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Background: Patients with unstable angina (UA) are regarded to be at low risk for future coronary events. Guidelines discourage routine coronary angiography and recommend early discharge after individualized risk stratification. The relative value of clinical risk indicators as compared to cardiac troponin (cTn) alone is unsettled in the era of high-sensitivity cardiac troponin (hsTn) assays. We aimed to investigate the clinical characteristics, therapies, and outcomes of UA patients with different hsTnT concentrations., Methods: During 12 months, 2525 patients were enrolled. UA was defined as unstable symptoms and either undetectable (< 5 ng/L), normal (5-14 ng/L) or stable elevated hsTnT (15-51 ng/L). Follow-up for 1-year mortality was available in 98.7%., Results: A total of 280 patients (11.1%) received a diagnosis of UA. Mortality rates at 12 months were 0%, 1.9% and 6.9% in presence of undetectable, normal and stable elevated hsTnT. Elevated hsTnT > 99th percentile but not unstable symptoms carried an independent 3.25-fold (1.78-5.93) higher risk for all-cause death after adjustment for other clinical risk indicators or the GRACE score. Utilization of guideline-recommended therapies was high albeit lower than for non-ST-elevation myocardial infarction (NSTEMI). Significantly fewer patients with UA received dual antiplatelet therapy (DAPT, odds ratio (OR) 0.51 [95% CI 0.44-0.59], P < 0.0001), coronary angiography (CA, OR 0.79, [95% CI 0.74-0.87], P < 0.0001), and percutaneous coronary intervention (PCI, OR 0.50, [95% CI 0.40-0.61], P < 0.0001), compared to NSTEMI. However, prevalence of significant obstructive coronary artery disease requiring PCI was 31.8%, even in patients with undetectable hsTnT, indicating the need for stress testing., Conclusions: The current dichotomization of patients into UA and NSTEMI is no longer appropriate. Additional risk stratification seems warranted including the presence and magnitude of hsTn concentration and additional risk indicators. Clinical Trials Identifier: NCT03111862.

Objective: To determine gender-specific reference limits of high-sensitivity (hs) cardiac troponins (cTn) and validity of hs assay designation for both genders., Methods: After screening with a questionnaire, 827 presumably healthy individuals were further selected based on clinical criteria (n = 740), clinical criteria plus cardiac imaging including stress magnetic resonance imaging or stress echocardiography (n = 726), and extended cardio-pulmonary parameters (n = 626). Blood samples were measured with hs-cTnT (Roche Diagnostics) on a cobas e602 analyzer as well as hs-cTnI (Abbott Diagnostics) on an ARCHITECT i 2000 SR . The impact of health definition, statistical methods, instrument selection and limit of detection (LoD) on overall and gender-specific 99th percentiles was assessed., Results: Median age was 56 years (50.9% female) for the total study cohort. 99th percentiles for females and males ranged between 13.1 and 13.3 ng/L and 16.8-19.9 ng/L for hs-cTnT as well as 10.3-12.5 ng/L and 27.4-29.7 ng/L for hs-cTnI depending on health definition. Utilization of stricter health definition criteria reduced the difference of the gender-specific 99th percentiles between males and females for hs-cTnT to 3.7 ng/L (males 16.8 ng/L, females 13.1 ng/L), whereas the difference rather increased for hs-cTnI to 19.4 ng/L (males 29.7 ng/L, females 10.3 ng/L). Values > LoD could be measured in the majority of males and females using hs-TnT (81.4-83.3% and 96.5-96.9%, respectively). In contrast, values > LoD could not be observed in the majority of females using hs-cTnI (38.4-41.1%)., Conclusions: In a well-phenotyped healthy cohort, reference values for hs-cTnT were slightly higher, whereas hs-cTnI cut-offs were considerably lower than previously observed. Gender differences were more pronounced in hs-cTnI than in hs-cTnT and were further reduced for hs-cTnT by application of stricter health definition criteria. Contrary to hs-cTnI, hs-cTnT fulfilled criteria for hs designation for both genders., Competing Interests: Declaration of Competing Interest E.G., honoraria for lecturers from Roche Diagnostics, BRAHMS Thermo Scientific, Bayer Vital GmbH and Mitsubishi Chemical Europe, institutional research grant from Roche Diagnostics and Daiichi Sankyo, consultant for Roche Diagnostics and BRAHMS Thermo Scientific, outside the submitted work; M.M.-H., research support by the Medical Faculty of Heidelberg University, during conduct of the study, research support from Roche Diagnostics and BRAHMS Thermo Scientific, speaker honoraria from Roche Diagnostics, non-financial support by BRAHMS Thermo Scientific, Bayer Vital GmbH, Daiichi-Sankyo, Metanomics Health GmbH and Philips Electronics, outside the submitted work; M.B., research support from AstraZeneca and travel support from BRAHMS Thermo Scientific, outside the submitted work; M.V., financial support from Bayer Vital GmbH and Daiichi Sankyo, reimbursement for travel expenses and fees associated with attending seminars and conferences by Bayer Vital GmbH, Lilly Germany, GlaxoSmithKline, Roche Diagnostics and Brahms, outside the submitted work; K.M.S., research supported by Bayer Vital GmbH, outside the submitted work; S.B., non-financial support from Abbott Diagnostics, grants and personal fees from Abbott Diagnostics, Siemens, Thermo Fisher and Roche Diagnostics, outside the submitted work; H.K., honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Roche Diagnostics, and Bayer, holds a Troponin T Test Invention patent jointly with Roche and receives royalties for this patent, outside the submitted work. All other authors have nothing to disclose., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although