High-Sensitivity Troponin I after Cardiac Surgery and 30-Day Mortality.

BACKGROUND: Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to ≥70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS: We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS: Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS: The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.).

The relative merits of using a high-sensitivity cardiac Troponin T assay compared to a nonhigh-sensitivity troponin T assay after noncardiac surgery.

INTRODUCTION: Troponin elevation after noncardiac surgery is associated with an elevated risk of 30-day mortality. Little is known about relative merit of using a high-sensitivity Troponin T (hsTnT), the fifth-generation assay, vs the nonhigh sensitivity Troponin T (non-hsTnT), the fourth-generation assay, in the noncardiac surgery setting. We aimed to identify whether hsTnT can identify additional patients at risk that would have gone undetected with non-hsTnT measurement. METHODS: The VISION Study included 40,004 noncardiac surgery patients with postoperative troponin measurements. Among them, 1,806 patients had both fourth-generation non-hsTnT and fifth-generation hsTnT concomitant measurements (4,451 paired results). We compared the absolute concentrations, the timing, and the impact of different thresholds on predicting 30-day major cardiovascular complications (composite of death, nonfatal cardiac arrest, coronary revascularization, and congestive heart failure). RESULTS: Based on the manufacturers' threshold of 14 ng/L, 580 (32.1%) patients had postoperative hsTnT concentrations greater than the threshold, while their non-hsTnT concentrations were below the manufacturer's threshold. These 580 patients had higher risk of major cardiovascular events (OR 2.33; CI 95% 1.04-5.23; P = .049) than patients with hsTnT concentrations below the manufacturer threshold. Among patients with myocardial injury after noncardiac surgery, only 50% would be detected by the fourth-generation non-hsTnT assay at 6 to 12 hours postoperative as compared to 85% with the fifth-generation hsTnT assay (P-value < .001). CONCLUSIONS: Within the first 3 postoperative days, fifth-generation hsTnT identified at least 1 in 3 patients with troponin elevation that would have gone undetected by fourth-generation non-hsTnT using published thresholds in this setting. Furthermore, fifth-generation hsTnT identified patients with an elevation earlier than fourth-generation non-hsTnT, indicating potential to improve postoperative risk stratification.

High-Sensitivity Cardiac Troponin and the Management of Congenital Heart Disease in Newborns and Infants.

BACKGROUND: Early cardiac interventions in newborns and infants suspected for congenital heart disease (CHD) decrease morbidity and mortality. After updating current evidence on the use of cardiac troponins (cTn) in the context of CHD for risk stratification at early ages, we discuss relevant issues, starting from the evidence that only the measurement of the cTnT form is useful in this population. CONTENT: In newborns/infants with CHD, the cTnT concentration increase is correlated with: (a) cardiac stress and hemodynamic parameters, but not with the type of CHD; (b) volume overload/right ventricular pressure overload; (c) postoperative hypoperfusion injury and mortality; and (d) effects of cardioprotective strategies. For infants with CHD, high-sensitivity cTnT (hs-cTnT) concentrations >25 ng/L are an independent predictor of poor outcomes. Transitioning from cTnT to hs-cTnT in newborns/infants improves the identification of: (a) physiopathological mechanisms and factors that increased hs-cTnT early after birth; (b) myocardial injury, even when subclinical; (c) identification of patients requiring immediate therapeutic interventions; and (d) 99th percentile upper reference limits (URLs). However, no reliable URLs are currently available to allow the detection of myocardial injury associated with CHD in newborns/infants. SUMMARY: Additional data evaluating the clinical value of hs-cTnT in the risk stratification of newborns/infants with CHD who may suffer myocardial injury is needed. Validating the measurement, possibly in amniotic fluid samples, and improving the interpretation of hs-cTnT concentrations in the prenatal period, at birth and within 1 year of age are crucial to change CHD mortality/morbidity trends in the pediatric population.

Determination of Clinically Acceptable Analytical Variation of Cardiac Troponin at Decision Thresholds.

