Clinical validation of a point of care whole blood high sensitive cardiac troponin I assay: a prospective real time study on 3306 consecutive presentations with suspected acute coronary syndrome

Biomarkers in the triage of chest pain: are we making progress?

Background High-sensitivity cardiac troponin (hs-cTn) is a well-established biomarker for the evaluation of Emergency Department (ED) patients with possible acute coronary syndrome. These patients often have comorbid conditions that may impact hs-cTn values. However, prior studies and current guidelines addressing the relationship between comorbidities and hs-cTn are limited. Purpose To determine whether an interaction exists between comorbidities and baseline hsTnT values on the risk of 30-day major adverse cardiac events (MACE) in a multicenter United States (US) cohort. Methods Adult ED patients with suspected acute coronary syndrome were prospectively enrolled in a multicenter cohort study in the US. Baseline blood samples were collected and hs-cTnT concentrations were measured at a central laboratory. Comorbid conditions, such as obesity, hypertension, hyperlipidemia, diabetes, coronary artery disease, congestive heart failure, renal disease, peripheral vascular disease, prior stroke, and history of coronary interventions, were collected at time of enrollment. The primary outcome was adjudicated MACE, defined as occurrence of myocardial infarction, cardiovascular or uncertain death, or coronary revascularization within 30 days. Hs-cTnT values were dichotomized using manufacturer's limit of quantification (LOQ) at 6 ng/dL and the upper reference limit (URL) of 19 ng/dL. The utility the LOQ and URL cut-offs in predicting MACE was evaluated using logistic regression. Effect modification of comorbid conditions was independently evaluated by including an interaction term between comorbidity and hs-cTnT. Results Among 1460 participants with a baseline hs-cTn measurement, 46.3% (676/1460) were female and 37.1% (542/1460) were Black with a mean age of 57.6±12.9 years. The prevalence of MACE was 14.4% (210/1460). Participants with a baseline hs-cTnT below LOQ were 0.08 (95% CI: 0.04–0.16) times less likely to have MACE compared to those exceeding LOQ. Those with a baseline hs-cTnT exceeding URL were 9.5 (95% CI: 7.0–12.9) times more likely to have MACE. The presence of prior stroke significantly modified the association between baseline hs-cTnT below LOQ and risk of MACE (p=0.006). Among those with prior stroke (n=158), there was no significant association between baseline hs-cTnT below LOQ and risk of MACE (p=0.451). For the association between hs-cTnT above URL and MACE, significant negative interaction was detected by hypertension (p<0.001), hyperlipidemia (p=0.002), coronary artery disease (p=0.002), percutaneous coronary intervention (p=0.001), and congestive heart failure (p=0.038) comorbidity. Conclusion In a diverse, multicenter, US cohort the association between baseline hs-cTnT and the risk of MACE was weakened by the presence of several comorbid conditions. This suggests that the safety of previously validated hs-cTnT diagnostic strategies may be diminished when applied to populations with a high prevalence of comorbid conditions. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Roche Diagnostics

