Summary
Background
High-sensitivity cardiac troponin assays have improved the detection of acute coronary syndrome.
Aim
To examine the possible incremental value of copeptin in the detection of acute coronary syndrome.
Methods
We designed a prospective cohort study to compare the performance of high-sensitivity cardiac troponin T (hs-cTnT) measured at admission in combination with copeptin, and the performance of hs-cTnT alone, measured at admission, 3 hours and 6 hours, in patients with suspected acute coronary syndrome of < 6 hours’ duration after onset of symptoms (exclusion of patients with ST-segment elevation myocardial infarction).
Results
Fifty-eight consecutive patients fulfilled our criteria and were included. After detailed investigations, the final adjudicated diagnosis was acute coronary syndrome in 30 patients (including acute myocardial infarction in 13 and unstable angina in 17) and non-acute coronary syndrome in 28 patients. Measured on admission, hs-cTnT concentration was > 14 ng/mL (99th percentile) in 22 patients with acute coronary syndrome; repetition of the measurement at 3 hours and 6 hours identified three and four additional patients, respectively. The combination of copeptin with hs-cTnT determined on admission identified 26 patients with acute coronary syndrome, with a negative predicted value of 82.6%. The area under the receiver operating characteristic curve was 0.90 for hs-cTnT measured on admission, and 0.94 if repeated at 3 hours and 6 hours or combined with copeptin measurement at admission (non-significant difference).
Conclusions
This prospective study demonstrated that a dual marker strategy that combines hs-cTnT with copeptin increased slightly the detection of acute coronary syndrome at admission.
Résumé
Rationnel
Les troponines hyper-sensibles (Tn-hs) améliorent la détection des syndromes coronariens aigus (SCA).
Objectif
Étudier la possible amélioration de la détection des SCA offerte par l’association de copeptine avec la TnT-hs.
Méthodes
Cohorte prospective qui a comparé les performances de TnT-hs mesurée à l’admission et associée à la copetine, à la mesure de TnT-hs seule, à l’admission, trois heures et six heures, chez les patients suspects de SCA évoluant depuis moins de six heures (exclusion des patients avec infarctus du myocarde avec sus-décalage du segment ST).
Résultats
Cinquante-huit patients consécutifs ont été inclus. Le diagnostic final était SCA chez 30 patients (13 patients avec IDM et 17 avec angor instable), et non-SCA pour 28 patients. Mesurée à l’admission, la TnT-hs était supérieure à 14 ng/mL (99 e percentile) chez 22 patients avec SCA. La répétition des dosages à trois heures a permis de détecter trois patients supplémentaires, et à six heures quatre patients supplémentaires. La mesure conjointe de copeptine et de TnT-hs a détecté 26 patients avec SCA, et sa valeur prédictive négative pour le diagnostic de SCA est de 82,6 %. L’aire sous la courbe de la courbe ROC est de 0,9 pour la TnT-hs mesurée à l’admission, 0,94 pour la mesure répétée à trois heures, six heures ou la mesure combinée de copeptine et de TnT-hs à l’admission ( p non significatif).
Conclusion
Cette cohorte prospective montre que l’utilisation combinée de copeptine et de TnT-hs à l’admission améliore modestement la détection des SCA.
Background
The management of patients with chest pain-related symptoms remains an important clinical challenge . The adequate ruling out of ACS in patients with chest pain is crucial, as the erroneous discharge of a patient with ACS is associated with a high risk of cardiac events . Over the past decades, cTns have emerged as key biomarkers for patients with acute chest pain, and have undoubtedly improved the rate of detection of occult ACS . hs-cTn assays have been developed recently, enabling measurements of concentrations that are ∼10-fold lower than those previously measurable. Recent studies have confirmed the increased accuracy of these high-sensitivity assays compared with conventional assays in the early detection of AMI . However, concerns have been raised about a possible specificity deficit with these new assays . In addition, a second measurement of hs-cTn may be warranted in order to increase the accuracy of the assay . Identification of the perfect biomarker remains an unmet need, and many researchers have advocated multimarker testing .