BACKGROUND: Clinical decision-making for risk stratification for possible myocardial infarction (MI) uses high-sensitivity cardiac troponin (hs-cTn) thresholds that range from the limit of detection to several-fold higher than the upper reference limit (URL). To establish a minimum analytical variation standard, we can quantify the effect of variation on the population clinical measures of safety (sensitivity) and effectiveness [proportion below threshold, or positive predictive value (PPV)]. METHODS: From large datasets of patients investigated for possible MI with the Abbott hs-cTnI and Roche hs-cTnT assays, we synthesized datasets of 1 000 000 simulated patients. Troponin concentrations were randomly varied several times based on absolute deviations of 0.5 to 3 ng/L and relative changes of 2% to 20% around the low-risk threshold (5 ng/L) and URLs, respectively. RESULTS: For both assays at the low-risk thresholds, there were negligible differences in sensitivity (<0.3%) with increasing analytical variation. The proportion of patients characterized as low risk reduced by 30% to 29% (Roche) and 53% to 44% (Abbott). At the URL, increasing analytical variation also did not change sensitivity; the PPV fell by less than 3%. For risk stratification, increased delta thresholds (change between serial troponin concentrations) increased sensitivity at the cost of a decreased percentage of patients below the delta threshold, with the largest changes at the greatest analytical variation. CONCLUSIONS: At the low-risk threshold, analytical variation up to 3 ng/L minimally impacted the safety metric (sensitivity) but marginally reduced effectiveness. Similarly, at the URL even relative variation up to 25% minimally impacted safety metrics and effectiveness. Analytical variation for delta thresholds did not negatively impact sensitivity but decreased effectiveness.

A Canadian survey of perceptions and practices related to ordering of blood tests in the intensive care unit.

PURPOSE: The ordering of routine blood test panels in advance is common in intensive care units (ICUs), with limited consideration of the pretest probability of finding abnormalities. This practice contributes to anemia, false positive results, and health care costs. We sought to understand practices and attitudes of Canadian adult intensivists regarding ordering of blood tests in critically ill patients. METHODS: We conducted a nationwide Canadian cross-sectional survey consisting of 15 questions assessing three domains (global perceptions, test ordering, daily practice), plus 11 demographic questions. The target sample was one intensivist per adult ICU in Canada. We summarized responses using descriptive statistics and present data as mean with standard deviation (SD) or count with percentage as appropriate. RESULTS: Over seven months, 80/131 (61%) physicians responded from 77 ICUs, 50% of which were from Ontario. Respondents had a mean (SD) clinical experience of 12 (9) years, and 61% worked in academic centres. When asked about their perceptions of how frequently unnecessary blood tests are ordered, 61% responded "sometimes" and 23% responded "almost always." Fifty-seven percent favoured ordering complete blood counts one day in advance. Only 24% of respondents believed that advanced blood test ordering frequently led to changes in management. The most common factors perceived to influence blood test ordering in the ICU were physician preferences, institutional patterns, and order sets. CONCLUSION: Most respondents to this survey perceived that unnecessary blood testing occurs in the ICU. The survey identified possible strategies to decrease the number of blood tests.

RéSUMé: OBJECTIF: La prescription à l'avance de tests sanguins de routine est courante dans les unités de soins intensifs (USI), avec une prise en compte limitée de la probabilité de découverte d'anomalies avant le test. Cette pratique contribue à l'anémie, aux résultats faussement positifs et aux coûts des soins de santé. Nous avons cherché à comprendre les pratiques et les attitudes des intensivistes pour adultes au Canada en ce qui concerne la prescription d'analyses sanguines chez la patientèle gravement malade. MéTHODE: Nous avons mené un sondage transversal à l'échelle nationale au Canada en posant 15 questions évaluant trois domaines (perceptions globales, commande de tests, pratique quotidienne), ainsi que 11 questions démographiques. L'échantillon cible était composé d'un·e intensiviste par unité de soins intensifs pour adultes au Canada. Nous avons résumé les réponses à l'aide de statistiques descriptives et présenté les données sous forme de moyennes avec écarts type (ET) ou de dénombrements avec pourcentages, selon le cas. RéSULTATS: Sur une période de sept mois, 80 médecins sur 131 (61%) ont répondu dans 77 unités de soins intensifs, dont 50% en Ontario. Les répondant·es avaient une expérience clinique moyenne (ET) de 12 (9) ans, et 61% travaillaient dans des centres universitaires. Lorsqu'on leur a demandé ce qu'ils ou elles pensaient de la fréquence à laquelle des tests sanguins inutiles étaient prescrits, 61% ont répondu « parfois ¼ et 23% ont répondu « presque toujours ¼. Cinquante-sept pour cent étaient en faveur de la réalisation d'une formule sanguine complète un jour à l'avance. Seulement 24% des personnes interrogées estimaient que la prescription de tests sanguins à l'avance entraînait fréquemment des changements dans la prise en charge. Les facteurs les plus souvent perçus comme influençant la prescription d'analyses sanguines à l'unité de soins intensifs étaient les préférences des médecins, les habitudes institutionnelles et les ensembles d'ordonnances. CONCLUSION: La plupart des répondant·es à ce sondage ont l'impression que des tests sanguins inutiles sont prescrits aux soins intensifs. L'enquête a permis d'identifier des stratégies possibles pour réduire le nombre de tests sanguins.

