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

Karin Wildi, Maria Rubini Gimenez, Raphael Twerenbold, Tobias Reichlin, Cedric Jaeger, Amely Heinzelmann, Christiane Arnold, Berit Nelles, Sophie Druey, Philip Haaf, Petra Hillinger, Nicolas Schaerli, Philipp Kreutzinger, Yunus Tanglay, Thomas Herrmann, Zoraida Moreno Weidmann, Lian Krivoshei, Michael Freese, Claudia Stelzig, Christian Puelacher, Katharina Rentsch, Stefan Osswald, Christian Mueller, Karin Wildi, Maria Rubini Gimenez, Raphael Twerenbold, Tobias Reichlin, Cedric Jaeger, Amely Heinzelmann, Christiane Arnold, Berit Nelles, Sophie Druey, Philip Haaf, Petra Hillinger, Nicolas Schaerli, Philipp Kreutzinger, Yunus Tanglay, Thomas Herrmann, Zoraida Moreno Weidmann, Lian Krivoshei, Michael Freese, Claudia Stelzig, Christian Puelacher, Katharina Rentsch, Stefan Osswald, Christian Mueller

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.

Keywords: acute cardiac care; biological markers; myocardial infarction; troponin.

© 2015 The Authors.

Figures

Figure 1.
Figure 1.
Distribution of high-sensitivity cardiac troponin I (hs-TnI) and high-sensitivity cardiac troponin T (hs-TnT) values in quadrants according to the approved uniform clinical decision values (A) at any time during serial sampling in the overall cohort regardless of the adjudicated diagnosis, (B) in patients with an adjudicated diagnosis of acute myocardial infarction for levels at presentation, and (C) at any time during serial sampling.
Figure 2.
Figure 2.
Receiver-operating characteristics curve for acute myocardial infarction (AMI). The approved clinical decision values (CDVs) for high-sensitivity cardiac troponin I (hs-TnI) and high-sensitivity cardiac troponin T (hs-TnT) are not biologically equivalent and therefore differ in their sensitivity and specificity for AMI.
Figure 3.
Figure 3.
Distribution of high-sensitivity cardiac troponin I (hs-TnI) and high-sensitivity cardiac troponin T (hs-TnT) values at presentation in quadrants according to the sex-specific clinical decision values in patients with an adjudicated diagnosis of acute myocardial infarction: (A) in women; and (B) in men.
Figure 4.
Figure 4.
Distribution of sensitive cardiac troponin (s-Tn) and high-sensitivity cardiac troponin (hs-Tn) I and T values at presentation in quadrants according to the approved uniform clinical decision values in patients with an adjudicated diagnosis of acute myocardial infarction. A, Pairs of hs-TnT and s-TnI Ultra (Siemens); (B) pairs of hs-TnI (Abbott) and s-TnI Ultra (Siemens); (C) pairs of hs-TnI (Abbott) and hs-TnI (Siemens); (D) pairs of hs-TnI (Abbott) and hs-TnI (Beckman Coulter); (E) pairs of hs-TnT and hs-TnI (Siemens); and (F) pairs of hs-TnT and hs-TnI (Beckman Coulter).
Figure 5.
Figure 5.
Kaplan–Meier survival curves in patients with consistent diagnoses of acute myocardial infarction (AMI), patients with inconsistent diagnoses resulting from biologically nonequivalent clinical decision values for the different pairs of cardiac troponin assays, and patients with diagnoses of unstable angina. A, Pairs of high-sensitivity cardiac troponin (hs-cTn) T and hs-cTnI (Abbott); and (B) pairs of hs-cTnT and sensitive cTnI Ultra (Siemens).

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