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Editorial |
1
Department of Laboratory Medicine, and Pathology, University of Minnesota, School of Medicine, Minneapolis, MN 55415
2
Department of Pathology, Hartford Hospital, Hartford, CT 06102
a Address correspondence to this author at: Hennepin County Medical Center, Clinical Laboratories MC 812, 701 Park Ave., Minneapolis MN 55415. Fax 612-904-4229; e-mail
fred.apple{at}co.hennepin.mn.us.
As we move into the new Millennium, "the times they are a changin" regarding the diagnostic criteria used to rule in and rule out acute myocardial infarction (AMI) (1). The purpose of this editorial is to comment on the new cardiology guidelines for the redefinition of AMI and unstable angina, as well as to compare them with previously published laboratory medicine recommendations. Some of the new recommendations made by clinical groups may appear to be in conflict with those published previously by laboratory medicine groups; thus, we document the chronology and evolution of all guidelines on the use of cardiac markers.
Consensus documents recently published by the European Society of Cardiology (ESC), the American College of Cardiology (ACC), and the American Heart Association (AHA) make specific recommendations on the use of biomarkers for the detection of myocardial infarction (MI) (2)(3)(4)(5). The redefined criteria used to classify acute coronary syndrome (ACS) patients presenting with ischemic symptoms as acute, evolving, or recent MI are heavily predicated on an increased serum/plasma cardiac troponin (I or T) concentration (2)(3)(4). Furthermore, in the new ACC/AHA guidelines for management of patients with unstable angina and non-ST-segment elevation MI (NSTEMI), an increased cardiac troponin value establishes the diagnosis of NSTEMI, whereas a normal cardiac troponin value establishes the diagnosis of unstable angina in ACS patients with ischemic discomfort (5).
The new guidelines emphasize the following clinical issues. First, increases of cardiac troponins are indicative of myocardial injury but are not synonymous with MI or an ischemic mechanism of injury. If an ischemic mechanism of injury is unlikely, other etiologies of myocardial injury should be pursued. Second, increases in cardiac troponin likely reflect irreversible rather than reversible injury, although there is continuing debate on this issue. Third, the degree of the increase of cardiac troponin in ischemia-induced injury patients is related to the patient’s prognosis. Fourth, patients who undergo interventional procedures, such as percutaneous transluminal coronary angioplasty (PTCA) or heart surgery, are likely to have increased cardiac troponin as a consequence of the procedure. In heart surgery patients, no biomarker is currently capable of distinguishing injury caused by a MI from the procedure-induced injury itself. However, increases of cardiac troponin after coronary angioplasty or stent placement is indicative of ischemic cell death and should be labeled as a MI.
The guidelines also emphasize the following laboratory (analytical)
issues. First, the diversity of the various cardiac troponin assays,
especially for cardiac troponin I (cTnI), has led to substantial
confusion among both clinicians and laboratorians. Standardization
issues will likely assist in resolving some of these concerns.
Acceptance of individual troponin assays should be based on the
peer-reviewed literature. Second, clinical studies in the peer-reviewed
literature should provide information pertaining to an
assay’s imprecision (CV), reference intervals,
potential analytical interferences, and acceptable specimen types. An
upper reference limit, defined as the 99th percentile with an
acceptable imprecision of 
10%, has been proposed. This places a
large responsibility on the manufacturers of all cardiac troponin
assays to optimize the low end of their assays. Although it is
presently recognized that relatively few, if any, companies can meet
this recommendation, it was the intent of the cardiology community to
challenge the troponin assay manufacturing industry to meet this
critical issue because diagnostic and therapeutic decisions will be
based on lower cardiac troponin cutpoints. Although the use of plasma
(heparin) instead of serum had initially been advocated as a means of
decreasing the overall turnaround time for reporting a result, recent
studies have shown that several cardiac troponin assays may give
variable and substantially lower concentrations for heparinized plasma
vs serum (6)(7). Therefore, each assay needs to
be validated for both serum and plasma. Third, cardiac troponin
concentrations should be measured on serial blood samples collected at
least 6–9 h after onset of symptoms, before a patient is ruled in or
ruled out for MI. Fourth, if cardiac troponin assays are not available,
the best alternative is creatine kinase MB (CK-MB) mass. Rapidly
appearing biomarkers, such as myoglobin or CK-MB isoforms, are
recommended for patients in need of an early triage, but they do not
confirm the diagnosis of MI. We completely support the new cardiology
guidelines and support the evidence-based literature that demonstrates
cardiac troponin as the definitive marker to be utilized for detection
of the MI, risk stratification, and to assist clinicians in optimizing
therapy.