the value of fast diagnostic protocols in suspected acute coronary syndrome has been validated, there is insufficient real world evidence including patients with lower pre-test probability, atypical symptoms and confounding comorbidities. The feasibility, efficacy and safety of European Society of Cardiology (ESC) 0/1 and 0/3-hour algorithms using high-sensitivity troponin T were evaluated in a consecutive cohort with suspected acute coronary syndrome., Methods: During 12 months, 2525 eligible patients were enrolled. In a pre-implementation period of 6 months, the prevalence of protocols, disposition, lengths of emergency department stay and treatments were registered. Implementation of the 0/1-hour protocol was monitored for another 6 months. Primary endpoints comprised the change of diagnostic protocols and 30-day mortality after direct discharge from the emergency department., Results: Use of the ESC 0/1-hour algorithm increased by 270% at the cost of the standard 0/3-hour protocol. After rule-out (1588 patients), 1309 patients (76.1%) were discharged directly from the emergency department, with an all-cause mortality of 0.08% at 30 days (one death due to lung cancer). Median lengths of stay were 2.9 (1.9-3.8) and 3.2 (2.7-4.4) hours using a single high-sensitivity troponin T below the limit of detection (5 ng/L) at presentation and the ESC 0/1-hour algorithm, respectively, as compared to 5.3 (4.7-6.5) hours using the ESC 0/3-hour rule-out protocol ( P <0.001). Discharge rates increased from 53.9% to 62.8% ( P <0.001), without excessive use of diagnostic resources within 30 days., Conclusion: Implementation of the ESC 0/1-hour algorithm is feasible and safe, is associated with shorter emergency department stay than the ESC 0/3-hour protocol, and an increase in discharge rates., Trial Registration: ClinicalTrials.gov , Unique identifier: NCT03111862.

Objective: To evaluate the long term biological variation of high-sensitivity cardiac troponin T (hs-cTnT) in stable outpatients with cardiovascular disease (CVD)., Methods: After applying 8 exclusion criteria to 965 patients, hs-cTnT was measured at index visit and at a 12-month interval in 169 stable outpatients presenting for routine follow-up visits for any CVD. Stability was defined as absence of any endpoint within the follow-up period. Reference change values (RCVs) and minimal important differences (MIDs) were determined to assess biological variation of hs-cTnT., Results: MID and RCV for the 12 months interval in patients were 3.8 ng/L or 44.2%, respectively. MID and transformed MID values were lower than the corresponding RCV with a value of 5.1 ng/L for the transformed RCV and 28.1% for the transformed MID. Similar patterns were shown in different subgroups as sex, age, and renal function. We observed a baseline hs-cTnT value dependent change of MID and RCV with increasing values for MID and decreasing values for RCV which converge to stable values between a baseline hs-cTNT value of 11 to 25 ng/L., Conclusions: Biological variation of hs-cTnT over 12 months in stable outpatients depends on the concentration at index visit, and is consistent among important prespecified subgroups. MID shows a low biovariability over 12 months. Clinical Trials Identifier:NCT01954303., (Copyright © 2019 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aims: Elevated levels of high-sensitivity cardiac troponin T (hsTnT) are associated with adverse outcomes in numerous patient populations. Their value in prediction of stroke risk in patients with atrial fibrillation (AF) is in debate., Methods: The study population included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Associations between hsTnT and stroke risk were assessed using multivariable Cox regression., Results: Elevated hsTnT levels (>14 ng/L) were associated with increased risk of stroke. Even after adjustment for various risk factors, elevated hsTnT remained independently associated with stroke risk in patients with AF, adjusted hazard ratio 2.35 [95% confidence interval (CI): 1.26-4.36] (P = 0.007). These results were consistent across important subgroups (age, renal function, ejection fraction, CHA2DS2-VASc score and main admission diagnosis). For hsTnT, area under the receiver-operating-characteristic curve (AUC) was 0.659 [95% CI: 0.575-0.742], compared to 0.610 [95% CI: 0.526-0.694] for the CHA2DS2-VASc score. Inclusion of hsTnT in the multivariable model for stroke risk prediction consisting of all variables of the CHA2DS2-VASc score was associated with a significant improvement of its discriminatory power., Conclusion: Elevated hsTnT levels are significantly associated with higher risk of stroke and provide prognostic information independent of CHA2DS2-VASc score variables. Measurement of hsTnT may improve prediction of stroke risk in patients presenting to an emergency department with AF as compared to risk stratification based only on clinical variables., Competing Interests: M.V. has received financial support for this clinical trial from Bayer Vital GmbH and Daiichi Sankyo and has been reimbursed for travel expenses and fees associated with attending seminars and conferences by Bayer Vital GmbH, Lilly Germany, GlaxoSmithKline, Roche Diagnostics and Brahms. E.G. has received financial support for clinical trials from Bayer Vital GmbH, reports consultancy fees and grants and lecture fees from Roche Diagnostics, lecture fees from AstraZeneca and Bayer Vital. M.M.