How Low Can We Go? The High-Sensitivity Cardiac Troponin Debate

Introduction High sensitivity troponin (hs-cTn) measurement is central to rapid diagnostic algorithms in acute coronary syndrome (ACS). Point of care (POC) testing reduces turnaround time when compared to central lab (CL) testing. Currently there is very little data on the performance of POC hs-cTn assays in a clinical environment with non-expert operators. Method In a nested sub-study of a randomised controlled trial (RCT), patients with suspected ACS were randomised to either the ESC 0/1 or 0/3 hour algorithm. They underwent whole blood (WB) sampling for Siemens Atellica VTLi hs-cTnI POC (VTLi POC), CL hs-cTnI and CL hs-cTnT assays. This was for both initial and repeat samples. Assay imprecision of the VTLi POC assay was assessed by 2 runs of 10 tests with whole blood at 9 different troponin levels. 4 devices were used with samples stored at room temperature.Final diagnosis was adjudicated based on all relevant clinical and imaging data together with CL hs-cTnT as the diagnostic biomarker in clinical use (10% coefficient of variation (CV) 3-5 ng/L, 99th percentile 14 ng/L) and using the 4th universal definition of myocardial infarction (MI). Clinical performance was assessed using Receiver Operator Characteristics (ROC) curves. Results 2144 patients consented and had WB VTLi POC, CL hs-cTnI and CL hs-cTnT available. The index adjudicated type 1 MI rate was 6.1%. Assay imprecision of the VTLi POC assay demonstrated a 10% Coefficient of Variation (CV) at 9.8ng/l. This was >50% lower than the 99th centile of 23ng/l (average for males and females) (Figure 1). Clinical performance of the VTLi POC assay was acceptable and equivalent to CL hs-cTnT: Area Under Curve (AUC) 0.92 (0.89-0.96), 0.98 (0.96-0.99) and 0.93 (0.87-0.98) at presentation (Figure 2), 1 and 3 hours respectively. However, clinical performance was inferior to CL hs-cTnI: AUC 0.96 (0.95-0.98) and 0.96 (0.93-0.98) at presentation (p=0.0007) and 3 hours (p<0.0001) respectively. Conclusion The Siemens Altellica VTLi hs-cTnI POC assay has imprecision levels consistent with a high sensitivity troponin assay. It has acceptable clinical performance though inferior to the equivalent CL hs-cTnI. Further validation of this assay, particularly with optimised single sample rule-out, could facilitate its use in routine clinical practice.

Background The ESC 0/1-hour algorithm using high sensitivity troponin (ESC 0/1-h) is a rapid triage protocol for diagnosing acute coronary syndrome, however the classification performance of the algorithm in the US population is uncertain. Further, evidence for the use of ESC 0/1-h in the long-term diagnosis of major adverse cardiovascular events (MACE) remains limited. Purpose To evaluate the performance of the ESC 0/1-h algorithm in diagnosing 90-day MACE in a diverse US cohort. Methods In this prospective, multicenter, observational cohort study, adult emergency department patients who were evaluated for suspected ACS were enrolled at eight sites in the US. Serial 1-hour blood samples were collected and high sensitivity troponin T (hs-cTnT) concentrations were measured in a central laboratory using the hs-cTnT assay. Primary outcome included major adverse cardiovascular events (MACE) within 90 (+30) days of enrollment. MACE defined as myocardial infarction (MI), cardiovascular or uncertain death, and coronary revascularization. Presence of MI and cardiovascular death were adjudicated by independent reviewers blinded to hs-cTnT results. Each participant was stratified to one of three risk groups as determined by ESC 0/1-h algorithm. Diagnostic classification performance metrics with exact confidence intervals (i.e. negative predictive value [NPV], positive predicted value [PPV], sensitivity, and specificity) were evaluated for each risk group where appropriate. Results Among 1430 eligible participants, 45.8% (655/1430) were women and 36.6% (524/1430) were African American with a mean age of 57.6±12.8 years. MACE at 90-days occurred in 15.5% (221/1430). ESC 0/1-h stratified 59.5% (851/1430) subjects in Rule-Out range and 13.0% (186/1430) subjects in Rule-In range. The Rule-Out criteria had an NPV and sensitivity for 90-day MACE of 96.8% (95% CI: 95.4–97.9%) and 87.8% (95% CI: 82.7–91.8%), respectively. For 90-day cardiovascular death or MI, Rule-Out criteria had an NPV of 98.2% (95% CI: 97.1–99.0%) and sensitivity was 92.4% (95% CI: 87.8–95.7%). The Rule-In criteria had a PPV of 60.8% (95% CI: 53.3–67.8%) for both outcomes. Rule-In criteria had a specificity for 90-day MACE and 90-day cardiovascular death or MI of 94.0% (95% CI: 92.5–95.2%) and 94.1% (95% CI: 92.6–95.3%), respectively. Among the 27.5% (393/1430) participants classified in neither risk groups, the prevalence of 90-day MACE was 20.6% (81/393) and the prevalence of 90-day cardiovascular death or MI was 17.8% (70/393) Conclusion In a prospective, multicenter, US cohort, the ESC 0/1-h algorithm was unable to achieve a sufficiently high NPV to safely exclude the diagnosis of MACE within 90 days after emergency department presentation. New hs-cTn algorithms specific to the US population may be warranted. ESC 0/1-h 90 Day Outcomes Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnostics

The European Cardiac Society have recommended high-sensitivity cardiac troponin testing can be used as part of a “rule-out” strategy for patients with suspected acute coronary syndrome. NICE have recommended the...

Background Rapid high-sensitivity cardiac troponin (hs-cTn) based algorithms have substantially improved the early rule-out of acute myocardial infarction (AMI) and thereby facilitated the selection of patients eligible for outpatient management. However, it remains unclear, which patients after rule-out of AMI should still undergo objective anatomic or functional cardiac testing for the detection of relevant coronary artery disease. A pilot study has derived a clinical decision rule for the selection of patients who do not need objective anatomic or functional cardiac testing for coronary artery disease (“No Objective Testing” (NOT) rule). Purpose To externally validate the performance of the NOT-rule in a multicentre study. Methods Patients presenting to the ED with symptoms suggestive of an acute coronary syndrome (ACS) were enrolled in a large prospective international multicentre study at 12 study sites in five European countries. Two independent cardiologists centrally adjudicated the final diagnosis using all clinical data including cardiac imaging and at least 90-day follow-up. The NOT-rule is applied in patients, in whom a 2h accelerated diagnostic protocol (using hs-cTnI concentrations at 0h/2h and ECG data) has ruled-out AMI and based on clinical variables. In brief, the first rule is a weighted score derived from independent predictors of ACS that classifies patients as low-risk if they score ≤4 points. The second rule was simplified and ruled patients out if they were younger than 50 years, had no history of an AMI or known CAD, and no prescribed nitrates. The third rule equals the second except nitrate use was omitted. Primary objective was the safety and efficacy of the NOT-rules for rule-out of major adverse cardiac events (MACE) including AMI, unstable angina pectoris, urgent or emergency revascularisation or cardiovascular death at 30-days of follow-up. Secondary objective was the safety and efficacy for rule-out of MACE at 2-years. Results Out of 3188 enrolled patients, 2162 (68%) had hs-cTnI concentrations at 0h and 2h below the 99th centile as well as a non-diagnostic ECG and were therefore eligible for the analysis. MACE at 30-days occurred in 302 (14%) patients. The second and third rule offered highest safety and efficacy for rule-out of MACE at 30-days. Both identified 492 (23%) patients at low-risk with a sensitivity of 99.7% (95% CI 98.2–99.9%) and a negative predictive value (NPV) of 99.8% (95% CI 98.6–99.9%). One MACE was missed within 30-days (revascularisation of a one-vessel CAD). Sensitivity 98.9% (95% CI 97.1–99.7%) and NPV 99.2% (95% CI 97.8–99.7) were also very high for 1-year MACE, as well as 2-year MACE 98.4% (95% CI 96.5–99.4%) and 98.4% (95% CI 96.5–99.3%), respectively. Conclusions The NOT rules proved to be a safe tool that identifies nearly one-fourth of patients at very low risk for MACE, who may not need objective anatomic or functional cardiac testing for coronary artery disease. Performance of NOT rules Funding Acknowledgement Type of funding source: Other. Main funding source(s): Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel, the University Hospital Basel

