Nam K. Tran, PhD, HCLD (ABB), FACB, Associate Professor and Director of Clinical Chemistry
On June 18, 2018, UC Davis Health will transition to a “high sensitivity” (hs) cardiac troponin T (cTnT) assay (Roche Diagnostics, Indianapolis, IN). This new test is presently the only hs-troponin test available in the United States1 and UC Davis will presently be the only institution in Northern California to offer this test. The hs-cTnT assay is also faster and exhibits enhanced analytical precision to enable short interval serial testing for emergency department (ED) patients.
European and internal studies indicate false positive rates remain acceptably low despite the increased sensitivity.2 In fact, large European multicenter trials found no statistically significant increase in cardiac catheterization events and observed a significant decrease in ED turnaround times and cardiac stress testing. This article focuses on lab best practices to optimize use of hs-cTnT testing at our institution.
Lab Best Practices
Choosing Troponin Testing Wisely: Cardiac troponin is the preferred biomarker for diagnosing acute MI.3 Troponin testing should only be ordered if there is clinical suspicion of cardiac injury and when results would change management. Excessive or unnecessary ordering of hs-cTnT, especially in patients with a low pre-test probability, increases risk for false positive results. As defined by the 3rd Universal Definitions, the diagnosis of MI is based on a rise and/or fall in a cardiac biomarker with at least one value above the 99th percentile of the upper reference limit (URL) and at least one of the following: (a) symptoms of ischemia, (b) new or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle branch block, (c) development of pathological Q waves in the electrocardiogram, (d) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, or (e) identification of an intracoronary thrombus by angiography or autopsy.
Emergency Department (ED) versus Inpatient hs-cTnT Testing: European studies have shown 1-hour or 2-hour MI rule out accelerated diagnostic protocols (ADP) can be safely employed in the ED setting.2 This is facilitated by ED patients taking an average of three hours to arrive following symptom onset4—allowing troponin levels to sufficiently increase to detectable levels and be reliably trended via serial testing. In contrast, ADPs have not been used for inpatients, thus, NOT recommended at UC Davis. The rationale is based on MI presentation likely being recognized very early among inpatients and troponin levels could remain undetectable for several hours despite electrocardiogram changes. To this end, it is recommended inpatient evaluation of MI follow traditional serial (time 0, 3, and 6 hour) testing schemes.
Elevated Troponins in Non-Ischemic Patients: By definition, high sensitivity troponin assays are capable of quantifying biomarkers in >50% of the healthy population.1,2 Patients with hs-cTnT levels near or at the 99th percentile of the URL (19 ng/L) or with a stable troponin values at or above the 99th percentile may require follow-up with their outpatient provider. In a recent study, patients with an elevated hs-troponins combined with renal impairment had a 2-fold greater risk of a major cardiac event irrespective of MI status.5 Prior studies have made similar observations with elevated hs-troponin assays identifying increased risk for cardiovascular death and heart failure at a median of 5.2 years.6,7 As with contemporary troponin assays, biomarker levels may be elevated in other conditions such as sepsis, myocarditis, thyroid disorders, renal dysfunction, among other diseases.
Interfering Substances: High sensitivity cardiac troponin assays have increased sensitivity to heparin8 and hemolysis9. These interferences impact both troponin I and T assays (hs-cardiac troponin I currently not available in the United States) assays. Heparin interference is typically encountered in specimens that are short sampled (inadequate volume).8,9 Both hemolysis and short sampling are detected by the clinical laboratory and specimens will need to be recollected. Heparin interference may also be encountered in coronary artery bypass graft (CABG) patients receiving high dose anticoagulation therapy. Both heparin and hemolysis interference cause falsely low hs-troponin values.8,9
Biotin interference is encountered in patients taking “mega” doses of greater than 100 to 300 mg/day.10,11 Patients using high doses of biotin are often those with multiple sclerosis and/or thyroid disorders. High dose biotin therapy is not approved by the United States Food and Drug Administration and has no documented benefit. Other populations taking biotin may include patients interested beauty products. Patients with normal renal function taking <10 mg/day of biotin should not affect hs-cTnT testing.11 However, since biotin is eliminated by renal pathways, patients with kidney dysfunction or on dialysis may have altered kinetics. Biotin falsely lowers hs-cTnT levels. Providers should ask patients if they are taking biotin supplements or “beauty supplements”. Internal studies evaluating biotin levels in ED patients at UC Davis have not identified concentrations that would interfere with the hs-cTnT.
Heterophilic antibodies in some patients may cause falsely high or falsely low troponin values on any assay.12 Some patients may produce these heterophilic antibodies against the assay’s detection antibodies and causing erroneous results. It is anticipated the hs-cTnT assay is less susceptible to heterophilic antibody interference compared to other high sensitivity or contemporary assays.
In the end, the diagnosis of MI should never be based on troponin alone and follow 3rd Universal Definitions.3 Patients with troponin levels that do not match the clinical presentation should be reported to the laboratory for troubleshooting.
- Roche Diagnostics website: http://www.cobas.com/home/news-room/cobas-stories/troponin-t-test-approved-fda.html, Accessed on June 12, 2018.
- Twerenbold R, Jaeger C, Gimenez MR, et al. Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction. Eur Heart J 2016;21:3324-3332.
- Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;16:1581-1598.
- Grossman SA, Brown DF, Chang Y, et al. Predictors of delay in presentation to the ED in patients with suspected acute coronary syndromes. Am J Emerg, Med 2003;21:425-428.
- Hodges EM, Anand A, Shah AS, et al. High sensitivity cardiac troponin and risk stratification of patients with renal impairment presenting with suspected acute coronary syndrome. Circulation 2018;137:425-435.
- Omland T, de Lemos JA, Sabatine JA, et al. Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease. Am Coll Cardiol 2013;61:1240–1249.
- Omland T, de Lemos JA, Sabatine JA, et al. Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial investigators, a sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009;361:2538–2547.
- Speth M, Seibold K, Katz N. Interaction between heparin and cardiac troponin T and troponin I from patients after coronary artery bypass. Clin Biochem 2002;35:355-362.
- Bais R. The effect of sample hemolysis on cardiac troponin I and T assays. Clin Chem 2010;56:1357-1359.
- United States Food and Drug Administration (FDA) website: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm586641.htm, Accessed on June 14, 2018.
- Grimsey P, Frey N, Bendig G, et al. Population pharmacokinetics of exogenous biotin and the relationship between biotin serum levels and in vitro immunoassay interference. Int J Pharmacokinet 2017;2:247-256.
- Xu RY, Zhu XF, Yang Y, et al. High sensitivity cardiac troponin T. J Geriatr Cardiol 2013;10:102-109.