-H. has received grants from the Medical Faculty of the University of Heidelberg as well as grants and speaker honoraria from Roche Diagnostics, during the conduct of the study; grants from BRAHMS Thermo Fisher, nonfinancial support from Bayer Vital GmbH, BRAHMS Thermo Fisher, Daiichi-Sankyo, Metanomics Health GmbH and Philips Electronics. M.B. has received support for clinical trials from AstraZeneca and travel support from Brahms Germany. E.M. has nothing to disclose. B.Y has nothing to disclose. H.A.K. has developed the cTnT assay and holds a patent jointly with Roche Diagnostics. He reports consultancy fees and grants and lecture fees from Roche Diagnostics, and grants and lecture fees from Bayer Vital, plus lecture fees from AstraZeneca. K.M.S. has conducted the present research supported by Bayer Vital GmbH. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: We aimed to directly compare the diagnostic and prognostic performance of a dual maker strategy (DMS) with combined testing of copeptin and high-sensitivity (hs) cardiac troponin T (cTnT) at time of presentation with other algorithms for rapid rule-out of acute myocardial infarction (AMI)., Methods: 922 patients presenting to the emergency department with suspected AMI and available baseline copeptin measurements qualified for the present TRAPID-AMI substudy. Diagnostic measures using the DMS (copeptin <10, <14 or < 20 pmol/L and hs-cTnT≤14 ng/L), the 1 h-algorithm (hs-cTnT<12 ng/L and change <3 ng/L at 1 h), as well as the hs-cTnT limit-of-blank (LoB, <3 ng/L) and -detection (LoD, <5 ng/L) were compared. Outcomes were assessed as combined end-points of death and myocardial re-infarction., Results: True-negative rule-out using the DMS could be achieved in 50.9%-62.3% of all patients compared to 35.0%, 45.3% and 64.5% using LoB, LoD or the 1 h-algorithm, respectively. The DMS showed NPVs of 98.1%-98.3% compared to 99.2% for the 1 h-algorithm, 99.4% for the LoB and 99.3% for the LoD. Sensitivities were 93.5%-94.8%, as well as 96.8%, 98.7% and 98.1%, respectively. Addition of clinical low-risk criteria such as a HEART-score ≤ 3 to the DMS resulted in NPVs and sensitivities of 100% with a true-negative rule-out to 33.8%-41.6%. Rates of the combined end-point of death/MI within 30 days ranged between 0.2% and 0.3% for all fast-rule-out protocols., Conclusion: Depending on the applied copeptin cut-off and addition of clinical low-risk criteria, the DMS might be an alternative to the hs-cTn-only-based algorithms for rapid AMI rule-out with comparable diagnostic measures and outcomes., (Copyright © 2018. Published by Elsevier B.V.)

Aims: Elevated levels of high-sensitivity cardiac troponin T (hsTnT) indicate underlying heart disease and are known to predict adverse outcomes in various patient populations. Their role in atrial fibrillation (AF) is still under debate., Methods and Results: This retrospective study included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Multivariable Cox regression was used to assess associations between hsTnT and mortality. Elevated hsTnT levels were associated with increased risk of all-cause mortality in all patients with AF, as well as in each subtype of AF. After adjustment for multiple risk factors, both detectable hsTnT below the 99th percentile (5-14 ng/L, adjusted hazard ratio (HR): 4.86 [95% CI: 1.77-13.34], P = 0.002) and elevated hsTnT (>14 ng/L, adjusted HR: 13.42 [95% CI: 4.95-36.40], P < 0.001) were associated with a higher risk of mortality in patients with AF, compared to undetectable hsTnT (<5 ng/L). Elevated hsTnT was also associated with higher mortality after exclusion of patients with myocardial infarction, as well as in the subgroup of patients with AF as main admission diagnosis. The inclusion of hsTnT significantly improved the performance of the multivariable model for mortality prediction., Conclusion: Elevated hsTnT levels are associated with higher mortality in patients with AF, and provide added prognostic information independent of major cardiovascular risk factors and clinical characteristics. Measurement of hsTnT should be considered for risk assessment in patients presenting to an emergency department with AF., Clinical Trial Registration: http://www.clinicaltrials.gov; Unique identifier: NCT02542189.

Background: Risk stratification of patients with cardiovascular disease remains challenging despite consideration of risk scores., Methods: We aimed to evaluate the prognostic performance of high-sensitivity cardiac troponin T in a low-risk outpatient population presenting for nonsecondary and secondary prevention. All-cause mortality, a composite of all-cause mortality, acute myocardial infarction, and stroke (end point 2), and a composite of all-cause mortality, acute myocardial infarction, stroke and rehospitalization for acute coronary syndrome, and decompensated heart failure (end point 3) were defined. The prognostic performance of high-sensitivity cardiac troponin T on index visit was compared with the PROCAM score and 3 FRAMINGHAM subscores., Results: In 693 patients with a median follow-up of 796 days, we observed 16 deaths, 32 patients with end point 2, and 83 patients with end point 3. All risk scores performed better in the prediction of all-cause mortality in nonsecondary prevention (area under the curve [AUC]: PROCAM: 0.922 vs 0.523, P = .001, consistent for all other scores). In secondary prevention, high-sensitivity cardiac troponin T outperformed all risk scores in the prediction of all-cause mortality (ΔAUC: PROCAM: 0.319, P <.001, consistent for all other scores) and performed superiorly in the prediction of end point 2 compared with the PROCAM, FRAMINGHAM-Coronary Heart Disease, and FRAMINGHAM-Hard Coronary Heart Disease scores (ΔAUC: PROCAM: 0.176, P = .047, consistent for FRAMINGHAM-Coronary Heart Disease and FRAMINGHAM-Hard Coronary Heart Disease). In nonsecondary prevention, we observed a comparable prognostic performance of high-sensitivity cardiac troponin T and multivariable risk