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Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study.

ABSTRACT: Background:High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed that quantify lower cTnI concentrations with better precision versus earlier generation assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification in patients presenting to the emergency department with suspected acute myocardial infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United States (HIGH-US) study design used to conduct studies for characterizing the analytical and clinical performance of hs-cTnI assays, as required by the US Food and Drug Administration for a 510(k) clearance application. This study was non-interventional and therefore it was not registered at clinicaltrials.gov. Methods:We conducted analytic studies utilizing Clinical and Laboratory Standards Institute guidance that included limit of blank, limit of detection, limit of quantitation, linearity, within-run and between run imprecision and reproducibility as well as potential interferences and high dose hook effect. A sample set collected from healthy females and males was used to determine the overall and sex-specific cTnI 99th percentile upper reference limits (URL). The total coefficient of variation at the female 99th percentile URL and a universally available American Association for Clinical Chemistry sample set (AACC Universal Sample Bank) from healthy females and males was used to examine high-sensitivity (hs) performance of the cTnI assays. Clinical diagnosis of enrolled subjects was adjudicated by expert cardiologists and emergency medicine physicians. Assessment of temporal diagnostic accuracy including sensitivity, specificity, positive predictive value, and negative predictive value were determined at presentation and collection times thereafter. The prognostic performance at one-year after presentation to the emergency department was also performed. This design is appropriate to describe analytical characterization and clinical performance, and allows for acute myocardial infarction diagnosis and risk assessment.

SUBMITTER: Christenson RH

PROVIDER: S-EPMC6384326 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study.

Christenson R H RH Peacock W F WF Apple F S FS Limkakeng A T AT Nowak R M RM McCord J J deFilippi C R CR

Contemporary clinical trials communications 20190215

<h4>Background</h4>High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed that quantify lower cTnI concentrations with better precision versus earlier generation assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification in patients presenting to the emergency department with suspected acute myocardial infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United States (HIGH-US) study design used to conduct studies for c ...[more]

PMID: 30834354

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Project description:BackgroundThe diagnosis of hypertension is often preceded by cardiac structural abnormalities. Thus, we assessed whether high-sensitivity cardiac troponin T (hs-cTnT), a marker of subclinical myocardial damage, can identify individuals at risk for hypertension or left ventricular hypertrophy.Methods and resultsWe studied 6516 Atherosclerosis Risk in Communities (ARIC) Study participants who were free of prevalent hypertension and cardiovascular disease at baseline (1990-1992). We examined the association of baseline hs-cTnT categories with incident diagnosed hypertension (defined by self-report of a diagnosis or medication use during a maximum of 19.9 years of follow-up) and with incident visit-based hypertension (defined by self-report, medication use, or measured blood pressure >140/90 mm Hg over 6 years). Relative to hs-cTnT <5 ng/L, adjusted hazard ratios for incident diagnosed hypertension were 1.16 (95% confidence interval, 1.08-1.25) for individuals with hs-cTnT of 5 to 8 ng/L, 1.29 (95% confidence interval, 1.14-1.47) for hs-cTnT of 9 to 13 ng/L, and 1.31 (95% confidence interval, 1.07-1.61) for hs-cTnT ≥14 ng/L (P for trend <0.001). Associations were stronger for incident visit-based hypertension. These associations were driven by higher relative hazard in normotensive people (compared with those with prehypertension; P for interaction=0.001). Baseline hs-cTnT was also strongly associated with incident left ventricular hypertrophy by electrocardiography over 6 years (eg, adjusted hazard ratio, 5.19 [95% confidence interval, 1.49-18.08] for hs-cTnT ≥14 versus <5 ng/L). Findings were not appreciably changed after accounting for competing deaths or adjusting for baseline blood pressure levels or N-terminal probrain natriuretic peptide.ConclusionsIn an ambulatory population with no history of cardiovascular disease, hs-cTnT was associated with incident hypertension and risk of left ventricular hypertrophy. Further research is needed to determine whether hs-cTnT can identify people who may benefit from ambulatory blood pressure monitoring or hypertension prevention lifestyle strategies.