High-sensitivity Troponin I Predicts Major Cardiovascular Events after Non-Cardiac Surgery: A Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Substudy.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS), based on measurement of troponin T, is associated with perioperative major adverse cardiovascular events (MACE). We therefore determined the high-sensitivity troponin I (hsTnI) thresholds associated with 30 day MACE after non-cardiac surgery. METHODS: We performed a nested biobank cohort study of 4553 patients from the Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Study. We measured hsTnI (ADVIA Centaur® hsTnI assay) on postoperative days 1 to 3 in patients ≥45 years undergoing non-cardiac surgery. An iterative Cox proportional hazard model determined peak postoperative hsTnI thresholds independently associated with MACE (i.e., death, myocardial infarction occurring on postoperative day 4 or after, non-fatal cardiac arrest, or congestive heart failure) within 30 days after surgery. RESULTS: MACE occurred in 89/4545 (2.0%) patients. Peak hsTnI values of <75 ng/L, 75 ng/L to <1000 ng/L, and ≥1000 ng/L were associated with 1.2% (95% CI, 0.9-1.6), 7.1% (95% CI, 4.8-10.5), and 25.9% (95% CI, 16.3-38.4) MACE, respectively. Compared to peak hsTnI <75 ng/L, values 75 ng/L to <1000 ng/L and ≥1000 ng/L were associated with adjusted hazard ratios (aHR) of 4.53 (95% CI, 2.75-7.48) and 16.17 (95% CI, 8.70-30.07), respectively. MACE was observed in 9% of patients with peak hsTnI ≥75 ng/L vs 1% in patients with peak hsTnI <75 ng/L (aHR 5.76; 95% CI, 3.64-9.11). A peak hsTnI ≥75 ng/L was associated with MACE in the presence (aHR 9.35; 95% CI, 5.28-16.55) or absence (aHR 3.99; 95% CI, 2.19-7.25) of ischemic features of myocardial injury. CONCLUSION: A peak postoperative hsTnI ≥75 ng/L was associated with >5-fold increase in the risk of 30 days MACE compared to levels <75 ng/L. This threshold could be used for MINS diagnosis when the ADVIA Centaur hsTnI assay is used.Clinicaltrials.gov Registration Number: NCT00512109.

Association of Preoperative Growth Differentiation Factor-15 Concentrations and Postoperative Cardiovascular Events after Major Noncardiac Surgery.

BACKGROUND: The association between growth differentiation factor-15 concentrations and cardiovascular disease has been well described. The study hypothesis was that growth differentiation factor-15 may help cardiac risk stratification in noncardiac surgical patients, in addition to clinical evaluation. METHODS: The objective of the study was to determine whether preoperative serum growth differentiation factor-15 is associated with the composite primary outcome of myocardial injury after noncardiac surgery and vascular death at 30 days and can improve cardiac risk prediction in noncardiac surgery. This is a prospective cohort study of patients 45 yr or older having major noncardiac surgery. The association between preoperative growth differentiation factor-15 and the primary outcome was determined after adjusting for the Revised Cardiac Risk Index. Preoperative N-terminal-pro hormone brain natriuretic peptide was also added to compare predictive performance with growth differentiation factor-15. RESULTS: Between October 27, 2008, and October 30, 2013, a total of 5,238 patients were included who had preoperative growth differentiation factor-15 measured (median, 1,325; interquartile range, 880 to 2,132 pg/ml). The risk of myocardial injury after noncardiac surgery and vascular death was 99 of 1,705 (5.8%) for growth differentiation factor-15 less than 1,000 pg/ml, 161 of 1,332 (12.1%) for growth differentiation factor-15 1,000 to less than 1,500 pg/ml, 302 of 1476 (20.5%) for growth differentiation factor-15 1,500 to less than 3,000 pg/ml, and 247 of 725 (34.1%) for growth differentiation factor-15 concentrations 3,000 pg/ml or greater. Compared to patients who had growth differentiation factor-15 concentrations less than 1,000 pg/ml, the corresponding adjusted hazard ratio for each growth differentiation factor-15 category was 1.93 (95% CI, 1.50 to 2.48), 3.04 (95% CI, 2.41 to 3.84), and 4.8 (95% CI, 3.76 to 6.14), respectively. The addition of growth differentiation factor-15 improved cardiac risk classification by 30.1% (301 per 1,000 patients) compared to Revised Cardiac Risk Index alone. It also provided additional risk classification beyond the combination of preoperative N-terminal-pro hormone brain natriuretic peptide and Revised Cardiac Risk Index (16.1%; 161 per 1,000 patients). CONCLUSIONS: Growth differentiation factor-15 is strongly associated with 30-day risk of major cardiovascular events and significantly improved cardiac risk prediction in patients undergoing noncardiac surgery.