scores. Our findings on the prediction of all-cause mortality compared with the FRAMINGHAM-Hard Coronary Heart Disease score were confirmed in an independent validation cohort on 2046 patients., Conclusions: High-sensitivity troponin T provides excellent risk stratification regarding all-cause mortality and all-cause mortality, acute myocardial infarction, and stroke in a secondary prevention cohort in whom risk scores perform poorly., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Guidelines for diagnosing acute myocardial infarction (AMI) recommend adding kinetic changes to the initial cardiac troponin (cTn) blood concentration to improve AMI diagnosis. We hypothesized that kinetic changes may not be required in patients presenting with highly abnormal cTn., Methods: Patients presenting with suspected AMI to the emergency department were enrolled in a prospective diagnostic study. We assessed the positive predictive value (PPV) of initial high-sensitivity cardiac troponin T (hs-cTnT) blood concentrations alone and in combination with kinetic changes for AMI. Predefined relative changes (δ change of ≥20%) and absolute changes (Δ change ≥9.2 ng/L) within different time intervals (1 h, 2 h, and 4-14 h after presentation) were assessed. The final diagnosis was adjudicated by 2 independent cardiologists., Results: Among 1282 patients, 213 (16.6%) patients had a final diagnosis of AMI. For AMI prediction, PPVs increased from 48.8% for an initial hs-cTnT >14 ng/L to 87.2% for >60 ng/L, whereas PPVs remained unchanged for higher hs-cTnT concentrations at baseline (87.1% for both >80 ng/L and >100 ng/L). With addition of 20% relative Δ change, PPVs were not further improved in patients with baseline hs-cTnT >80 ng/L using the 1-h (84.0%) and 2-h (88.9%) intervals, and only minimally when extending the interval to 4-14 h (91.2% for >80 ng/L and 90.4% for >100 ng/L, respectively). Similar findings were observed when applying absolute changes., Conclusions: In chest pain patients with highly abnormal hs-cTnT concentrations at presentation, subsequent blood draws may not be required, as they do not provide incremental diagnostic value for prediction of AMI diagnosis., (© 2016 American Association for Clinical Chemistry.)

Aims: To investigate the prognostic implications of elevated high-sensitivity cardiac troponin T (hs-cTnT) values in presumably stable ambulatory coronary artery disease patients., Methods and Results: We conducted a retrospective, single-centre pilot observational study in a low-risk population. All patients received routine measurement of hs-cTnT at index and follow-up visits. Endpoints were all-cause mortality and a composite of all-cause mortality, acute myocardial infarction, stroke and rehospitalization for acute coronary syndrome and heart failure. Nine hundred and sixty-five consecutive patients presenting to our outpatient clinic between June 2009 and June 2010 were screened; 693 patients with a stable clinical course, at least one hs-cTnT value and at least one follow-up visit qualified for analysis. Follow-up was 796 days. Five hundred and forty-seven patients (78.9%) had hs-cTnT values below and 146 patients (21.1%) had values above 14 ng/l, which was defined to categorize high and low levels as it was reported to be the 99th percentile of a reference population. We observed 13 deaths (all-cause mortality) including four cardiovascular deaths. Age, N terminal pro-brain natriuretic peptide levels and impaired renal function were independently associated with an elevated hs-cTnT in a multivariate analysis. Hs-cTnT values >14 ng/l were strongly associated with all-cause mortality (hazard ratio 12.9, 95% confidence interval (CI): 3.5-46.9, p=0.0001), the composite clinical endpoint (hazard ratio 2.35, 95% CI: 1.48-3.72, p=0.0003) and rehospitalization for heart failure (hazard ratio 3.36, 95% CI: 1.73-6.53, p=0.0004). Compared with the multivariable Framingham score hs-cTnT revealed a significantly better performance (area under the receiver operating characteristics curve (AUC) hs-cTnT: 0.882 vs. AUC Framingham score 0.639, p=0.0005)., Conclusion: Elevated hs-cTnT levels provide excellent prognostic information regarding all-cause mortality and a combined clinical endpoint in presumably stable ambulatory coronary artery disease outpatients presenting for routine evaluation., (© The European Society of Cardiology 2015.)

Aims: We sought to evaluate rates and mechanisms of myocardial injury and type 4a myocardial infarction (MI) after an elective diagnostic coronary angiography (CAG) as detected by high-sensitivity cardiac troponin T (hsTnT) assay., Methods and Results: Cardiac troponin concentrations were measured in consecutive patients before and after undergoing an elective CAG -with or without coronary intervention (PCI)- using an hsTnT assay. The study population consisted of 545 patients: 320 (58.7%) patients received only an elective CAG and another 225 patients (41.3%) received an additional PCI. Significant hsTnT increases occurred in 97 (30.3%) cases within the CAG group and in 152 (67.6%) cases within the PCI group. Rates of normal baseline hsTnT values (<99th percentile upper reference limit) were 75.9% in the CAG group and 71.6% in the PCI group. In cases with normal baseline hsTnT values, peak levels meeting criteria of MI type 4a according to the second or third version of the universal MI definition were observed in five (1.6%) and one (0.3%) cases within the CAG group, as well as in 32 (14.2%) and 22 (9.8%) cases within the PCI group, respectively., Conclusions: Use of the hsTnT assay may allow identification of myocardial injury during an uneventful diagnostic coronary angiography in the absence of any coronary or non-coronary interventions.

