Correspondence
Sensitive Cardiac Troponin Assays
N Engl J Med 2009; 361:2575-2577December 24, 2009
- Article
To the Editor:
Keller et al.1 and Reichlin et al.2 (Aug. 27 issue) unequivocally report the superiority of new sensitive troponin assays over standard assays in the diagnosis of acute myocardial infarction. In both studies, statements of superiority were based primarily on the finding of a significantly larger area under the receiver-operating-characteristic (ROC) curve that was observed for the newer tests. However, the ROC curves for the new assays and the standard assays separated only at high levels of sensitivity (e.g., >83% in Fig. 2A in the article by Reichlin et al.), whereas the predictive accuracy was similar at lower levels. The use of cutoff values at these high levels, however, resulted in a significant loss of specificity and, as a consequence, in a substantially higher number of false positive findings. Since it is known that troponin levels can be elevated in various diseases,3 this problem might be aggravated when the pretest probability of acute myocardial infarction decreases. This might be the case when sensitive assays are widely used in general clinical practice and not only in preselected patients in chest-pain units, as in the present studies.
Axel Bauer, M.D.
Meinrad Gawaz, M.D.
Eberhard Karls Universität Tübingen, Tübingen, Germany
axel.bauer@med. uni-tuebingen. de No potential conflict of interest relevant to this letter was reported.
3 References1
Keller T ,Zeller T ,Peetz D , et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-877
Full Text | Web of Science | Medline2
Reichlin T ,Hochholzer W ,Bassetti S , et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361:858-867
Full Text | Web of Science | Medline3
Inbar R ,Shoenfeld Y . Elevated cardiac troponins: the ultimate marker for myocardial necrosis, but not without a differential diagnosis. Isr Med Assoc J 2009;11:50-53
Web of Science | Medline
To the Editor:
The studies by Keller et al. and Reichlin et al. confirm previous data indicating that sensitive cardiac troponin assays can improve the detection of myocardial injury in the emergency setting.1 Both groups investigated how the change in troponin levels may be used to improve the performance of such tests. However, defining what constitutes acute evolving myocardial injury by a rise in the troponin level in patients presenting early after the onset of chest pain requires further investigation, especially in light of the new high-sensitivity troponin assays.2 Reichlin et al. conclude that early changes did not improve the diagnostic performance. However, the exact criteria that were used were not explained — only that absolute values of early changes (≤2 hours) were used. At these early time intervals, preliminary data regarding both absolute and percent change criteria indicated that a high-sensitivity troponin assay (not yet commercially available) was superior to current assays.1 (Siemens Ultra and Abbott Architect assays are designated as contemporary, not high-sensitivity, assays.2) Thus, defining change in troponin levels is not only important with contemporary assays but will be critical for the next generation of high-sensitivity assays, for which even lower concentrations (>10 pg per milliliter) portend a poor prognosis at presentation.3
Peter Kavsak, Ph.D.
McMaster University, Hamilton, ON, Canada
kavsakp@mcmaster.ca Allan S. Jaffe, M.D.
Mayo Clinic, Rochester, MNDr. Kavsak reports receiving grant support and honoraria from Beckman Coulter and consulting fees from Ortho Clinical Diagnostics. Dr. Jaffe reports receiving research funding from Siemens and Beckman Coulter and receiving consulting fees from or serving on an advisory board for Siemens, Beckman Coulter, Ortho Clinical Diagnostics, Singulex, Nanosphere, Inverness, Critical Diagnostics, GlaxoSmithKline, and Novartis. No other potential conflict of interest relevant to this letter was reported.