The arginine-vasopressin system plays a crucial role in the regulation of the individual endogenous stress response . Previous studies have demonstrated that copeptin (the c-terminal part of the vasopressin prohormone) is increased in AMI . Moreover, copeptin measurement adds valuable information to conventional assays of cTn in the early detection of AMI, according to two recent studies . The possible merit of copeptin in addition to hs-cTn is unknown. This study examined the diagnostic accuracy of serial measurements of hs-cTn (at 0, 3 and 6 hours after admission) and of the combination of copeptin with hs-cTn measured on admission, in the detection of ACS.
Study population and methods
Between June and November 2009, we enrolled consecutive patients who were admitted to the Department of Cardiology of Cochin Hospital (Paris, France) for suspected recent ACS, defined as chest pain of ≤ 6 hours’ duration since onset, suggestive of myocardial ischaemia, and lasting > 5 minutes at rest or upon minimal exertion. Patients presenting after a cardiac arrest or with ST-segment elevation myocardial infarction were excluded from the study.
This study was approved by the ethics committee of Cochin Hospital and all patients granted their written informed consent to participate.
Clinical assessment and investigations
Upon admission to the hospital, all patients underwent a detailed clinical evaluation, including medical history, 18-lead ECG, continuous bedside ECG monitoring, screening blood tests and chest X-ray. Decisions to obtain an echocardiogram or coronary angiograms were left to the discretion of the primary physicians. Analysis of cTn was done using a conventional cTnI assay for routine assessment of patients and an hs-cTnT assay for research purposes.
Conventional cardiac troponin I assay
Measurement of cTnI was done using an Xpand ® HM analyser (Siemens Healthcare Diagnostics Inc., Newark, NJ, USA). The 99th percentile is achieved at 0.07 μg/L with a CV between 15 and 22%; a CV ≤ 10% between measurements is achieved at 0.14 μg/L.
High-sensitivity cardiac troponin T assay
Hs-cTnT (Roche Diagnostic, Meylan, France) was measured in heparinized samples collected on admission, and at 3 and 6 hours. The assay was performed on an Elecsys ® 2010 analyser using an electrochemiluminescence immunoassay. The analytical performances of this assay have been previously reported; the 99th percentile with a CV < 10% is achieved at 14 ng/L . In our laboratory, the CV was found to be < 4% (3.6% at 27.5 ng/L and 2.8% at 2.36 ng/L).
Copeptin measurements
Copeptin was measured in heparinized samples collected on admission. The assay was performed on a Kryptor ® analyser using the commercial sandwich immunoluminometric assay (Brahms Copeptin Kryptor, Brahms Aktiengesellschaft, Hennigsdorf, Germany). The assay principle lies in Time-Resolved Amplified Cryptate Emission (TRACE) technology. The lower detection limit is 4.8 pmol/L and the functional assay sensitivity (< 20% interassay CV) is < 12 pmol/L. The limit of quantification is 14.1 pmol/L (data from manufacturer). In our laboratory, the CV was found to be < 5% (4.4% at 28.86 pmol/L and 4.6% at 95.84 pmol/L).
Adjudication of the final diagnosis
Two independent cardiologists adjudicated the final diagnosis based on all medical charts; disagreements were settled by consensus. ACS was defined as AMI or unstable angina. AMI was diagnosed when there was evidence of myocardial necrosis in association with clinical signs of myocardial ischaemia. Necrosis was diagnosed on the basis of a rising or falling pattern of cTnI concentration (conventional assay), with at least one value above the 99th percentile, at a level of imprecision of < 10% . Unstable angina was diagnosed in the presence of: clinical manifestations suggestive of myocardial ischaemia, without evidence for myocardial necrosis; an ECG indicative of ongoing ischaemia or a > 70% stenosis of an epicardial coronary artery on coronary angiography (> 50% of the left main trunk); and the absence of an alternative diagnosis.
A non-ACS was defined in the presence of a cardiac but non-coronary diagnosis, non-cardiac origin or when the diagnosis remained unknown despite careful investigations.
Statistical analysis
The data are expressed as means ± standard deviations for continuous variables, and numbers and percentages for categorical variables. As cTn and copeptin measurements may not have a normal distribution, they are reported as medians [25th–75th percentile]. Continuous variables were compared using Student’s t test for normally distributed variables and the non-parametric Mann-Whitney test for non-normally distributed variables. Categorical variables were compared using the Chi 2 test or Fisher’s exact test, as appropriate. ROC curves were generated to assess sensitivity and specificity throughout the concentration ranges of hs-cTnT and copeptin, and to compare the ability of hs-cTnT alone and in combination with copeptin to diagnose ACS, compared as suggested by DeLong et al. . A p value < 0.05 was considered significant. The STATA statistical software, version 10.1 (StataCorp LP, College Station, TX, USA) was used for all analyses.