Objectives: To evaluate the impact of age- and gender-specific cut-offs for high-sensitivity cardiac troponin T (hs-cTnT) compared to the general 99th percentile hs-cTnT cut-off on diagnosis and prognosis of acute myocardial infarction (AMI)., Methods: 1282 unselected patients presenting to the emergency department with suspected AMI were enrolled as part of the TRAPID-AMI study. In the present sub-analysis, reclassification of AMI diagnosis was performed by comparing the general hs-cTnT cut-off of 14ng/L to previously proposed age- and gender-dependent hs-cTnT 99th percentile cut-offs (28ng/L for ≥65years, 9ng/L for female and 15.5ng/L for male patients). Patients were further clinically adjudicated into acute coronary syndrome (ACS) and non-ACS., Results: For patients ≥65years, application of age-specified cut-offs resulted in a decrease of AMI from 29.8% to 18.3% in the entire cohort (n=557) and 54.7% to 40.9% in the ACS subcohort (n=225). Using gender-specific cut-offs, AMI-rate increased from 16.6% to 22.6% (entire cohort, n=477) and 62.6% to 71.7% (ACS subcohort, n=99) in women, whereas in men, rates decreased from 23.1% to 21.1% (entire cohort, n=805) and 48.8% to 45.9% (ACS, n=281), respectively. Age-specified cut-offs significantly reclassified patients for outcomes of 1-month and 3-month mortality in the entire and ACS cohort (14.2% net reclassification improvement, p<0.001, respectively). Contrary, no significant differences in outcomes could be found using gender-specific cut-offs., Conclusions: While influence of gender-specific hs-cTnT cut-offs on diagnostic and prognostic reclassification was only modest in patients with suspected AMI, age-specific cut-offs showed a significant impact and may be considered for further validation., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: The search for improved strategies for safe and early discharge of patients with suspected acute coronary syndrome in emergency departments is ongoing. This Biomarkers in Cardiology (BIC)-8 biomarker substudy evaluated the usefulness of high-sensitivity troponin T (hsTnT) below or above the limit of detection (LoD) in low-to-intermediate-risk patients with suspected acute coronary syndrome in the emergency department., Methods: Patients were categorized into hsTnT ≥ the 99th percentile, between the 99th percentile and LoD, or undetectable hsTnT (

Background: Point of care testing (POCT) assays for cardiac troponin (cTn) are hampered by lower analytical sensitivity and thus suboptimal rule-out of myocardial infarction (MI). We investigated, whether additional measurement of copeptin using an ultrasensitive assay improves diagnostic performance of POCT for cTn T compared to a high sensitivity troponin T (hsTnT) assay., Methods: 131 patients with suspected acute coronary syndrome were prospectively enrolled in our center 08/2010 to 11/2011. In blood samples obtained at presentation, ultrasensitive copeptin (Kryptor, BRAHMS) and two commercially available POCT assays, AQT90 Flex Radiometer (Radiometer) and Cobas h232 POC-System (Cobas), were tested. HsTnT (Cobas E411, Roche) at baseline and after 3 and 6h in the central laboratory served as reference., Results: Copeptin improved rule-out of non-STEMI combined with all tested troponin assays. Addition of copeptin increased sensitivity of Cobas from 67.9% (95% CI: 0.506; 0.852) to 89.3% (95% CI: 0.778; 1.007) and Radiometer from 71.4% (95% CI: 0.547; 0.882) to 85.7% (95% CI: 0.728; 0.987), achieving the sensitivity of hsTnT alone at admission of 85.7% (95% CI: 0.728; 0.987). The area under the curve (AUC) of Radiometer (0.822) was numerically but insignificantly (p=0.17) higher than AUC of Cobas (0.725). Addition of copeptin increased AUC of Radiometer to 0.826 (p=0.96) and AUC of Cobas to 0.814 (p=0.20)., Conclusions: Additional use of ultrasensitive copeptin improves diagnostic performance of conventional sensitive POCT assays overcoming lower sensitivities at the cost of a drop of clinical specificity. When hsTn is temporarily unavailable, copeptin and POCT for cTn may allow initial evaluation at a comparable performance as hsTnT at admission., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: Diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) varies depending on presenting symptoms in patients with suspected acute coronary syndrome (ACS)., Methods: We compared performance measures of hs-cTnT among patients admitted to the emergency department with typical chest pain (angina), dyspnea, and atypical symptoms and assessed outcomes by leading presenting symptoms., Results: A total of 658 patients suspected of ACS and presenting with typical chest pain (n = 241, 36.6%), dyspnea (n = 142, 21.6%), or atypical symptoms (n = 275, 41.8%) were included. Diagnostic accuracy of hs-cTnT on admission was higher among patients with typical chest pain compared to those with atypical symptoms [area under the curve (AUC) 0.823 vs AUC 0.776 vs AUC 0.705, P > 0.05 and P = 0.04]. Absolute concentration changes within 6 h improved accuracy among all subgroups, with the smallest added benefit in typical chest pain and dyspnea (ΔAUC, 0.078; P = 0.02 and 0.05, P > 0.05). During 1-year follow-up, dyspnea was associated with a higher risk of death (hazard ratio, 2.36; 95% CI, 1.26-4.43, P = 0.008) and death/AMI (hazard ratio, 2.23; 95% CI, 1.21-4.11, P = 0.01) compared to typical chest pain. Optimal discriminating values for hs-cTnT were higher among patients presenting with dyspnea compared to those with typical chest pain (91.2 vs 14.1 ng/L, P < 0.001)., Conclusion: The diagnostic performance of hs-cTnT in patients with suspected ACS depends on the leading presenting symptom. Patients admitted with dyspnea represent a high-risk cohort in which the diagnosis of ACS is less frequent and with inferior performance of serial hs-cTnT measurements. Higher hs-cTnT cutoffs at baseline and absolute changes after 6 h help to identify non-STEMI (ST segment elevation myocardial infarction) in this population., (© 2015 American Association for Clinical Chemistry.)