3 References1
Kavsak PA ,MacRae AR ,Yerna MJ ,Jaffe AS . Analytic and clinical utility of a next-generation, highly sensitive cardiac troponin I assay for early detection of myocardial injury. Clin Chem 2009;55:573-577
CrossRef | Web of Science | Medline2
Apple FS . A new season for cardiac troponin assays: it's time to keep a scorecard. Clin Chem 2009;55:1303-1306
CrossRef | Web of Science | Medline3
Kavsak PA ,Wang X ,Ko DT ,MacRae AR ,Jaffe AS . Short- and long-term risk stratification using a next-generation, high-sensitivity research cardiac troponin I (hs-cTnI) assay in an emergency department chest pain population. Clin Chem 2009;55:1809-1815
CrossRef | Web of Science | Medline
To the Editor:
In his editorial, Morrow1 focuses on the clinical application of sensitive troponin assays. However, it would be useful to include a discussion on the application of negative troponin levels. It appears that in the study by Keller et al., the greater diagnostic accuracy of the sensitive troponin assays was driven by its much enhanced diagnostic sensitivity at the cost of a modest reduction in specificity. Therefore, an important advantage of the newer assays is in reliably ruling out myocardial infarction early in the diagnostic process. For patients at intermediate-to-high risk of myocardial infarction, two consecutively negative troponin levels obtained 3 hours apart virtually excluded the diagnosis of myocardial infarction with 100% sensitivity. For patients at low clinical risk, a single negative troponin level drawn at presentation (negative predictive value, >94%) would probably exclude myocardial infarction, although this application was not directly tested by the investigators.
Brian Y.L. Wong, M.D.
Sudbury Regional Hospital, Sudbury, ON, CanadaNo potential conflict of interest relevant to this letter was reported.
1 References1
Morrow DA . Clinical application of sensitive troponin assays. N Engl J Med 2009;361:913-915
Full Text | Web of Science | Medline
Author/Editor Response
We fully agree with Bauer and Gawaz that the widespread use of a very low cutoff level on sensitive troponin assays will result in an increased detection of patients with small areas of myocardial necrosis that would not have been detected with previous assays. It is therefore important to emphasize that the sensitive tests should always be used only in conjunction with clinical assessment and electrocardiography to differentiate acute myocardial infarction from other medical conditions associated with an elevation in the troponin level, such as myocarditis, acute heart failure, pulmonary embolism, and septic shock.1-3 The increased sensitivity provided by the new assays offers the possibility to advance from mainly qualitative (i.e., positive or negative) to quantitative information regarding the presence and extent of myocardial necrosis.
Kavsak and Jaffe highlight the importance of changes in troponin levels, which provided some incremental diagnostic value when added to the absolute troponin values at presentation in our study. However, we fully agree that with the use of sensitive troponin assays for the diagnosis of myocardial infarction and perhaps even more with the introduction of high-sensitivity troponin assays, the documentation of changes will be of even greater importance to differentiate acute disease from advanced chronic cardiac disease associated with small areas of myocardial necrosis.
Tobias Reichlin, M.D.
Christian Mueller, M.D.
University Hospital Basel, Basel, Switzerland
chmueller@uhbs.ch Since publication of their article, the authors report no further potential conflict of interest.
3 References1
Keller T ,Zeller T ,Peetz D , et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-877
Full Text | Web of Science | Medline2
Thygesen K ,Alpert JS ,White HD , et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-2653
CrossRef | Web of Science | Medline3
Mueller C ,Muller B ,Perruchoud AP . Biomarkers: past, present, and future. Swiss Med Wkly 2008;138:225-229
Web of Science | Medline
Author/Editor Response
With respect to the comments of Bauer and Gawaz: the initial design of our study was to evaluate the diagnostic value of a sensitive troponin I assay for the diagnosis of acute myocardial infarction, according to the universal definition of myocardial infarction,1 in patients with chest pain. The recommended and used low cutoff value, according to the 99th percentile of a reference population, provides excellent diagnostic performance in such patients. Therefore, our data do not allow us to draw conclusions on the use of more sensitive troponin assays in a general emergency department or in daily clinical routine. The determination and application of suitable cutoff values for sensitive troponin assays in different settings remain to be elucidated.
For comparison of different diagnostic biomarkers, ROC curves that are based on sensitivity and specificity of continuous values regardless of possible thresholds are a valid statistical approach. The application of low cutoff values leads to better sensitivity with a subsequent reduction in specificity because of false positive results. We found that the sensitive troponin I assay still delivers a positive predictive value of 82% in patients presenting within 3 hours after the onset of chest pain, illustrating that the downside of reduced specificity is of minor relevance in patients with suspected acute myocardial infarction.