From a clinical perspective, there is clear evidence that any amount of
detectable cardiac troponin release is associated with risk of adverse
clinical events. For cardiac troponin T (cTnT), the FRISC II study
demonstrated that risk stratification was achieved with use of a cutoff
concentration at the 99th percentile (8.5% incidence of death or AMI
at 12 months for cTnT <0.01 µg/L vs 18.0% for cTnT 
0.01 µg/L;
P <0.001) (8). Similar results have been
demonstrated for cTnI, where use of the 97.5th percentile cutoff of 0.1
µg/L produced significant odds ratios of 2.2 (confidence interval,
1.3–3.6), 2.8 (1.5–5.1), and 3.0 (1.5–5.7) with the Immuno 1
(Bayer), ACS:180 (Bayer), and Dimension RxL (Dade Behring) analyzers,
respectively (9). For each assay, the values at the 97.5th
vs 99th percentiles are similar. Although preliminary trials
show risk stratification benefits at the low end of cardiac troponin
assays, as noted above, the majority of manufacturers cannot meet the
10% imprecision (CV) recommendations at the 99th percentile. It is our
opinion, therefore, that in the context of clinical medicine, a
predetermined higher concentration that meets the goal of 10%
imprecision be used for each assay as a medical diagnostic guide for
therapy until the goal of a 10% CV can be achieved at the 99th
percentile. The magnitude of the medical problem stemming from a
CV-related misclassification of patients is unknown, but this likely
will be answered over time. In any event, the clinical assessment of
the patient still needs to be part of the medical decision process, as
highlighted in the new guidelines (2)(3)(4)(5).
With these newly published guidelines, we feel it is important and
timely to revisit the National Academy of Clinical Biochemistry (NACB)
(10) and the IFCC (11) guidelines
pertaining to the use of cardiac markers published in 1999, and compare
and contrast them with the ACC/ESC/AHA guidelines. First, both the NACB
and IFCC guidelines recommended the use of two markers (an early marker
and a late marker). The NACB recommended specimen collection at
admission, 2–4 h, 6–9 h, and an optional collection at 12–24 h,
whereas the IFCC recommended specimen collection at admission, 4, 8,
and 12 h (or next morning). The ESC/ACC and the ACC/AHA guidelines
state that for early MI diagnosis (within 6 h of the onset of
symptoms), an early biomarker of cardiac injury (myoglobin or CK-MB
subforms) should be considered in addition to a definitive marker that
increases later (troponin) (2)(3)(4). It is inferred that use
of an earlier marker would require collection of an earlier blood
sample, between admission and 6 h. Thus, there appears to be a
consensus between the laboratory and cardiology recommendations.
Furthermore, both groups acknowledge that only cardiac troponin testing
is necessary if a very early triage protocol is not being followed, and
we concur with this. A similar approach was recommended by the American
College of Emergency Physicians, who suggest a "repeat CK-MB at 2–3
h after baseline or repeat myoglobin at 1–2 h after baseline and
utilization of the 
CK-MB or myoglobin ... "
(12).
In the original criteria for MI, WHO listed unequivocal changes of serial enzyme measurements as one of the three criteria for diagnosis, the other two being electrocardiographic changes and clinical features such as chest pain (13). With the development of protein markers such as myoglobin and cardiac troponin, the NACB and IFCC Committees made a recommendation to expand on the enzyme diagnostic criteria for MI to include proteins. However, the NACB recommendations stopped short of actually changing the definition of MI and instead stated that it was the responsibility of cardiology groups, and not laboratorians, to redefine all of the criteria for diagnosis of MI. Thus, the redefinition of MI proposed by the joint ESC/ACC Committee is the appropriate next step.