Purpose: The aim of this study was to test the prognostic performance of rising and falling kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) and the GRACE score., Methods: Rising and falling hs-cTnT changes in an unselected emergency department population were compared., Results: 635 patients with a hs-cTnT >99th percentile admission value were enrolled. Of these, 572 patients qualified for evaluation with rising patterns (n=254, 44.4%), falling patterns (n=224, 39.2%), or falling patterns following an initial rise (n=94, 16.4%). During 407days of follow-up, we observed 74 deaths, 17 recurrent AMI, and 79 subjects with a composite of death/AMI. Admission values >14ng/L were associated with a higher rate of adverse outcomes (OR, 95%CI:death:12.6, 1.8-92.1, p=0.01, death/AMI:6.7, 1.6-27.9, p=0.01). Neither rising nor falling changes increased the AUC of baseline values (AUC: rising 0.562 vs. 0.561, p=ns, falling: 0.533 vs. 0.575, p=ns). A GRACE score ≥140 points indicated a higher risk of death (OR, 95%CI: 3.14, 1.84-5.36), AMI (OR, 95%CI: 1.56, 0.59-4.17), or death/AMI (OR, 95%CI: 2.49, 1.51-4.11). Hs-cTnT changes did not improve the prognostic performance of a GRACE score ≥140 points (AUC, 95%CI: death: 0.635, 0.570-0.701 vs. 0.560, 0.470-0.649 p=ns, AMI: 0.555, 0.418-0.693 vs. 0.603, 0.424-0.782, p=ns, death/AMI: 0.610, 0.545-0.676 vs. 0.538, 0.454-0.622, p=ns). Coronary angiography was performed earlier in patients with rising than with falling kinetics (median, IQR [hours]:13.7, 5.5-28.0 vs. 20.8, 6.3-59.0, p=0.01)., Conclusion: Neither rising nor falling hs-cTnT changes improve the prognostic performance of elevated hs-cTnT admission values or the GRACE score. However, rising values are more likely associated with the decision for earlier invasive strategy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: We sought to evaluate the prognostic impact of absolute and relative kinetic changes of high-sensitivity cardiac Troponin T (hs-cTnT) in comparison to baseline hs-cTnT elevations for risk stratification in acute coronary syndrome (ACS) and non-ACS conditions with increased hs-cTnT., Methods: hs-cTnT was measured serially in patients presenting with acute symptoms to our emergency department. We assessed the prognostic performance of baseline and serial hs-cTnT concentrations in all consecutive patients with ACS (n=406) or hs-cTnT increases not due to ACS (n=442) within 3-6h after admission., Results: Mortality rates were higher, albeit not statistically, in non-ACS (53/442=12.0%) than ACS patients (36/406=8.9%). In ACS patients, receiver operating characteristics (ROC) revealed optimized cut-off values of 12.2 ng/L for absolute δ-change (AUC=0.66, p<0.001), 31.2 ng/L for baseline hs-cTnT (AUC=0.71, p<0.001) and 45.2 ng/L for maximal hs-cTnT (AUC=0.68, p<0.001). C-statistics showed superiority of absolute δ-changes (p=0.0003), baseline hs-cTnT (p=0.04) and maximal hs-cTnT (p=0.02) compared to relative δ-changes. However, the combination of baseline hs-cTnT values with either absolute or relative δ-changes did not improve risk prediction compared to baseline hs-cTnT alone (p=n.s.). In non-ACS conditions, the ROC-optimized cut-off value of 46.2 ng/L for baseline hs-cTnT (AUC=0.661, p<0.001) was superior to absolute (p=0.007) and relative δ-changes regarding prognostication (p=0.045)., Conclusions: Our data suggest that the magnitude of baseline hs-cTnT, and not acute dynamic changes, convey superior long-term prognostic information in ACS and non-ACS conditions. Moreover, absolute and relative kinetic δ-changes of hs-cTnT do not add significant incremental value in risk assessment in both conditions., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Current ESC guidelines for the diagnosis of myocardial infarction consider a rise and/or fall of cardiac biomarkers. However, whether rising or falling patterns of high-sensitivity cardiac troponin T (hs-cTnT) improve the discrimination of ST-elevation myocardial infarction (non-STEMI) from non-acute coronary syndromes (ACS) has not been evaluated yet., Methods: We compared protocols of rising and falling absolute and relative hs-cTnT changes in an unselected emergency department population., Results: A total of 635 patients with unstable angina pectoris (UAP), non-STEMI, or acute symptoms and increased hs-cTnT (>99th percentile) were enrolled. Of these, 572 patients met the inclusion criteria of consistently rising patterns (n=254, 44.4%), consistently falling patterns (n=224, 39.2%), or falling patterns after an initial rise (n=94, 16.4%). Final diagnoses included 66 (11.5%) patients with UAP, 141 (24.7%) patients with non-STEMI, and 365 (63.8%) patients with hs-cTnT elevations not due to ACS. Rising values were found more frequently in patients with non-STEMI, as compared to non-ACS (OR 3.69, 95% CI 2.46-5.53; p<0.0001), and falling patterns were observed more frequently in patients with non-ACS conditions (OR 3.56, 95% CI 2.24-5.63; p<0.001). Addition of rising but not falling changes increased diagnostic performance of hs-cTnT concentrations at presentation: positive: AUC 0.680 (95% CI 0.618-0.742) vs. 0.861 (95% CI 0.822-0.900; p<0.0001), negative: AUC 0.678 (95% CI 0.545-0.812) vs. 0.741 (95% CI 0.635-0.847). A 20% criterion as proposed by ESC guidelines performed equally for positive and negative changes only when admission hs-cTnT values were considered: AUC 0.785 (95% CI 0.726-0.845) vs. AUC 0.763 (95% CI 0.681-0.845); p=ns., Conclusions: Detection of rising but not falling hs-cTnT values improves discrimination of non-STEMI from non-ACS in an unselected emergency department population.

