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      Misdiagnosis of Myocardial Infarction Related to Limitations of the Current Regulatory Approach to Define Clinical Decision Values for Cardiac Troponin

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          Background—

          Misdiagnosis of acute myocardial infarction (AMI) may significantly harm patients and may result from inappropriate clinical decision values (CDVs) for cardiac troponin (cTn) owing to limitations in the current regulatory process.

          Methods and Results—

          In an international, prospective, multicenter study, we quantified the incidence of inconsistencies in the diagnosis of AMI using fully characterized and clinically available high-sensitivity (hs) cTn assays (hs-cTnI, Abbott; hs-cTnT, Roche) among 2300 consecutive patients with suspected AMI. We hypothesized that the approved CDVs for the 2 assays are not biologically equivalent and might therefore contribute to inconsistencies in the diagnosis of AMI. Findings were validated by use of sex-specific CDVs and parallel measurements of other hs-cTnI assays. AMI was the adjudicated diagnosis in 473 patients (21%). Among these, 86 patients (18.2%) had inconsistent diagnoses when the approved uniform CDV was used. When sex-specific CDVs were used, 14.1% of female and 22.7% of male AMI patients had inconsistent diagnoses. Using biologically equivalent CDV reduced inconsistencies to 10% ( P<0.001). These findings were confirmed with parallel measurements of other hs-cTn assays. The incidence of inconsistencies was only 7.0% for assays with CDVs that were nearly biologically equivalent. Patients with inconsistent AMI had long-term mortality comparable to that of patients with consistent diagnoses ( P=NS) and a trend toward higher long-term mortality than patients diagnosed with unstable angina ( P=0.05).

          Conclusions—

          Currently approved CDVs are not biologically equivalent and contribute to major inconsistencies in the diagnosis of AMI. One of 5 AMI patients will receive a diagnosis other than AMI if managed with the alternative hs-cTn assay.

          Clinical Trial Registration—

          URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

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          Most cited references27

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          How to use high-sensitivity cardiac troponins in acute cardiac care.

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            One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T.

            High-sensitivity cardiac troponin (hs-cTn) assays seem to improve the early diagnosis of acute myocardial infarction (AMI), but it is unknown how to best use them in clinical practice. Our objective was to develop and validate an algorithm for rapid rule-out and rule-in of AMI. A prospective multicenter study enrolling 872 unselected patients with acute chest pain presenting to the emergency department. High-sensitivity cardiac troponin T (hs-cTnT) was measured in a blinded fashion at presentation and after 1 hour. The final diagnosis was adjudicated by 2 independent cardiologists. An hs-cTnT algorithm incorporating baseline values as well as absolute changes within the first hour was derived from 436 randomly selected patients and validated in the remaining 436 patients. The primary prognostic end point was death during 30 days of follow-up. Acute myocardial infarction was the final diagnosis in 17% of patients. After applying the hs-cTnT algorithm developed in the derivation cohort to the validation cohort, 259 patients (60%) could be classified as "rule-out," 76 patients (17%) as "rule-in," and 101 patients (23%) as in the "observational zone" within 1 hour. Overall, this resulted in a sensitivity and negative predictive value of 100% for rule-out, a specificity and positive predictive value of 97% and 84%, respectively, for rule-in, and a prevalence of AMI of 8% in the observational zone group. Cumulative 30-day survival was 99.8%, 98.6%, and 95.3% (P < .001) in patients classified as rule-out, observational zone, and rule-in, respectively. Using a simple algorithm incorporating hs-cTnT baseline values and absolute changes within the first hour allowed a safe rule-out as well as an accurate rule-in of AMI within 1 hour in 77% of unselected patients with acute chest pain. This novel strategy may obviate the need for prolonged monitoring and serial blood sampling in 3 of 4 patients.
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              Multicenter analytical evaluation of a high-sensitivity troponin T assay.

              High-sensitivity cardiac troponin assays are being introduced clinically for earlier diagnosis of acute myocardial infarction (AMI). We evaluated the analytical performance of a high-sensitivity cardiac troponin T assay (hscTnT, Roche Diagnostics) in a multicenter, international trial. Three US and 5 European sites evaluated hscTnT on the Modular® Analytics E170, cobas® 6000, Elecsys 2010, and cobas® e 411. Precision, accuracy, reportable range, an inter-laboratory comparison trial, and the 99th percentile of a reference population were assessed. Total imprecision (CVs) were 4.6-36.8% between 3.4 and 10.3 ng/L hscTnT. Assay linearity was up to 10,000 ng/L and the limit of blank and detection were 3 and 5 ng/L, respectively. The 99th percentile reference limit was 14.2 ng/L (n=533). No significant differences between specimen types, assay incubation time, or reagent lots existed. A substantial positive bias (76%) exists between the 4th generation and hscTnT assays at the low end of the measuring range (<50 ng/L). hscTnT serum pool concentrations were within 2SD limits of the mean of means in the comparison trial, indicating comparable results across multiple platforms and laboratories. The Roche hscTnT assay conforms to guideline precision requirements and will likely identify additional patients with myocardial injury suspicious for AMI. Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Circulation
                Circulation
                CIR
                Circulation
                Lippincott Williams & Wilkins
                0009-7322
                1524-4539
                9 June 2015
                08 June 2015
                : 131
                : 23
                : 2032-2040
                Affiliations
                From Department of Cardiology and Cardiovascular Research Institute Basel (K.W., M.R.G., R.T., T.R., C.J., A.H., S.D., P.H., P.H., N.S., P.K., Y.T., T.H., Z.M.W., L.K., M.F., C.S., C.P., S.O., C.M.) and Laboratory Medicine (K.R.), University Hospital Basel, Switzerland; Servicio de Urgencias y Pneumologia, CIBERES ISC III, Hospital del Mar–Institut Municipal d’Investigació Mèdica, Barcelona, Spain (M.R.G.); and Department of Internal Medicine, Kantonsspital Olten, Switzerland (C.A.).
                Author notes
                Correspondence to Christian Mueller, MD, Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail Christian.Mueller@ 123456usb.ch
                Article
                00003
                10.1161/CIRCULATIONAHA.114.014129
                4456170
                25948541
                3aec6851-d7ee-4a7c-b10f-2e14f0e8443c
                © 2015 The Authors.

                Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

                History
                Categories
                33
                Original Articles
                Coronary Heart Disease
                Custom metadata
                TRUE
                CME

                acute cardiac care,biological markers,myocardial infarction,troponin

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