Approximately 90% of patients presenting to the emergency department with suspected acute coronary syndrome have acute myocardial infarction excluded, but they remain at risk of major adverse cardiovascular events. This study assessed the long-term outcomes of such patients, focusing on the incremental value of multiple biomarkers combined with clinical risk scores for risk stratification. In this prospective observational study, 487 patients with suspected acute coronary syndrome but excluded acute myocardial infarction were recruited from a large urban hospital, with a median follow-up of 5.8 years. The primary end point was major adverse cardiovascular events, including adjudicated type 1 myocardial infarction, unstable angina requiring urgent revascularization, and cardiovascular death. Biomarkers assessed were hs-cTnT (high-sensitivity cardiac troponin T), hs-cTnI (high-sensitivity cardiac troponin I), HFABP (heart-type fatty acid binding protein), GDF-15 (growth differentiation factor 15), NT-proBNP (N-terminal prohormone of brain naturetic peptide), galectin-3, and hs-CRP (high-sensitivity C-reactive protein (). Statistical methods included receiver operating characteristic analysis, Kaplan-Meier curves, net reclassification index, and Cox proportional hazards models to evaluate biomarker utility independently and combined with Thrombolysis in Myocardial Infarction and History, ECG, Age, Risk Factors, Troponin scores. Of the 487 patients (median age 56 years; 44% female), 9.9% experienced major adverse cardiovascular events. Annualized major adverse cardiovascular events rates for patients with troponin levels below the limit of detection were 0.5% (hs-cTnT) and 0.7% (hs-cTnI), with no cardiovascular deaths over 5 years. Both hs-cTnT and hs-cTnI levels modestly enhanced risk stratification when added to Thrombolysis in Myocardial Infarction or History, ECG, Age, Risk Factors, Troponinscores. Of the non-necrosis biomarkers, only GDF-15 demonstrated independent prognostic value in multivariable models. Hs-cTnT, hs-cTnI, and GDF-15 improve the long-term risk stratification of the History, ECG, Age, Risk Factors, Troponinand Thrombolysis in Myocardial Infarction scores in patients with suspected acute coronary syndrome and acute myocardial infarction excluded. Hs-cTn of either type at or below limit of detection was associated with excellent short- and long-term outcomes. URL: https://clinicaltrials.gov; Unique identifier: NCT03628586.

Background Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice and confers a significant burden to morbidity and mortality. High-sensitivity cardiac troponin T (hs-cTnT) levels have provided a significant contribution in the early diagnosis of cardiovascular events; however, the significance of hs-cTnT elevation in the setting of acute AF is not clearly understood. Purpose The aim of this study was to evaluate the factors associated with hs-cTnT elevation and its prognostic implication in patients with acute AF. Methods This single-center prospective study included 406 consecutive patients who presented to the emergency department (ED) with acute AF. Acute AF was defined as a rapid, irregular, and chaotic atrial activity of <48 hours' duration including both the first symptomatic onset of chronic or persistent AF, and episodes of paroxysmal AF. The association between hs-cTnT and outcomes were evaluated using multivariate analyses. Results The mean age of the population was 67.3±12.2 and 74% were male. The median time from the onset of symptoms to ED consultation was 230 minutes (interquartile range: 123–450 minutes). The median hs-cTnT value was 12 ng/L, with 39% of patients with values above the 99 thpercentile. AF was reverted to sinus rhythm in 76% of the patients (83% attempted cardioversion). At one-year, AF recurrence was observed in 38% of the patients and major adverse cardiovascular events (MACE) (death, myocardial infarction, acute coronary syndrome or stroke) were observed in 6% of the patients. After adjusting for demographic and clinical characteristics in multivariate analysis, hs-cTnT elevation was associated with increasing age and left atrial area (p=0.001). Hs-cTnT levels were not associated with 1-year AF recurrence (p=0.132) or with AF reversion (p=0.869). Hs-cTnT levels were significantly higher in patients who experienced MACE at 1-year (12 ng/L vs 24 ng/L, p=0.001) and hs-cTnT was a predictor of MACE on multivariate analysis (OR 3.486, 95% CI 1.256–5.379, p=0.009). Variable Result AF rate 110 (90–118) Atrial area, cm2 22 (19–27) Cardioversion attemped 82.5% Conclusions Hs-cTnT elevation accounted for a large proportion of patients with acute AF. Elevated levels of hs-cTnT were not associated with AF reversion or with 1-year AF recurrence, however hs-cTnT was highly predictive of MACE at 1-year.