Background: Current European guidelines recommend the use of sensitive or high-sensitivity cardiac troponin assays to reduce the minimal sampling interval from 6 to 3h., Methods: We compared a 3-hour versus a 6-hour protocol for diagnosis of non-STEMI and used the 99th percentile for rule-out, and relative and absolute concentration changes for rule-in of non-STEMI., Results: 459 patients with either an NSTE-ACS or elevated hs-cTnT not due to MI and hs-cTnT measurements at 0, 3 and 6h were enrolled. Among the 404 patients excluded due to an incomplete sampling protocol performance was comparable to the 459 patients with a complete sampling protocol (AUC 0.79 vs 0.80, p=ns). In the study group, non-STEMI was diagnosed in 111 cases (24.2%) and elevated hs-cTnT not due to MI was observed in 215 cases (46.8%). For rule-out of non-STEMI, NPVs were 94.9%, 98.7% and 100% on admission, at 3 and 6h with comparable performance at 3 and 6h (AUC 0.782 vs 0.790, p=ns). For rule-in a 3-hour protocol performed as well as a 6-hour protocol, with a significantly (p<0.0001) better performance of absolute (AUC 0.851 vs. 0.845, p=0.740) as compared to relative concentration changes (AUC 0.771 vs. 0.739, p=0.169)., Conclusions: Rule-in and rule-out of non-STEMI may be accomplished comparably effective at 3 or 6h. For rule-in, absolute kinetic changes perform better than relative changes at all time points. ROC-optimal absolute δ-change was 6.95 ng/L at 3h and 8.9 ng/L at 6h., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Cardiac troponins (cTns) T and I are exclusively expressed at high concentrations in cardiac muscle and have emerged as the preferred biomarker in the universal definition of myocardial infarction (MI). With the recent introduction of high-sensitivity (hs) assays, diagnostic sensitivity for earlier detection of MI has substantially improved. However, lowering the diagnostic cut-off has increased the detection of myocardial injuries in various non-acute coronary syndrome (ACS) conditions, which are not related to myocardial ischemia, leading to rising difficulties in diagnosing MI in clinical situations. Several approaches, such as serial sampling and incorporation of relative or absolute δ-changes, have been proposed to overcome the limitation of decreased sensitivity for MI diagnosis with hs-cTn assays. Current consensus for rapid rule-in proposes a 20% increase within 3 or 6h when baseline cTn levels are elevated. In the case of negative baseline values, relative increases ≥50% above the 99(th) percentile were found to be adequate to improve accuracy of MI diagnosis. Besides improved diagnostic accuracy for myocardial injury, even minor cTn elevations provide important prognostic information, and increased levels of cTn are associated with adverse outcomes in both the ACS and non-ACS condition, irrespective of whether the underlying cause is an acute or chronic illness. Thus, it is highly likely that lowering the diagnostic cut-off with even more sensitive assays might improve risk stratification in both conditions.

Background: Elevated cardiac troponin (cTn) has been reported to occur with AVNRT. Little is known about prevalence, kinetic changes, and possible reasons of increased cTn., Methods: We evaluated 139 consecutive patients presenting with AVNRT to the emergency department between 2006 and 2010. Cardiac troponin T (cTnT) was measured serially at baseline, after three and six hours. Patients were evaluated for the presence of structural heart disease or CAD. Troponin was defined as elevated if a value exceeded the lower limit of detection (10 ng/l) using the fourth generation cTnT, or if the value > 99 th percentile (14 ng/l) using the new highly sensitive cTn assay., Results: A cTnT > LLD (n = 29) or > 99 th percentile (n = 16) was found in 45 patients (32.4%) within the initial six hours after hospitalization. All patients were symptomatic with palpitations, chest discomfort or dyspnea. A complete cardiac evaluation was carried out, including coronary angiography in 32 patients demonstrating an underlying structural heart disease or CAD in 18 cases (56%). Significant CAD was detected in 16 cases. 8 cases required PCI during hospitalization. Elevated cTnT was seen in patients with and without structural heart disease., Conclusions: AVNRT is a possible reason for elevated cTnT, even in the absence of relevant structural heart disease or CAD.

