Undetectable Concentrations of a Food and Drug Administration–approved High‐sensitivity Cardiac Troponin T Assay to Rule Out Acute Myocardial Infarction at Emergency Department Arrival

Abstract

BackgroundThe objective of this study was to quantify the sensitivity of very low concentrations of high‐sensitivity cardiac troponin T (hsTnT) at ED arrival for acute myocardial infarction (AMI) in a large cohort of chest pain patients evaluated in real‐world clinical practice.MethodsThis retrospective study included consecutive ED patients with suspected cardiac chest pain evaluated in four urban EDs, excluding those with ST‐elevation AMI, cardiac arrest or abnormal kidney function. The primary outcomes were AMI at 7, 30, and 90 days. Secondary outcomes included major adverse cardiac events (MACE; all‐cause mortality, AMI, and revascularization) and the individual MACE components. Test characteristics were calculated for hsTnT values from 3 to 200 ng/L .ResultsA total of 7,130 patients met inclusion criteria. AMI incidences at 7, 30, and 90 days were 5.8, 6.0, and 6.2%. When the hsTnT assay was performed at ED arrival, the limit of blank of the assay (3 ng/L) ruled out 7‐day AMI in 15.5% of patients with 100% sensitivity and negative predictive value (NPV). The limit of detection of the assay (5 ng/L) ruled out AMI in 33.6% of patients with 99.8% sensitivity and 99.95% NPV for 7‐day AMI. The limit of quantification (the Food and Drug Administration [FDA]‐approved cutoff for lower the reportable limit) of 6 ng/L ruled out AMI in 42.2% of patients with 99.8% sensitivity and 99.95% NPV. The sensitivities of the cutoffs of <3, <5, and <6 ng/L for 7‐day MACE were 99.6, 97.4, and 96.6%, respectively. The NPVs of the cutoffs of <3, <5, and <6 ng/L for 7‐day MACE were 99.8, 99.5, and 99.4%, respectively. A secondary analysis was performed in a subgroup of 3,549 higher‐risk patients who underwent serial troponin testing. In this subgroup, a cutoff of 3 ng/L ruled out 7‐day AMI in 9.6% of patients with 100% sensitivity and NPV, a cutoff of 5 ng/L ruled out 7‐day AMI in 23.3% of patients with 99.7% sensitivity and 99.9% NPV, and a cutoff of 6 ng/L ruled out 7‐day AMI in 29.8% of patients with 99.7 and 99.9% NPV. In the higher‐risk subgroup, the sensitivities of cutoffs of <3, <5, and <6 ng/L for 7‐day MACE were 99.8, 97.4, and 96.6%, respectively. In this higher‐risk subgroup, the NPV of cutoffs of <3, <5, and <6 ng/L for 7‐day MACE were 99.7, 98.5, and 98.4%, respectively.ConclusionsWhen used in real‐world clinical practice conditions, hsTnT concentrations < 6 ng/L (below the lower reportable limit for an FDA‐approved assay) at the time of ED arrival can rule out AMI with very high sensitivity and NPV. The sensitivity for MACE is unacceptably low, and thus a single‐troponin rule‐out strategy should only be used in the context of a structured risk evaluation.

High-sensitivity troponin T and long-term adverse cardiac events among patients presenting with suspected acute coronary syndrome in Singapore

“…A total of 552 (22.6%) patients had one or more troponin readings ≥ 10 ng/L. This was associated with both 30 The cut-off of hsTnT at 50 ng/L, which corresponded to conventional troponin T (Roche Diagnostics) of 30 ng/L (10% CV precision of assay), gave PPVs of approximately 70% for 30-day and one-year MACE (Table II). There were 42 (25.3%) patients with hsTnT ≥ 50 ng/L at any one reading (i.e.…”

“…(29) As a rule-out strategy, hsTnT alone is still not sufficient for the purposes of identifying patients with high risk of MACE, and should be combined with assessment of other clinical factors. (30) Variables identified from multivariate logistic regression analysis as independent predictors of MACE other than hsTnT include: presentation with history of radiation of pain to both arms, pain relieved by rest, presence of diaphoresis, history of smoking and serum low-density lipoprotein cholesterol levels ≥ 3.4 mmol/L. Alternative strategies also include investigating the use of hsTnT when used with other biomarkers, such as soluble isoform of suppression of tumorigenicity 2 (sST2), which has been shown to be useful in prognosticating 30-day cardiac mortality among ED patients with chest pain.…”

Sex-specific, high-sensitivity cardiac troponin T cut-off concentrations for ruling out acute myocardial infarction with a single measurement

“…Previously published studies using this cohort have validated the test characteristics of an undetectable hs-cTnT concentration at ED arrival as a universal (i.e., not sex-specific) cut-off to rule out acute MI. 6 A secondary analysis was performed on a subsample of 722 patients with hs-cTnT concentrations measured at 2-hour intervals to validate published 2-hour rapid diagnostic algorithms. 11…”

“…5 The limit of quantitation approved by the U.S. Food and Drug Administration (FDA), 6 ng/L, can achieve similar high diagnostic sensitivity for MI. 6 Sex-specific diagnostic cut-offs for high-sensitivity troponin assays have been proposed for ruling-in MI. [7][8][9][10] In the rule-in scenario, sex-specific cut-offs improve diagnostic specificity and classification performance.…”

Low High-Sensitivity Troponin Thresholds Identify Low-Risk Patients With Chest Pain Unlikely to Benefit From Further Risk Stratification

“…Although there is a large body of research demonstrating the high sensitivity of very low hs-cTn thresholds on presentation to exclude index AMI for patients with chest pain presenting to the ED, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] there is less research examining the exclusion of 30-day AMI and major adverse cardiac events (MACE). 22 Moreover, many of the multicenter hs-cTn studies to date have been conducted in Europe or Australasia, relying on samples processed by a single core laboratory (likely representing optimal assay performance), and their results may not be generalizable to everyday clinical practice.…”