretation of data as well as writing of the paper was entirely done by the investigators.

References

Footnotes

  • Collaborators Investigators participating in the COPED study: Hospital Dr Negrin, Las Palmas de Gran Canarias: Ana Bella Alvarez-Medina, Jose M Pavón Monzo. Hospital La Fe, Valencia: Mª José Pérez Durá, José Manuel Vallés Tarazona. Hospital de La Ribera de Alzira, Valencia: Pedro García, Sara Esteve Poblador. Hospital Reina Sofía, Murcia: Daniela Rosillo Castro, Esther Tomás Jiménez. Hospital Arrixaca, Murcia: Yolanda Jarabo López, Yolanda Morales. Hospital Clínico San Carlos, Madrid: Juan González del Castillo, Pedro Ruiz Artacho. Hospital el Bierzo, Ponferrada: José Ramón Casal Codesido, Mª Jesús Corullón Fernández. Hospital Virgen de la Concha, Zamora: Sebastián Martínez Fernández, José Lázaro González. Hospital Universitario Salamanca: Cristina Gil Castillo, Marta Fuentes de Frutos. Hospital Universitario Central de Asturias, Oviedo: José Juan Gil Román, Rocío Marino Genicio. Hospital Marqués de Valdecilla, Santander: Luis García-Castrillo Riesgo, Héctor Alonso Valle. Hospital Clínic Barcelona: Beatriz López Barbeito, Xavier Alemany González. Hospital Bellvitge, Barcelona: Ferrán Llopis Roca, Dr Javier Jacob Rodríguez. Hospital Parc Tauli, Sabadell: Emili Gené Tous, Mónica Mariñosa Marré. Hospital Joan XXIII, Tarragona: Mª Carme Boqué Oliva, Nuria Alba Molina. Hospital Zumarraga, Guipúzcoa: Francisco José Ezponda Inchauspe, Ana Alonso de Miguel. Hospital Miguel Servet, Zaragoza: Javier Povar Marco, José Miguel Franco Sorolla. Hospital Navarra: Gonzalo López Vaquera, Elena Baztarrica Echarte. Hospital Virgen de las Nieves, Granada: Juan Sánchez López, Mª José Moral Cabrera. Hospital Clínico Universitario, Málaga: Patricia Godoy Rodríguez, Francisco Temboury. Hospital Virgen de la Macarena, Sevilla: José Manuel Garrido Castilla, Carmen Navarro Bustos. Hospital Valme, Sevilla: Francisco Ruiz Romero, Ángel Alvarez Márquez. Hospital Reina Sofía, Córdoba: Luis Jiménez Murillo, Julio Aparicio Sánchez. Hospital de Guadix, Granada: Francisco Manuel Parrilla Ruiz, Dolores Cárdenas Cruz. Hospital Do Salnés, Pontevedra: Manuel J Vázquez Lima, Celestino Sieira Ferrin. Hospital Plasencia: Jesús Santos Velasco, Pedro Hernández Arenillas. Hospital General, Alicante: Bernardo Oliveras, José Carbajosa-Dalmau. Complejo Hospitalario Universitario, Santiago: Enrique Villena, Cesar Gonzalez.

  • Contributors All authors did contribute in the conception and design. OM and PH analysed the data. MS wrote the first draft of the article, and all authors revised it critically for important intellectual content and final approval of the version to be published.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The study complied with the Declaration of Helsinki and was approved by the local ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.