linical implications of measurable cardiac troponin (cTn) within the reference interval in emergency department patients remain uncertain. Using highsensitivity (hs) cTnI, our goals were 3-fold. First, we examined clinical features of patients with hs-cTnI within sex-specific reference intervals. Second, we examined the prognostic impact of hs-cTnI within sex-specific reference intervals using baseline and serial measurements. Third, using hs-cTnI reference change values (RCVs; biological variation), we determined the prognostic impact of serial changes within sex-specific intervals.

The role of NT-proBNP as a cardiac biomarker for predicting short-term major adverse cardiovascular events (MACEs) in acute coronary syndrome (ACS) remains unclear. This study investigated the utility of the NT-proBNP level for predicting MACEs within a 6-month period in patients with ACS. This prospective study included 241 consecutively enrolled adults with ACS between September 2023 and February 2024. Demographic data, clinical characteristics, GRACE score, and high-sensitivity cardiac troponin T (hs-cTnT) and NT-proBNP levels were compared between patients who were MACE-positive vs. MACE-negative within a 6-month period. The overall mortality rate was 8.7%, and the incidence of MACEs was 43.2%. The mean serum levels of hs-cTnT and NT-proBNP were significantly higher in the MACE-positive than in the MACE-negative group. Age, concomitant coronary artery disease, NT-proBNP, and GRACE score were independent predictors of MACEs in patients with ACS. An NT-proBNP level of 250pg/mL had a sensitivity of 73.1% and a specificity of 88.3% for predicting MACEs, with an area under the curve of 0.847. The estimated risk of MACEs was 70% and 90% for NT-proBNP values of 600pg/mL and 900pg/mL, respectively. The NT-proBNP level measured at ED admission was strongly associated with short-term MACEs in patients with all ACS subtypes and was an important prognostic biomarker. Therefore, combining the NT-proBNP level with the GRACE score in ACS patients may provide significant benefits in terms of predicting MACEs and obtaining a more accurate risk stratification.

CAN PATIENTS PRESENTING TO THE ED WITH CHEST PAIN WHO HAVE INTERMEDIATE-RISK HEART SCORES BE MANAGED AS OUTPATIENTS? A RETROSPECTIVE REVIEW OF TWO RAPID ACCESS CHEST PAIN CLINICS

Background The use of high-sensitivity troponin (hs-cTnI) assays is recommended in current guidelines for managing patients with acute coronary syndrome (ACS) symptoms. However, point-of-care (POC) assays are frequently used in emergency departments (EDs) to reduce turnaround time and length of stay. This study aimed to compare the results of POC-cTnI testing with those of the gold standard, automated central laboratory testing of troponin (i.e., hs-cTnI). The primary and secondary outcomes were the diagnostic performance of POC-cTnI in diagnosing acute myocardial infarction (AMI) and major adverse cardiovascular events (MACE) during 30 days, respectively. Materials and Methods In this diagnostic accuracy study, 136 patients with suspected ACS who were referred or admitted to the Al Zahra Hospital, Shiraz, Iran, were included between March (2020) and July (2020). For the diagnosis of AMI, central laboratory cTnI levels were assessed at the time of presentation (0 hour) and reassessed at least 3 hours later. The POC-cTnI was measured at 0 hour in all patients and at 3 hours if a patient was diagnosed with AMI but had a 0-hour negative result for the POC-cTnI assay. Additionally, the 30-day follow-up period for these participants began on the day of the initial presentation to assess MACE. Results Out of 180 patients, 136 patients (median age of 59.5 years; 57.5% male) were left for the qualitative POC-cTnI and hs-cTnI assays. In 86 (63.24%) subjects, hs-cTnI was positive (either initial or serial); however, AMI was diagnosed in 85 patients according to positivity of troponin by hs-cTnI and clinical signs and symptoms, which were diagnosed by a cardiologist. The sensitivity, specificity, and negative predictive value of 0-hour POC-cTnI were observed to be 91.76% (95% CI: 83.77–96.62%), 98.04% (95% CI: 89.55–99.95%), and 87.72% (95% CI: 77.82–93.56%), respectively. Moreover, considering both the 0-hour and 3-hour POC-cTnI, all AMI cases were correctly identified, yielding a perfect test performance result. None of the 50 patients with negative cTnI results (by 0-hour and 3-hour POC-cTnI and hs-cTnI) experienced at least one MACE. Conclusion In this small sample-size study, a new qualitative POC-cTnI assay was statistically equal to a hs-cTnI assay in terms of diagnostic accuracy for AMI or MACE in patients with suspected myocardial infarction. The POC-cTnI was observed to be acceptable for the identification of AMI and prediction of MACE in the ED environment.