With respect to the comments of Kavsak and Jaffe: we provided data on the ROC performance on the difference in levels between admission and 3 hours after admission. In this analysis, the absolute change in the troponin level was inferior to a single troponin measure on admission. On the other hand, in patients presenting within 3 hours after the onset of chest pain, a single troponin I level of more than 0.04 ng per milliliter on admission had a positive predictive value of 86.7% for myocardial infarction.
The use of a change in the level of creatine kinase MB as a marker of myocardial necrosis outperforms a single determination.2 Recent data suggesting that a change of more than 30% in the troponin level improves diagnostic specificity have been published.3 With clinical availability of sensitive troponin assays allowing the detection of small changes in troponin levels over time and with high-sensitive assays just around the corner, the measurement of troponin levels (including changes in such measures) promises to be a strong diagnostic marker.
Till Keller, M.D.
Thomas F. Münzel, M.D.
Stefan Blankenberg, M.D.
Johannes Gutenberg University Mainz, Mainz, Germany
blankenberg@2-med.klinik. uni-mainz. de Since publication of their article, the authors report no further potential conflict of interest.
3 References1
Thygesen K ,Alpert JS ,White HD , et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-2653
CrossRef | Web of Science | Medline2
Fesmire FM ,Christenson RH ,Fody EP ,Feintuch TA . Delta creatine kinase-MB outperforms myoglobin at two hours during the emergency department identification and exclusion of troponin positive non-ST-segment elevation acute coronary syndromes. Ann Emerg Med 2004;44:12-19
CrossRef | Web of Science | Medline3
Apple FS ,Pearce LA ,Smith SW ,Kaczmarek JM ,Murakami MM . Role of monitoring changes in sensitive cardiac troponin I assay results for early diagnosis of myocardial infarction and prediction of risk of adverse events. Clin Chem 2009;55:930-937
CrossRef | Web of Science | Medline
Author/Editor Response
Wong highlights an important potential advance of the more sensitive assays for cardiac troponin. The improved sensitivity of the assays studied by Keller and Reichlin, as well as other emerging assays for troponin,1,2 has substantially enhanced the negative predictive value of troponin testing, particularly early after presentation. As noted by Wong, the very high negative predictive value of testing with these assays holds promise to expedite the emergency evaluation of patients with suspected acute coronary syndrome by means of a rapid rule-out protocol that may shorten the period of observation in busy emergency departments. Moreover, the use of more sensitive troponin assays will probably obviate the need for the testing of other early biomarkers of necrosis, such as myoglobin, or putative biomarkers of ischemia. Nevertheless, as in the case of other tests that are used primarily for their negative predictive value (e.g., D-dimer), emergency providers should be aware of the trade-off in clinical specificity for the diagnosis of ischemic myocardial injury with newer-generation assays for troponin.
David A. Morrow, M.D., M.P.H.
Brigham and Women's Hospital, Boston, MASince publication of his article, the author reports no further potential conflict of interest.
2 References1
Wilson SR ,Sabatine MS ,Braunwald E ,Sloan S ,Murphy SA ,Morrow DA . Detection of myocardial injury in patients with unstable angina using a novel nanoparticle cardiac troponin I assay: observations from the PROTECT-TIMI 30 Trial. Am Heart J 2009;158:386-391
CrossRef | Web of Science | Medline2
Sabatine MS ,Morrow DA ,de Lemos JA ,Jarolim P ,Braunwald E . Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart J 2009;30:162-169
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Peter A. Kavsak, Lynn C. Allen, Fred S. Apple, Ronald A. Booth, Pak-Cheung Chan, Edgard Delvin, Albert Fraser, Lei Fu, Douglas Gornall, Christine Collier, Stephen Hill, Barry Hoffman, Yun Huang, Joël Lavoie, Amy Lou, Andre Mattman, Matthew McQueen, Qing H. Meng, Curtis Oleschuk, Morris Pudek, Edward Randell, Kun-Young Sohn, Laurel Thorlacius, Paul M. Yip, Nagib Dahdah, P.J. Devereaux, Sukhbinder Dhesy-Thind, Sebastien J. Hotte, Andrew Worster. (2011) Cardiac troponin testing in the acute care setting: Ordering, reporting, and high sensitivity assays—An update from the Canadian society of clinical chemists (CSCC). Clinical Biochemistry 44:16, 1273-1277
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