Project description:BACKGROUND:It is unclear if isolated postoperative cardiac-troponin elevation, often referred to as myocardial injury, represents a pathological event, as control studies in otherwise healthy adults are lacking. METHODS:In this single-centre prospective observational cohort study, serial high-sensitivity cardiac troponin T (hscTnT) plasma concentrations were obtained from young, healthy adults undergoing elective orthopaedic surgery at three time points: before operation, 2-6 h, and 18-30 h after surgery. End points were hscTnT increases after surgery: ?20% (exceeding analytical variability), ?50% (exceeding short-term biological variability), and ?85% (exceeding long-term biological variability). The secondary end point was myocardial injury, defined as new postoperative hscTnT elevation >99th % upper reference limit (URL) (women >10 ng litre-1; men >15 ng litre-1). RESULTS:Amongst the study population (n=95), no hscTnT increase ?20% was detected in 68 patients (73%). A hscTnT increase between 20% and 49% was observed in 17 patients (18%), 50-84% in seven patients (7%), and ?85% in three patients (3%). Twenty patients (21%) had an absolute ?hscTnT between 0 and 2 ng litre-1, 12 patients (13%) between 2 and 4 ng litre-1, three patients between 4 and 6 ng litre-1, and one patient (1%) between 6 and 8 ng litre-1. Myocardial injury (new hscTnT elevation >99th%) was diagnosed in one patient (1%). The median hscTnT concentrations did not increase after operation, and were 4 (3.9-5, inter-quartile range) ng litre-1 at baseline, 4 (3.9-5) ng litre-1 at 2-6 h after surgery, and 4 (3.9-5) ng litre-1 on postoperative day 1. CONCLUSIONS:One in four young adult patients without known cardiovascular disease developed a postoperative hscTnT increase, but without exceeding the 99th% URL and without evidence of myocardial ischaemia. These results may have important ramifications for the concept of postoperative myocardial injury, as they suggest that, in some patients, postoperative cardiac-troponin increases may be the result of a normal physiological process in the surgical setting. CLINICAL TRIAL REGISTRATION:NCT 02394288.

Project description:BackgroundHigh-sensitivity cardiac troponin (hs-cTn) assays have different analytic characteristics.ObjectivesThe goal of this study was to quantify differences between assays for common analytical benchmarks and to determine whether they may result in differences in the management of patients with suspected acute coronary syndrome (ACS).MethodsThe authors included patients with suspected ACS enrolled in the ROMICAT (Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography) I and II trials, with blood samples taken at emergency department presentation (ROMICAT-I and -II) or at 2 and 4 h thereafter (ROMICAT-II). hs-cTn concentrations were measured using 3 assays (Roche Diagnostics, Elecsys 2010 platform; Abbott Diagnostics, ARCHITECT i2000SR; Siemens Diagnostics, HsVista). Per blood sample, we determined concordance across analytic benchmarks (99th percentile). Per-patient, the authors determined concordance of management recommendations (rule-out/observe/rule-in) per the 0/2-h algorithm, and their association with diagnostic test findings (coronary artery stenosis >50% on coronary computed tomography angiography or inducible ischemia on perfusion imaging) and ACS.ResultsAmong 1,027 samples from 624 patients (52.8 ± 10.0 years; 39.4% women), samples were classified as <LOD (56.3% vs. 10.4% vs. 41.2%; p < 0.001), LOD-99th percentile (36.5% vs. 83.5% vs. 52.6; p < 0.001), >99th percentile (7.2% vs. 6.0% vs. 6.2%) by Roche, Abbott, and Siemens, respectively. A total of 37.4% (n = 384 of 1,027) of blood samples were classified into the same analytical benchmark category, with low concordance across benchmarks (<LOD 11.1%; LOD-99th percentile 29.3%; >99th percentile 43.6%). Serial samples were available in 242 patients (40.1% women; mean age: 52.8 ± 8.0 years). The concordance of management recommendations across assays was 74.8% (n = 181 of 242) considering serial hs-cTn measurements. Of patients who were recommended to discharge, 19.6% to 21.1% had positive diagnostic test findings and 2.8% to 4.3% had ACS at presentation.ConclusionsCaregivers should be aware that there are significant differences between hs-cTn assays in stratifying individual samples and patients with intermediate likelihood of ACS according to analytical benchmarks that may result in different management recommendations. (Rule Out Myocardial Infarction by Computer Assisted Tomography [ROMICAT]; NCT00990262) (Multicenter Study to Rule Out Myocardial Infarction by Cardiac Computed Tomography [ROMICAT-II]; NCT01084239).

Dataset Information

Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study.

Publications

Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study.

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