A new season for cardiac troponin assays: it's time to keep a scorecard.

Advancements in cardiac troponin (cTn) assay technology have created a conundrum for clinicians and laboratory scientists, who must determine which assays are best for optimal patient care. Unfortunately, few resources are available to guide the medical and scientific communities in this regard. International guidelines (1–3 ) have defined an increased cTn above the 99th percentile limit as an abnormal result; what is lacking, unfortunately, is an approach to define this limit across the heterogeneity of the assays. In spite of the evidence-based literature demonstrating that cTn concentrations tend to increase in individuals .60 years old (4 ), 99th percentile reference limits are often determined across wide age ranges using subjects as old as 70 years (convenience samples). Further frustrating the problem of selecting relevant reference subjects, in clinically defined “normal” individuals without known cardiovascular disease, increased cTn concentrations are indicative of a significantly higher risk of death (4, 5 ). The occurrence of such individuals in reference populations may reflect inadequate screening for comorbidities at the time of sample acquisition. Given such problems, a majority of laboratories either accept the manufacturer’s reference limit from the US Food and Drug Administration (FDA)-cleared package insert, perform an underpowered normal range study to establish a reference limit, or accept a reference limit published in the literature. To validate cTn assays, however—to level the playing field for all users—is necessary for the best patient care. cTnI and cTnT are established as the standard biomarkers for the detection of myocardial injury and prognostic evaluation of patients with acute coronary syndrome (ACS) and without (1–3 ). The consensus guidelines from the Global Task Force for the Universal Definition of Myocardial Infarction (1 ) and the National Academy of Clinical Biochemistry (2 ), plus the updated American College of Cardiology/American Heart Association guidelines (3 ), have recommend that, in patients who present with ischemic symptoms, at least 1 cTn concentration higher than the 99th percentile value during the first 24 h after onset of symptoms indicates myocardial necrosis consistent with myocardial infarction (MI). A rising and/or falling pattern of cTn is typically sought to distinguish increased cTn caused by a chronic, nonischemic pathophysiology from an acute ischemic presentation indicative of an evolving MI. It is been further recommended that only cTn assays with appropriate quality control and optimal total imprecision (CV #10%) at the 99th percentile value (“guideline acceptable,” Table 1) be used. Better imprecision at low cTn concentrations appears to improve the value of cTn as both diagnostic and risk indicator (2, 4 ). Use of cTn assays with intermediate imprecision (10% to 20% CV) at the 99th percentile, however, does not lead to significant patient misclassification when interpreting serial cTn results (6 ). This evidence serves as part of the proposed scorecard designation of “clinically usable” (Table 1). One challenge that arises as the FDA clears improved cTn assays with higher analytical sensitivity for use in laboratory practice is determining how these new assays compare to older assays already in the marketplace. Diagnostic sensitivities using specimens collected at presentation for detection of MI have improved from 15%–35% for early cTn assays to 50%– 75% for contemporary assays (7–9 ). Over the past 10 years, the science and technology of cTn assays has improved to allow measurement of this biomarker with greatly improved precision at concentrations approaching an assay’s limit of detection (10, 11 ). Much confusion has been generated, however, as cTn assays are neither standardized nor harmonized, and likely never will be— every assay uses a different set of antibodies for capture and detection of circulating cTn forms in blood (12 ). Using a high-sensitivity (hs) cTn assay, changes over 4 h as small as 2 ng/L at cTn concentrations between 3 and 8 ng/L (which is less than any measurable contemporary FDA-cleared assay) are associated with transient stress-induced myocardial ischemia detected by myocardial perfusion imaging (11 ). The development of assays able to measure small cTn concentration changes or deltas within the normal 1 Hennepin County Medical Center and University of Minnesota School of Medicine, Department of Laboratory Medicine and Pathology Minneapolis, MN.  Address correspondence to the author at: Hennepin County Medical Center, Clinical Labs P4, 701 Park Ave., Minneapolis, MN 55415. Fax 612-904-4229;  2009; accepted April 27, 2009. Previously published online at DOI: 10.1373/clinchem.2009.128363 2 Nonstandard abbreviations: cTn, cardiac troponin; FDA, US Food and Drug Administration; ACS, acute coronary syndrome; MI, myocardial infarction; hs, high-sensitivity.  (2009)