Background: The effect of age on diagnostic and prognostic performance of high-sensitivity cardiac troponin T (hs-cTnT) has not been addressed adequately, so far., Methods: High-sensitivity cardiac troponin T was measured serially in patients with acute symptoms presenting to our emergency department. We tested the diagnostic and prognostic performance of baseline and serial hs-cTnT concentrations related to age in all consecutive patients with acute coronary syndrome (ACS) (n = 342) or hs-cTnT increases not due to ACS (n = 442)., Results: Prevalence of elevated hs-cTnT in the study population was higher among patients ≥75 years compared with younger patients (89.1 % vs 73.3 %, hazard ratio [HR] 1.2, P < .0001). Elevated hs-cTnT was more likely due to ACS in the younger patients (HR 1.4, P = .001) and conversely more frequently due to non-ACS conditions in the elderly patients (HR 1.3, P = .0001). Diagnostic performance of hs-cTnT using the 99th percentile was significantly superior in younger than in elderly patients (P < .0001). For receiver operating characteristic-optimized cutoffs, a trend to significance was found between younger and older patients (area under the curve 0.87 vs 0.79, P = .074), with higher sensitivities (98.2 % vs 72.6%) and negative predictive values (97.3% vs. 78.5%) for patients <75 years. Moreover, receiver operating characteristic-optimized cutoff values for diagnosis of non-ST-segment elevation myocardial infarction were significantly higher in elderly patients (32.9 ng/L) compared with younger patients (12.9 ng/L). The prognostic information of single and serial hs-cTnT measurements was comparably poor in both age groups, showing no better prognostic information to hs-cTnT measurement on presentation., Conclusions: Elevated hs-cTnT is more common in the elderly due to higher prevalence of non-ACS conditions and significantly impairs diagnostic performance in discriminating non-ST-segment elevation myocardial infarction., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: The study sought to compare the clinical performance of two more sensitive cardiac troponin (cTn) assays, a novel high-sensitivity (hs) troponin T assay and a contemporary cTnI assay., Methods: We measured hs-cTnT (Roche TnThs) and cTnI (Siemens Centaur Ultra) on presentation in 1,384 patients with suspected acute coronary syndrome (ACS) who underwent early invasive strategy within 24 h after presentation. Kaplan-Meier, Cox proportional hazards, and receiver-operating characteristic (ROC) analysis was used to compare their prognostic performance for the prediction of all-cause death and death/MI (myocardial infarction) after a median of 271 days. We also compared the diagnostic performance of these assays on presentation for early diagnosis of non-STEMI., Results: Both hs-cTnT and cTnI were independently predictive of long-term death (OR 3.51 vs. 2.19) and the composite of death/MI (OR 9.24 vs. 3.61), across the spectrum of ACS and in patients without ACS. When used as a continuous variable, ROC analysis demonstrated significantly higher areas under the curve (AUC) for hs-cTnT as compared to cTnI for the prediction of death/MI (0.721 vs. 0.672, P = 0.024), a trend to better prediction of all-cause death (0.721 vs. 0.672, P = 0.093) and significantly higher AUC for early diagnosis of non-STEMI (0.965 vs. 0.901, P < 0.001)., Conclusion: Using the 99th percentile cutoff for hs-cTnT and cTnI, both assays enable prediction of adverse long-term outcomes and earlier diagnosis of non-STEMI. Used as a continuous variable, the hs-cTnT assay showed superior performance compared to the cTnI assay, especially in regard to prognosis.

Background: We evaluated kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) in patients with acute coronary syndrome (ACS) and patients with hs-cTnT increases not due to ACS to rule in or rule out non-ST-segment elevation myocardial infarction (STEMI)., Methods: hs-cTnT was measured serially in consecutive patients presenting to the emergency department. Patients with ACS who had at least 2 hs-cTnT measurements within 6 h and non-ACS patients with hs-cTnT concentrations above the 99th percentile value (14 ng/L) were enrolled to compare absolute and relative kinetic changes of hs-cTnT., Results: For discrimination of non-STEMI (n=165) in the entire study population (n=784), the absolute δ change with the ROC-optimized value of 9.2 ng/L yielded an area under the curve of 0.898 and was superior to all relative δ changes (P<0.0001). The positive predictive value for the absolute δ change was 48.7%, whereas the negative predictive value was 96.5%. In a specific ACS population with exclusion of STEMI (n=342), the absolute δ change with the ROC-optimized value of 6.9 ng/L yielded a positive predictive value of 82.8% and a negative predictive value of 93.0%. In comparison to the ≥20% relative δ change, the ROC-optimized absolute δ change demonstrated a significantly added value for the entire study population and for the ACS cohort (net reclassification index 0.331 and 0.499, P<0.0001)., Conclusions: Absolute δ changes appear superior to relative δ changes in discriminating non-STEMI. A rise or fall of at least 9.2 ng/L in the entire study population and 6.9 ng/L in selected ACS patients seems adequate to rule-out non-STEMI. However, δ-values are useful to rule-in non-STEMI only in a specific ACS population.

Background: Two recent clinical trials showed that adding copeptin to a conventional cardiac troponin assay improved diagnostic performance for patients with chest pain early after symptom onset. We prospectively tested whether copeptin adds information to that provided by a high-sensitivity cardiac troponin T (hscTnT) assay in the early evaluation of patients with suspected acute myocardial infarction, particularly non-ST-segment elevation myocardial infarction (non-STEMI)., Methods: We enrolled 503 patients with suspected acute coronary syndrome and onset of chest pain occurring within the previous 12 h. Copeptin was measured on presentation, and hscTnT was measured serially at baseline and after 3 and 6 h. We used ROC curve analysis and likelihood ratio χ² statistics for nested models. Diagnostic sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) were calculated for admission values of copeptin alone, hscTnT alone, and the combination of both markers., Results: For ruling out non-STEMI (after excluding STEMI), an hscTnT concentration <14 ng/L (99th percentile) plus a copeptin concentration <14 pmol/L yielded a diagnostic sensitivity of 97.7% (95% CI, 91.9%-99.7%), an NPV of 99.03% (95% CI, 96.6%-99.9%), a diagnostic specificity of 55.9% (95% CI, 50.6%-61.0%), and a PPV of 34.4% (95% CI, 28.5%-40.7%). ROC curve analysis of the continuous biomarker values on admission demonstrated no added value of using this marker combination for ruling out non-STEMI when hscTnT was used as the standard for diagnosing non-STEMI., Conclusions: A strategy using copeptin with hscTnT at prespecified cutoffs improves the ruling out of non-STEMI, compared with using hscTnT alone; thus, this strategy could help to obviate a prolonged stay in the emergency department.