High sensitivity cTnI results are used to assist in the diagnosis of acute myocardial infarction and to aid in the risk stratification of patients with acute coronary syndromes with respect to their relative risk of mortality [1-6].
Precision at low concentrations
The imprecision profile at low concentrations was determined by using plasma samples. The within-run and total standard deviations were calculated by CLSI EP5-A2 guidelines. The following results were obtained:
Sensitivity and measurable normal value
The limit of blank (LoB) and the limit of detection (LoD) of the PATHFASTTM hs-cTnI assay were determined, where LoB was 1.23 ng/L and LoD was 2.33 ng/L. The limit of quantitation (LoQ) at 20% coefficient of variation (CV) was determined to be 4 ng/L. The limit of quantitation (LoQ) at 10% coefficient of variation (CV) was determined to be 15 ng/L. These results were obtained from plasma samples.
The measurable number of healthy subjects between LoD and 99th percentile was 487 from 734 healthy subjects, in whom cardiovascular diseases were excluded by the following criteria: age <18; HbA1c ≥6.5%; NTpro-BNP ≥125 ng/L <75; NTpro-BNP ≥450 ng/L ≥75 years; eGFR <60 mL/min/1.73m².
PATHFASTTM hs-cTnI was classified as a high sensitive assay according to IFCC guidelines. With PATHFASTTM hs-cTnI assay classified as a high sensitivity assay, the gender specific 99th percentile and the measurable number of healthy subjects between LoD and 99th percentile were identified .
The reference interval for the PATHFASTTM hs-cTnI assay was determined by testing 490 healthy individuals. The 99th percentile of the reference interval is 29 ng/L. The CV value at the 99th percentile concentration is 6.1% .
Diagnostic performance criteria
cTnI concentrations were measured by using the PATHFASTTM hs-cTnI assay in EDTA plasma samples obtained at 0 hour, 1 hour and 3 hours after admission to the chest pain unit (CPU) from 993 patients with suspicion of acute coronary syndrome. The final diagnosis identified 219 AMI patients (23.5%). The ROC analysis revealed AUC values for the discrimination between AMI and non-AMI patients including the clinical sensitivity and specificity, as well as the positive (PPV) and negative (NPV) predictive values based on the 99th percentile upper reference limit (URL) of 27.0 ng/L .
Diagnostic algorithms for PATHFASTTM hs-cTnI
The ESC guidelines recommended rule-in and rule-out algorithms using hs-cTn assays in patients admitted with suspected NSTEMI to the ED .
Rule-out of NSTEMI at admission for PATHFASTTM hs-cTnI (0 h)
According to the ESC guideline rule-out is possible already at admission (0 h) if the value is below a cut off level (A) and if onset of chest pain > 3 h. Regarding the LoD of 2.3 ng/L  recent s tudy data of PATHFASTTM hs-cTnI using a cut off level A of 3 ng/L with targeted NPV of 100% revealed the following results :
For 0 h rule-out only individuals with a symptoms onset over 3 h before presentation were used.
0 h / 1 h Rule-out algorithm of NSTEMI for PATHFASTTM hs-cTnI
A rule-out of NSTEMI is possible by the combination of a baseline concentration below a cut off level B and the delta from 0 h to 1 h < C (Fig. 1). 2015 ESC Guidelines recommend that in large validation cohorts the NPVs for rule-out of NSTEMI should exceed 98% . A diagnostic algorithm for a high-sensitive troponin I point of care assay was developed in a derivation dataset with 669 patients and validated in additional 610 patients. For PATHFASTTM hs-cTnI wide range of the combination was tested for 1.221 patients with suspected NSTEMI to achieve a NPV of above 99.5% with the highest number of patients ruled-out and the following cut off values have been identified [11-12] (Tab. 1).
0 h / 1 h Rule-in algorithm of NSTEMI for PATHFASTTM hs-cTn I
A rule-in for the likelihood of NSTEMI is possible if the hs-cTn value at admission (0 h) is measured above of a cut off level ≥ D or the hs-cTn concentration shows a rise within the first hour above the delta cut off level ≥ E (Table 2).
2015 ESC Guidelines recommend that the PPVs for validation cohorts should meet the rule-in criteria of 75-80% . For PATHFASTTM hs-cTnI the clinical study with 1.221 patients with suspected NSTEMI showed PPVs above 75% with specifities above 95%. The following cut off values have been identified [11-12] (Tab. 2). Regarding the clinical situation of the individual patient the user may decide which cut off values may be applicable for optimal rule-out or rule-in.
- Thygesen K, Alpert JS, White HD. Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J. 2007;28:2525-382)The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary
- Syndromes of the European Society of Cardiology. Guidelines for the diagnosis and treatment of non-ST-elevation acute coronary syndromes. Eur Heart J 2007;28:1598-1660.
- Apple FS. High-sensitivty cardiac troponin assays: what analytical and clinical issues need to be addressed before introduction into clinical practice? Clin Chem 2010;56:886-91.
- Peetz D et al. Method comparison of cardiac marker assays on PATHFAST, StratusCS, Axsym, Immulite 2000, Triage, Elecsys and Cardiac reader. Clin Lab 2006;52:605-14.
- Sandoval Y, Smith SW, Love SA, Sexter A, et al. Single high-sensitivity cardiac troponin I to rule-out acute myocardial infarction. Am J Med. 2017;130(9):1076-83.
- Sandoval Y, Smith SW, Shah ASV, Anand A, et al. Rapid Rule-Out of Acute Myocardial Injury Using a Single High-Sensitivity Cardiac Troponin I. Clin Chem 2017; 63:369-76.
- Cristenson et al. High-Sensitivity Cardiac Troponin I Assay for Point-of-Care or Laboratory Measurement: Pathfast® TnI-II System. TnI-II : in preparation.
- Neuman JT, Sörensen NA, Schwemer T, et al. Diagnosis of Myocardial Infarction Using a High-Sensitivity Troponin I 1-Hour Algorithm. JAMA Cardiol. 2016;1:397-404.
- Roffi M, Patrono C, Collet JP, et al.2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2016; 37(3): 267-315
- Christenson RH, Duh S-H, et al. Validation of high-sensitivity performance for a United States Food and Drug Administration cleared cardiac troponin I assay. Clin Biochem. 2018 Jun; 56:4-10
- Sörensen NA, Neumann JT, Ojeda F, et al. Diagnostic evaluation of a high-sensitivity troponin I point-of-care I assay. Clin Chem 2019; (65): 1592-1601
- Sörensen NA, Neumann JT, Ojeda F, et al. Rule-out and rule-in of non-ST-elevation myocardial infarction using a novel high-sensitivity troponin I point of care assay. ESC Congress Paris 2019, P2675