Redefining the Gold Standard of Myocardial Infarction Using Troponin T.
Sir William Osler taught us that observations from patients could inform us. In my case, an event during my internship in 1981 led me to question how accurate the diagnosis of myocardial infarction (MI)  was. A 28-yearold man was admitted after he collapsed at the end of the Dublin marathon race. His electrocardiogram (ECG) was very abnormal. Myocardial biomarkers were increased, with high total creatine kinase (CK) and CK-MB activities. Later coronary angiograms demonstrated normal coronary arteries. I followed this up by a formal study showing that the prior "gold standard" markers of MI, CK, and CK-MB were frequently increased in marathon runners, while infarct-avid scanning failed to detect any MI (1). At the time, troponin testing was in its infancy and a standardized test was not available.
This interest in biomarkers continued after I came to Duke University in 1987, but focused more on the kinetics and the relationship to the ECG. Collaboratively with Galen Wagner and Rob Christensen, we performed several studies on a small cohort of patients with established MI who received fibrinolytic therapy to establish reperfusion (2). I enjoyed digesting the data together and exploring it in several ways. It became clear that small studies, although very carefully performed, were not going to move the biomarker field forward in any substantial way. On rounds in the Duke Coronary Care Unit, Rob Califf also famously announced that he was not sure why we were doing all the CK and CK-MB testing, as "it does not change what we do to our patients." This stimulated me to think of ways we could change this, and the need for large cohorts of patients to have an impact.
Eric Topol and Rob Califf had started a collaboration that evolved into the largest ever trial of MI, the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) trial. After an overwhelming success of their first trial of 41021 study participants, they had started to focus on patients with the full spectrum of acute coronary syndromes that included patients with unstable angina, as well as those with MI. A large multicenter clinical trial [GUSTO-IIa (3)] was designed that included 275 hospitals in 12 countries, which ultimately was stopped prematurely with 2564 study participants. This turned out to be the perfect environment for testing a new biomarker and to establish its role in acute coronary syndromes.
Hugo Katus and Christian Hamm had published an important paper in 1992 of 109 patients with unstable angina where cardiac troponin T (TnT) appeared to be a better indicator of MI than CK-MB activity, the standard biomarker for MI at the time (4). This early observation suggested that TnT would have the potential to replace CK-MB as the new gold standard for MI. The question arose, however, how do you replace a gold standard? The insight came from multiple discussions with key members of the GUSTO steering committee, statisticians Kerry Lee and Frank Harrell, and the physicians behind the early TnT work, Hugo Katus and Christian Hamm. The consensus was that the best approach was to link the increase of a biomarker with mortality. If the new biomarker was closely associated with 30-day mortality and was related to myocardial damage, then it should replace the old MI marker CK-MB. We knew of the utility of stepwise logistic regression modeling to better understand diagnostic tools and MI (5). This statistical principle did require that all test results be available in all participants, which was a tall order for a diagnostic study to be carried out in 96 hospitals in the US and Canada. To achieve the highest scientific standard of the interpretation of the tests, independent core laboratories were established for the ECG and biomarkers.
Conducting this type of large-scale collaborative diagnostic study did not come without challenges. First, our goal had been to collect data on approximately 1000 individuals, but as noted, the GUSTO-IIa study was stopped prematurely (3). Fortunately, the mortality rate at 30 days was higher than estimated so having complete data on only 855 study participants proved to be sufficient to show that TnT was a powerful predictor of mortality, and that it still showed prognostic value even if the ECG findings and CK-MB activities were accounted for.
Second, we submitted our paper featured here in the fall of 1995 with 13 authors, but the journal changed its authorship rule in 1996 to only allow 12. When we resubmitted our paper with extensive revisions, we were told that it was acceptable for publication, but we had to remove an author! No pleading with the editor helped. However, one of the key statisticians, Kerry Lee, graciously agreed to remove his name from the paper. It gives me great pleasure now, 20 years later, to set the record straight; his philosophical approach to changing the gold standard and authorship rules showed tremendous integrity seldom seen in academic medicine.
It took another 5 years before we could prove to Rob Califf that measuring TnT was a useful biomarker since we were able to link it to the use of a therapeutic strategy that led to better outcomes (6). The changing of the gold standard from CK-MB to troponin was also accomplished with the first collaborative group of redefinition of MI in 2000. There was some debate, but nobody questioned whether a troponin increase was linked to mortality. To date, no other biomarker has replaced its role in diagnosing MI.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: E.M. Ohman, Abbott Vascular, Abiomed, AstraZeneca, Biotie, Boehringer Ingelheim, Daiichi Sankyo, Faculty Connection, Medscape, Merck, St. Jude Medical, Stealth Peptides, and The Medicines Company.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: E.M. Ohman, Daiichi Sankyo, Gilead Sciences, and Janssen Pharmaceuticals to the institutions.
Expert Testimony: None declared.
Patents: None declared.
(1.) Ohman EM, Teo KK, Johnson AH, Collins PB, Dowsett DG, Ennis JT, Horgan JH. Abnormal cardiac enzyme responses after strenuous exercise-alternative diagnostic aids. Br Med J 1982;285:1523-6.
(2.) Christenson RH, Ohman EM, Clemmensen P, Grande P, Toffaletti J, Silverman LM, et al. Characteristics of creatine kinase-MB and MB isoforms in serum after reperfusion in acute myocardial infarction. Clin Chem 1989;35:2179-85.
(3.) The Global Use of Strategies to Open Occuluded Coronory Arteries (GUSTO) Ila Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994;90:1631-7.
(4.) Hamm CW, Ravkilde J, Gerhardt W, Jorgensen P, Peheim E, Ljungdahl L, et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327: 146-50.
(5.) Ohman EM, Casey C, Bengtson JR, Pryor D, Tormey W, Horgan JH. Early detection of acute myocardial infarction: additional diagnostic information by serum myoglobin in patients without ST elevation. Br Heart J 1990;63:335-8.
(6.) Newby LK, Ohman EM, Christenson RH, Moliterno DJ, Harrington RA, White HD, et al. for the PARAGON-B Investigators. Benefit of glycoprotein llb/llla inhibition in patients with acute coronary syndromes and troponin T-positive status: the PARAGON-B Troponin Substudy. Circulation 2001;103:2891-6.
E. Magnus Ohman  *
 The Program for Advanced Coronary Disease, Division of Cardiology and Duke Clinical Research Institute, Duke University, Durham, NC.
* Address correspondence to the author at: Duke University Medical Center, Box 3126 DUMC, Durham, NC27710. Fax 919-681-6443; email@example.com.
 This article has been cited more than 800 times since its publication.
Received September 13,2016; accepted September 16,2016.
Previously published online at DOI: 10.1373/clinchem.2016.267047
 Nonstandard abbreviations: MI, myocardial infarction; ECG, electrocardiogram; CK, creatine kinase; GUSTO, Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries trial; TnT, cardiac troponin T.
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|Author:||Ohman, E. Magnus|
|Date:||Jan 1, 2017|
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