Second, regarding cutoff concentrations for cardiac markers, the NACB and IFCC recommended the use of two decision limits for cardiac troponin, a low limit that establishes the first presence of myocardial injury (97.5th percentile) and a high limit that establishes injury to the extent that it qualifies as MI (ROC curve determined), as defined previously by WHO. At that time, the NACB Committee was concerned about the "social, psychological, and socioeconomic" impact of designating patients with minor myocardial injury as MI, and by lowering the cutoff, the incidence of MI would dramatically increase. Again, the NACB Committee opined that "until the criteria for diagnosis of AMI are redefined by WHO or other clinical groups such as the American Heart Association or American College of Cardiology, the NACB Committee recommends a two-cutoff designation for cardiac troponin." The ESC/ACC Committee has noted that improvements in biomarker assay technologies have continuously led to a more accurate ability to diagnose MI, leading to a gradual increase in MI incidence over the years since the inception of the WHO criteria. The introduction of cardiac troponin is simply the next step in the ever-evolving medical technology. Again, we agree with this approach. As the joint ESC/ACC redefinition of MI is fully endorsed and implemented, there will no longer be the need for the NACB recommendation for two cutoff concentrations.
Third, in establishing the lower of the two cutoffs, the NACB and IFCC
recommended use of the 97.5th percentile of the normal healthy
population, consistent with other clinical laboratory tests. By
definition, this will produce an analytical false-positive rate of
2.5%. The ESC/ACC and AHA/ACC guidelines have adopted a 99th
percentile as a single cut point, which is between the low and high
cutoffs recommended by the NACB and IFCC. The rationale for increasing
the lower cutoff from the 97.5th to the 99th percentile was to limit
the number of false-positive designations of myocardial injury.
Manufacturers of cardiac troponin assays must now ensure that their
assays have the necessary sensitivity and imprecision (CV 10%) to
meet these new cutoffs. Although this process of improving imprecision
will not occur overnight, we continually will stress the importance of
improving low-end assay imprecision. We anticipate that, as CVs of 10%
or less are achieved at concentrations corresponding to the 99th
percentile for each assay, medical decision cutpoints will continue to
be lowered (8)(9). Nevertheless, as the
precision and performance of cardiac troponin assays improve, more
clinical trials will be necessary to define the optimal cutpoints for
specific clinical decisions.
Finally, the NACB and IFCC recommended that cardiac troponin be the new biomarker standard for detection of myocardial damage. In the context of unstable angina, both the NACB and IFCC Committees stated that patients with small increases in cardiac troponin should be acutely treated to minimize the risk associated with myocardial injury. Other clinical groups have concurred with this recommendation. The ACC/AHA Task Force listed cardiac troponin as the preferred marker for early risk stratification (5). Results of cardiac troponin were added to the Braunwald class IIIB classification of unstable angina (14). The United States Agency for Health Care Policy and Research guidelines added an increased serum troponin I or T as one of the major criteria for entry of unstable angina patients into the high-risk group for short-term risk of adverse cardiac events (15). The Cardiac Society of Australia and New Zealand also lists cardiac troponin as the marker of choice for ACS (16). Each of these clinical groups along with the laboratory community has independently reached the conclusion that cardiac troponin is the best marker for diagnosis, risk stratification, and guidance of therapy in ACS. Again, we totally support the recommendation that only cardiac troponin is necessary. We further recommend that clinicians begin moving away from the use of CK-MB as their primary marker of choice.
In summary, we feel the ESC/ACC and ACC/AHA guidelines (2)(3)(4) should now become required reading for all healthcare professionals, including clinicians, laboratorians, residents, students, hospital administrators, and industry personnel, as their medical and societal impact will be far reaching. We support the overall conclusions of the new cardiology guidelines that have underscored the initially published laboratory guidelines asserting that cardiac troponin testing is the new, definitive laboratory standard for the diagnosis of MI.