Background The European Society of Cardiology (ESC) 0/1-hour high sensitivity troponin (hs-cTn) algorithm is widely used in the evaluation of patients presenting to the Emergency Department (ED) with symptoms suspicious for non ST-segment elevation myocardial infarction (NSTEMI). The effect of increasing patient age with its use has not been studied in any detail. Purpose The objective of this secondary analysis of the STOP-CP (High Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification) United States (US) multicenter study was to evaluate the efficacy and safety of use of the ESC 0/1-hour hs-cTnT algorithm in younger, middle-aged, and older patients. Methods Patients (≥21 years old) presenting to the (ED) with symptoms suggestive of NSTEMI were enrolled (1/25/2017–9/6/2018) at 8 US medical centers. The ESC hs-cTnT 0/1-hour hs-cTnT algorithm was used to place patients into rule-out, observe, and rule-in NSTEMI zones. Algorithm performance for rapid NSTEMI rule-out and 30-day adverse outcomes was studied in 3 patient age (years) intervals: younger (21–45). middle aged (46–64) and older (≥65). Major adverse cardiovascular events (MACE) consisted of cardiac death, myocardial infarction, or coronary revascularization at 30-days. Fisher's exact tests were used to compare NSTEMI ruled out and MACE rates between patient age intervals. Negative likelihood ratios (NLR) with 95% confidence interval (CI) were calculated for 30-day MACE. Results Overall 1430 participants were enrolled with 15.7% (224/1430) young, 57.4% (821/1430) middle-aged, and 26.9% (385/1430) being older. The ESC 0/1 hour hs-cTnT algorithm NSTEMI rule-out rates were 79.9% (179/224), 62.1% (510/821) and 35.6% (137/385) respectively for these age groups (p<0.0001). The overall 30-day MACE rate was 14.2% (203/1430) with interval age rates of 7.1% (16/224) in younger, 13.1% (108/821) middle aged and 20.5% (79/385) older patients. Amongst NSTEMI ruled-out patients MACE occurred in 1.1% (2/179) of younger, 3.3% (17/510) middle aged and 2.9% (4/137) older individuals (p=0.320). NLR for 30-day MACE was 0.15 (95% CI 0.04, −0.54) in younger, 0.23 (95% CI 0.15–0.35) middle aged and 0.12 (95% CI 0.04–0.31) for older patients. Conclusions With increasing age ED patients were less often rapidly ruled out for NSTEMI during their initial cardiac evaluations. The STOP-CP US study demonstrated that older age interval alone was not an independent variable that increased the risk for 30-day MACE in patients ruled out for NSTEMI using the ESC 0/1 hour hs-cTnT algorithm. Our report suggests that cardiac risk stratification scores using age as an independent variable for predicting 30-day MACE in these patients require reevaluation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Roche, Basel, Switzerland

IntroductionChest pain is a common presentation to the ED. Differentiating those with an Acute Coronary Syndrome from the majority without, within 4 hours, is a priority. Introduction of high-sensitivity Troponin...