Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin

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Abstract

Background

We examined whether undetectable levels of high-sensitivity cardiac Troponin (hs-cTn) can be used to rule out acute myocardial infarction (AMI) with a single blood draw at presentation to the emergency department (ED).

Methods and results

In a prospective multicenter study we used 4 different hs-cTn assays (hs-cTnT Roche, and hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting with acute chest pain. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available data including serial hs-cTnT levels. Mean follow up was 24 months. Among 2072 consecutive patients with available hs-cTnT levels, 21% had an adjudicated diagnosis of AMI. Among AMI patients, 98.2% had initially detectable levels of hs-cTnT (sensitivity 98.2%, 95%CI 96.3%–99.2%, negative predictive value (NPV) 98.6%, 95%CI 97.0%–99.3%). Undetectable levels of hs-cTnT ruled out AMI in 26.5% of patients at presentation. The NPV was similar with the three hs-cTnI assays: among 1180 consecutive patients with available hs-cTnI (Siemens), the NPV was 98.8%; among 1151 consecutive patients with available hs-cTnI (Beckman Coulter), the NPV was 99.2%; among 1567 consecutive patients with available hs-cTnI (Abbott), the NPV was 100.0%. The percentage of patients with undetectable levels of hs-cTnI was similar among the three hs-cTnI assays and ranged from 11.4% to 13.9%.

Conclusions

Undetectable levels of hs-cTn at presentation have a very high NPV and seem to allow the simple and rapid rule out of AMI. This criteria applies to much more patients with hs-TnT as compared to the investigated hs-cTnI assays.

Introduction

Acute myocardial infarction (AMI) is a major cause of death and disability worldwide. Patients with symptoms suggestive of AMI account for about 10% of all emergency department (ED) consultations, even so only 10–20% of them eventually suffer from AMI. Rapid identification of this diagnosis is critical for early treatment and management of these patients [1].

In the early 90s several studies showed that cardiac troponins (cTn) were proteins unique to heart and specific and sensitive biomarkers of myocardial damage [2], [3], [4]. Currently cTn and 12-lead electrocardiogram (ECG) form the diagnostic cornerstones of clinical assessment in the evaluation of chest pain patients [5], [6]. A limitation of conventional cTn assays is their low sensitivity at the time of a patient's presentation, owing to a delayed increase of circulating levels for 3 to 4 h and requiring serial sampling for 6 to 9 h in a significant number of patients [2].

Delays in confirming the diagnosis of AMI (rule in) may increase the risk of complications [7] but also delays in excluding the diagnosis (rule out) interfere with the evaluation of alternative diagnoses and contribute to overcrowding in the ED and increasing the cost to the health care system.

Recent studies reported that using more sensitive cTn assays can improve the accuracy of the diagnosis of AMI at the time of presentation to the ED. However using the conventional cut-off (99th percentile) the sensitivities (often < 90%) are not high enough to allow immediately clinical decision making [8], [9], [10], [11], [12], [13]. In contrast, using undetectable levels of hs-cTnT as the criteria for rule out of AMI at presentation seemed to provide very high sensitivity and NPV in initial pilot studies [8], [10]. Our aim was to evaluate undetectable levels of four hs-cTn assays (hs-cTnT Roche, hs-cTnI Siemens, hs-cTnI Beckman Coulter & hs-cTnI Abbott) for the rapid rule out of AMI.

Section snippets

Study design and population

Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) is an ongoing prospective international multicenter study designed and coordinated by the University Hospital Basel Switzerland [10], [14], [15]. From April 2006 to November 2011, consecutive patients older than 18 years presenting to the ED with symptoms suggestive of AMI with an onset or peak within the last 12 h were recruited, after informed consent was obtained.

Patients with terminal kidney failure requiring regular

Statistical methods

The data are expressed as medians ± interquartile range (IQR) for continuous variables, and for categorical variables as numbers and percentages. Continuous variables were compared with the Mann-Whitney–U test, and categorical variables using the Pearson chi-square test. Kaplan–Meier analysis was performed for the endpoint of death and AMI, and log-rank testing was used to assess statistical significance.

All hypothesis testing was two-tailed and p-value of less than 0.05 was considered

Characteristics of patients

The detailed flow of patients in this observational study is shown in Fig. 1. A total of 2072 consecutive patients had levels of hs-cTnT available, the first 1180 consecutive patients had levels of hs-cTnI (Siemens) available, the first 1151 consecutive patients had levels of hs-cTnI (Beckman Coulter) available and the first 1567 consecutive patients had levels of hs-cTnI (Abbott) available.

Table 1 shows baseline characteristics of all patients in the analysis of hs-cTnT. Baseline

Discussion

This analysis derived from a prospective multicenter study evaluated the criteria of undetectable levels using four different hs-cTn assays as a single variable to rule out the diagnosis of AMI in patients with acute chest pain at the time of presentation to the ED.

We report three major findings that extend and corroborate previous experience with hs-cTn assays [8], [9], [10], [11], [12], [13]. First, the percentage of patients having undetectable levels of hs-cTn at presentation varied

Study limitations

Several limitations of our study merit consideration. First, we analysed the performance of undetectable levels using four different novel hs-cTn assays (hs-cTnT Roche; hs-cTnI Siemens; hs-cTnI Beckman Coulter; hs-cTnI Abbott). As our findings regarding NPV were consistent among the four different assays, we assume that it can be generalized to all hs-cTn assays. Of course, this assumption needs to be confirmed in additional studies. Second, the analysis of the three hs-cTnI assays was based on

Conclusions

In conclusion, undetectable levels of hs-cTnT and hs-cTnI at presentation to the ED of patients with acute chest pain have a very high NPV for AMI, particularly in patients presenting 3 h or more since chest pain onset. Therefore using them as a suitable variable in conjunction with other clinical information including the 12-lead ECG, undetectable levels seem a very safe and effective tool to rule out AMI. This criteria applies to much more patients with hs-cTnT as compared to the investigated

Funding

This study was supported by research grants from the Swiss National Science Foundation (PP00B-102853), the Swiss Heart Foundation, Abbott, Roche, Siemens, and the Department of Internal Medicine, University Hospital Basel.

Conflict of interest

Prof. Mueller has received research grants from the Swiss National Science Foundation (PP00B-102853) and the Swiss Heart Foundation, the StiftungfürkardiovaskuläreForschung Basel, 8sense, Abbott, ALERE, Brahms, Critical Diagnostics, Nanosphere, Roche, Siemens, and the Department of Internal Medicine, of the University Hospital Basel, as well as speaker honoraria from Abbott, ALERE, Brahms, Novartis, Roche, and Siemens. We disclose that Dr. Reichlin has received research grants from the Swiss

Acknowledgements

We thank the patients who participated in the study, the staff of the emergency department, the laboratory technicians (particularly Michael Freese, Claudia Stelzig, Esther Garrido, Irina Klimmeck, Melanie Wieland, Beate Hartmann, Janine Voegele, Ina Ferel, Kirsten Hochholzer, and Fausta Chiaverio) for their most valuable efforts and Pascal Benkert for expert statistical advice.

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