References
The following articles in journals at HighWire Press have cited this article:
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  R Sharma, D C Gaze, D Pellerin, R L Mehta, H Gregson, C P Streather, P O Collinson, and S J D Brecker Cardiac structural and functional abnormalities in end stage renal disease patients with elevated cardiac troponin T Heart, June 1, 2006; 92(6): 804 - 809. [Abstract] [Full Text] [PDF]
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 F. S. Apple, C. A. Parvin, K. F. Buechler, R. H. Christenson, A. H.B. Wu, and A. S. Jaffe Validation of the 99th Percentile Cutoff Independent of Assay Imprecision (CV) for Cardiac Troponin Monitoring for Ruling Out Myocardial Infarction Clin. Chem., November 1, 2005; 51(11): 2198 - 2200. [Full Text] [PDF]
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 M. Panteghini Role and importance of biochemical markers in clinical cardiology Eur. Heart J., July 2, 2004; 25(14): 1187 - 1196. [Abstract] [Full Text] [PDF]
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 M. Kemp, J. Donovan, H. Higham, and J. Hooper Biochemical markers of myocardial injury Br. J. Anaesth., July 1, 2004; 93(1): 63 - 73. [Abstract] [Full Text] [PDF]
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M. Panteghini, F. Pagani, K.-T. J. Yeo, F. S. Apple, R. H. Christenson, F. Dati, J. Mair, J. Ravkilde, and A. H.B. Wu Evaluation of Imprecision for Cardiac Troponin Assays at Low-Range Concentrations Clin. Chem., February 1, 2004; 50(2): 327 - 332. [Abstract] [Full Text] [PDF]
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J. C. Lin, F. S. Apple, M. M. Murakami, and R. V. Luepker Rates of Positive Cardiac Troponin I and Creatine Kinase MB Mass among Patients Hospitalized for Suspected Acute Coronary Syndromes Clin. Chem., February 1, 2004; 50(2): 333 - 338. [Abstract] [Full Text] [PDF]
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 J. T. MacGregor The Future of Regulatory Toxicology: Impact of the Biotechnology Revolution Toxicol. Sci., October 1, 2003; 75(2): 236 - 248. [Abstract] [Full Text] [PDF]
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F. S. Apple, H. E. Quist, P. J. Doyle, A. P. Otto, and M. M. Murakami Plasma 99th Percentile Reference Limits for Cardiac Troponin and Creatine Kinase MB Mass for Use with European Society of Cardiology/American College of Cardiology Consensus Recommendations Clin. Chem., August 1, 2003; 49(8): 1331 - 1336. [Abstract] [Full Text] [PDF]
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D. A. Morrow, N. Rifai, M. S. Sabatine, S. Ayanian, S. A. Murphy, J. A. de Lemos, E. Braunwald, and C. P. Cannon Evaluation of the AccuTnI Cardiac Troponin I Assay for Risk Assessment in Acute Coronary Syndromes Clin. Chem., August 1, 2003; 49(8): 1396 - 1398. [Full Text] [PDF]
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S. Eriksson, M. Junikka, P. Laitinen, K. Majamaa-Voltti, H. Alfthan, and K. Pettersson Negative Interference in Cardiac Troponin I Immunoassays from a Frequently Occurring Serum and Plasma Component Clin. Chem., July 1, 2003; 49(7): 1095 - 1104. [Abstract] [Full Text] [PDF]
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R. Ziebig, A. Lun, B. Hocher, F. Priem, C. Altermann, G. Asmus, H. Kern, R. Krause, B. Lorenz, R. Mobes, et al. Renal Elimination of Troponin T and Troponin I Clin. Chem., July 1, 2003; 49(7): 1191 - 1193. [Full Text] [PDF]
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 M. Beciani, A. Tedesco, A. Violante, S. Cipriani, M. Azzarito, A. Sturniolo, and G. Splendiani Cardiac troponin I (2nd generation assay) in chronic haemodialysis patients: prevalence and prognostic value Nephrol. Dial. Transplant., May 1, 2003; 18(5): 942 - 946. [Abstract] [Full Text] [PDF]