Results
Baseline characteristics and diagnosis of acute coronary syndrome
Fifty-eight patients fulfilled our inclusion criteria during the study period; their characteristics are reported in Table 1 . The final adjudicated diagnosis was ACS in 30 patients, including 13 patients with AMI (non-ST-segment elevation myocardial infarction) and 17 patients with unstable angina; ACS was excluded in 28 patients. The diagnosis was based on complete medical charts that were available for all patients, including ECG record during chest pain in 33% of patients, echocardiography recorded on admission in 69% of patients, and coronary angiogram available data in 83% of patients. Patients with ACS as their final adjudicated diagnosis were older than those without ACS and had more frequent ST-segment changes on ECG; other characteristics were similar in both groups ( Table 1 ).
| All patients ( n = 58) | Patients with ACS ( n = 30) | Patients without ACS ( n = 28) | P value a | |
|---|---|---|---|---|
| Age (years) | 57.9 ± 13.5 | 61.8 ± 13.6 | 53.7 ± 12.3 | 0.022 |
| Men/women ( n / n ) | 37/21 | 22/8 | 15/13 | 0.118 |
| Coronary risk factors | ||||
| Hypertension | 24 (41.4) | 14 (46.7) | 10 (35.7) | 0.397 |
| Hypercholesterolaemia | 22 (37.9) | 14 (46.7) | 8 (26.7) | 0.156 |
| Diabetes | 13 (22.4) | 8 (26.7) | 5 (17.9) | 0.421 |
| Obesity | 19 (32.8) | 11 (36.7) | 8 (28.6) | 0.512 |
| Family history | 20 (34.5) | 7 (23.3) | 13 (46.4) | 0.064 |
| Current smoking | 19 (32.8) | 8 (26.7) | 6 (21.4) | 0.591 |
| Past medical history | ||||
| Myocardial infarction | 12 (20.7) | 5 (16.7) | 7 (25.0) | 0.434 |
| Coronary revascularization | 11 (19.0) | 6 (20.0) | 5 (17.9) | 0.574 |
| Drug regimen | ||||
| Aspirin | 20 (34.5) | 9 (30.0) | 11 (39.4) | 0.47 |
| Clopidogrel | 9 (15.5) | 4 (13.3) | 5 (17.9) | 0.726 |
| Beta-adrenergic blocker | 18 (31.0) | 8 (26.7) | 10 (35.7) | 0.457 |
| ACE inhibitor or ARB | 20 (34.5) | 11 (36.7) | 9 (32.1) | 0.717 |
| Statin | 24 (41.4) | 12 (40.0) | 12 (42.9) | 0.825 |
| Duration of chest pain (hours) | 3.2 ± 1.4 | 7.5 ± 8.6 | 7.6 ± 11.7 | 0.953 |
| Electrocardiogram | ||||
| Q wave | 7 (12.1) | 6 (14.0) | 4 (9.1) | 0.477 |
| ST-segment depression | 12 (20.7) | 10 (23.3) | 3 (6.8) | 0.039 |
| T-wave inversion | 16 (28.1) | 20 (47.6) | 12 (27.3) | 0.051 |
| Echocardiography | ||||
| Recorded on admission | 40 (69.0) | 32 (74.4) | 30 (68.2) | 0.520 |
| Abnormal wall motion | 11 (19.0) | 13 (30.2) | 6 (13.6) | 0.061 |
| Screening blood tests | ||||
| Creatinine (μmol/L) | 94 ± 37 | 97 ± 28 | 91 ± 44 | 0.484 |
| GFR (mL/min/1.73 m 2 ) | 77 ± 20 | 73 ± 20 | 81 ± 20 | 0.111 |
| cTnI > 0.07 μg/L on admission b | 14 (46.7) | 14 (46.7) | 0 (0.0) | < 0.001 |
| cTnI > 0.07 μg/L at 6 hours b | 18 (60.0) | 18 (60.0) | 0 (0.0) | < 0.001 |
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