Author + information
- Raphael Twerenbold, MD,
- Patrick Badertscher, MD,
- Jasper Boeddinghaus, MD,
- Thomas Nestelberger, MD,
- Karin Wildi, MD,
- Maria Rubini Gimenez, MD,
- Òscar Miró, MD,
- F. Javier Martín-Sánchez, MD,
- Tobias Reichlin, MD and
- Christian Mueller, MD∗ ()
- ↵∗CRIB and Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
The early and accurate diagnosis of myocardial infarction (MI) is a prerequisite for the timely initiation of life-saving treatment. The fifth-generation cardiac troponin T assay (hs-cTnT) has recently been approved by the U.S. Food and Drug Administration (FDA) as the first clinically available, more sensitive cardiac troponin (cTn) assay in the United States (1). These more sensitive assays have been used clinically in Europe, Australia, Canada, and other countries for several years due to their diagnostic superiority over conventional cTn assays. Higher sensitivity and accuracy for MI already at presentation to the emergency department (ED) allowed interval shortening to the second cTn measurement and development of the 0/1-h algorithm (2). This strategy allows rapid and safe triage of patients with suspected MI toward rule-out or -in based on hs-cTn concentrations determined at presentation and after 1 h, and has a Class I recommendation for clinical use in the current European guideline (2).
The FDA-approved use of hs-cTnT differs in 2 important details from the contemporary use of hs-cTnT in most other countries. First, very low concentrations are only reported down to the limit of quantification (6 ng/l) compared with the limit of blank (3 ng/l). Second, the FDA-approved 99th percentile upper reference limit (19 ng/l) is slightly higher, as it was determined in a reference population matched to the age of patients presenting to the ED with suspected MI; in contrast, the 99th percentile for use outside of the United States (14 ng/l) was determined in healthy and often younger individuals. The performance of the 0/1-h algorithm and the alternative 0/3-h algorithm, which combines hs-cTn concentrations below the 99th percentile with clinical criteria (GRACE [Global Registry of Acute Coronary Events] score <140 and pain-free without opioids), in the FDA-approved setting is unknown.
We therefore prospectively assessed the safety and efficacy of the 0/1-h algorithm using hs-cTnT as approved by the FDA in a large, diagnostic, multicenter study enrolling unselected patients presenting with suspected MI to the ED. Patients presenting with ST-segment elevation MI were excluded. The final diagnosis was centrally adjudicated by 2 independent cardiologists based on all available clinical information, including cardiac imaging and serial measurements of hs-cTnT. Safety of rule-out was quantified as the negative predictive value and sensitivity for MI, rule-in performance by positive predictive value and specificity, and efficacy as proportion of patients assigned to rule-out/-in based on the 0- and 1-h blood sample. The 0/1-h algorithm was applied twice using: 1) the original 0/1-h algorithm with hs-cTnT concentrations reported down to 3 ng/l, a direct rule-out criteria for hs-cTnT concentrations <5 ng/l, and adjudication based on the 99th percentile approved in the rest of the world (14 ng/l); and 2) using a minimally modified 0/1-h algorithm according to the FDA approval, allowing direct rule-out for hs-cTnT baseline concentrations <6 ng/l and adjudication based on the FDA-approved 99th percentile (19 ng/l) (Figure 1). Similarly, rule-out performance of the alternative 0/3-h algorithm was assessed (2).
Among 3,267 patients, MI was the adjudicated final diagnosis in 516 (15.8%) and 508 (15.5%) patients using the original and the FDA-approved 99th percentile, respectively. Safety of the original and the modified 0/1-h algorithm was very high and comparable (negative predictive value 99.8% vs. 99.9% [p = 0.928]; sensitivity 99.4% vs. 99.6% [p = 0.667], respectively). No patient with MI was missed by the original (<5 ng/l) or the modified (<6 ng/l) direct rule-out criteria applicable for patients with chest pain onset >3 h prior to ED presentation. Rule-in performance was excellent and comparable for both 0/1-h algorithms (positive predictive value 76.9% vs. 76.7% [p = 0.969]; specificity 95.5% for both algorithms [p = 0.929]). Both 0/1-h algorithms allowed rapid rule-out and -in of MI in 3 of 4 patients (76.7% vs. 77.0%; p = 0.774). Of the 8 (0.2%) patients downgraded from MI to unstable angina using the FDA-approved higher 99th percentile, 6 underwent percutaneous coronary intervention at index admission.
For the 0/3-h algorithm, safety in the FDA-approved setting using 19 ng/l as the 99th percentile was high, with a minor, not statistically significant reduction of sensitivity, missing 6 compared with 3 MI patients using the original setting of 14 ng/l (sensitivity 98.5% vs. 99.3%; p = 0.301). Using 14 ng/l for adjudication of MI in both settings, 13 compared with 3 MI patients were missed.
Using hs-cTnT as approved by the FDA, the 0/1-h algorithm seems to provide very high safety and efficacy for the triage toward rapid rule-out or -in of MI.
Please note: The APACE (Advantageous Predictors of Acute Coronary Syndromes Evaluation) study was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel, Abbott, Beckman Coulter, Biomerieux, Brahms, Roche, Siemens, and Singulex. Dr. Twerenbold has received research support from the Swiss National Science Foundation (P300PB-167803/1); and has received speaker honoraria/consulting honoraria from Roche, Abbott, Siemens, and Brahms. Dr. Boeddinghaus has received speaker honoraria from Siemens. Dr. Rubini has received speaker honoraria from Abbott. Dr. Reichlin has received research grants from the Goldschmidt-Jacobson-Foundation, the Swiss National Science Foundation (PASMP3-136995), the Swiss Heart Foundation, the Professor Max Cloëtta Foundation, the Uniscientia Foundation Vaduz, the University of Basel, and the Department of Internal Medicine, University Hospital Basel; and has received speaker honoraria from Brahms and Roche. Dr. Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the Stiftung für kardiovaskuläre Forschung Basel, Abbott, Alere, AstraZeneca, Beckman Coulter, Biomerieux, Brahms, Roche, Siemens, Singulex, Sphingotec, and University of Basel; and has received speaker/consulting honoraria from Abbott, Alere, AstraZeneca, Biomerieux, Boehringer Ingelheim, BMS, Brahms, Cardiorentis, Novartis, Roche, Sanofi, Siemens, and Singulex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study; NCT00470587).
- 2017 American College of Cardiology Foundation
- ↵U.S. Food and Drug Administration. 510(k) substantial equivalence determination decision summary. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/K162895.pdf. Accessed April 13, 2017.
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