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M. Herrmann, J. Scharhag, M. Miclea, A. Urhausen, W. Herrmann, and W. Kindermann Post-Race Kinetics of Cardiac Troponin T and I and N-Terminal Pro-Brain Natriuretic Peptide in Marathon Runners Clin. Chem., May 1, 2003; 49(5): 831 - 834. [Full Text] [PDF]
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Y. E.C. Taes, N. H. Lameire, M. L. De Buyzere, A. Shoja, G. De Backer, and J. R. Delanghe Exercise-induced Myocardial Ischemia Is Accompanied by Increased Serum Creatine Concentrations Clin. Chem., April 1, 2003; 49(4): 684 - 686. [Full Text] [PDF]
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 F. S. Apple, M. M. Murakami, L. A. Pearce, and C. A. Herzog Predictive Value of Cardiac Troponin I and T for Subsequent Death in End-Stage Renal Disease Circulation, December 3, 2002; 106(23): 2941 - 2945. [Abstract] [Full Text] [PDF]
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J. R. Tate, T. Badrick, G. Koumantakis, J. M. Potter, and P. E. Hickman Reporting of Cardiac Troponin Concentrations Clin. Chem., November 1, 2002; 48(11): 2077 - 2080. [Full Text] [PDF]
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A. H.B. Wu and F. S. Apple Drs. Wu and Apple respond: Clin. Chem., November 1, 2002; 48(11): 2080 - 2082. [Full Text] [PDF]
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F. S. Apple, M. M. Murakami, R. L. Jesse, M. A. Levitt, A. K. Berger, L. A. Pearce, and P. Collinson Near-Bedside Whole-Blood Cardiac Troponin I Assay for Risk Assessment of Patients with Acute Coronary Syndromes Clin. Chem., October 1, 2002; 48(10): 1784 - 1787. [Full Text] [PDF]
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V. Scharnhorst, H. L. Vader, and F. van der Graaf Characteristics of the Cardiac Troponin I Assay on the Immulite 2000 Analyzer Clin. Chem., September 1, 2002; 48(9): 1626 - 1627. [Full Text] [PDF]
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D. Peetz, G. Hafner, and K. J. Lackner Analytical Characteristics of the AxSYM Cardiac Troponin I and Creatine Kinase MB Assays Clin. Chem., July 1, 2002; 48(7): 1110 - 1111. [Full Text] [PDF]
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M. Panteghini Performance of Today's Cardiac Troponin Assays and Tomorrow's Clin. Chem., June 1, 2002; 48(6): 809 - 810. [Full Text] [PDF]
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D. Uettwiller-Geiger, A. H.B. Wu, F. S. Apple, A. W. Jevans, P. Venge, M. D. Olson, C. Darte, D. L. Woodrum, S. Roberts, and S. Chan Multicenter Evaluation of an Automated Assay for Troponin I Clin. Chem., June 1, 2002; 48(6): 869 - 876. [Abstract] [Full Text] [PDF]
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A. Cerutti, L. Corsini, R. Finotto, and C. Perazzi Comparison of Cardiac Troponin I in Serum and Heparin Plasma with the Dimension RxL Assay Clin. Chem., May 1, 2002; 48(5): 790 - 791. [Full Text] [PDF]
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G. P. Armstrong, A. N. Barker, H. Patel, and H. H. Hart Reference Interval for Troponin I on the ACS:Centaur Assay: A Recommendation Based on the Recent Redefinition of Myocardial Infarction Clin. Chem., January 1, 2002; 48(1): 198 - 199. [Full Text] [PDF]
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F. S. Apple, A. S. Jaffe, L. K. Newby, A. L. Kaplan, R. H. Tuttle, S. E. McNulty, E. M. Ohman, A. B. Storrow, W. B. Gibler, J. L. Garvey, et al. Bedside Multimarker Testing for Risk Stratification in Chest Pain Units: The Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I (CHECKMATE) Study Response Circulation, November 27, 2001; 104 (22): e125 - e126. [Full Text] [PDF]
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