Using logistic regression models to investigate the effects of high-sensitivity cardiac troponin T confounders on ruling in acute myocardial infarction.

OBJECTIVES: Confounding factors, including sex, age, and renal dysfunction, affect high-sensitivity cardiac troponin T (hs-cTnT) concentrations and the acute myocardial infarction (AMI) diagnosis. This study assessed the effects of these confounders through logistic regression models and evaluated the diagnostic performance of an optimized, integrated prediction model. METHODS: This retrospective study included a primary derivation cohort of 18,022 emergency department (ED) patients at a US medical center and a validation cohort of 890 ED patients at a Canadian medical center. Hs-cTnT was measured with 0/3 h sampling. The primary outcome was index AMI diagnosis. Logistic regression models were optimized to predict AMI using delta hs-cTnT and its confounders as covariates. The diagnostic performance of model cutoffs was compared to that of the hs-cTnT delta thresholds. Serial logistic regressions were carried out to evaluate the relationship between covariates. RESULTS: The area under the curve of the best-fitted model was 0.95. The model achieved a 90.0% diagnostic accuracy in the validation cohort. The optimal model cutoff yielded comparable performance (90.5% accuracy) to the optimal sex-specific delta thresholds (90.3% accuracy), with 95.8% agreement between the two diagnostic methods. Serial logistic regressions revealed that delta hs-cTnT played a more predominant role in AMI prediction than its confounders, among which sex is more predictive of AMI (total effect coefficient 1.04) than age (total effect coefficient 0.05) and eGFR (total effect coefficient -0.008). CONCLUSIONS: The integrated prediction model incorporating confounding factors does not outperform hs-cTnT delta thresholds. Sex-specific hs-cTnT delta thresholds remain to provide the highest diagnostic accuracy.

Reference intervals for thyroid biomarkers to enhance the assessment of thyroid status in childhood and adolescence.

OBJECTIVES: The determination of assay-dependent upper and lower reference limits (URL, LRL) of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) during childhood and adolescence, is challenging. METHODS: Thyroid hormones were measured via the Abbott Alinity system in 502 euthyroid children partitioned in the following age groups: ≤2, 2.1-10, and 10.1-18 years. The 97.5th and 2.5th percentiles (URL and LRL) were derived according to CLSI EP28- A3c guidelines. Quantile regression models were used to assess: (a) 90% confidence intervals of the URL and LRL, (b) the effect of age on URL and LRL within each age class and on overall age range, (c) the difference between the URLs and LRLs estimated for each age partition with an estimate of the confidence interval divided by the reference interval being derived (CI/RI). RESULTS: The CI/RI for the LRLs are smaller as compared to the URLs, except for FT4 for the 2.1-10 years age group. Considering the CI/RI and the overlap between CIs across the three age groups, one single LRL might be considered for TSH, FT3 and FT4 between 0 and 18 years. However, for the URL, there was a noticeable decrease in the URL over the 3 age groups for all three biomarkers, with there being no overlap in CIs for the URL between the ≤2 vs. the 10.1-19 years age groups. CONCLUSIONS: A common LRL for TSH, FT4 and FT3 for patients aged ≤18 years may be utilized when these biomarkers are measured with the Alinity system. For the URLs the use of age-specific URLs for these biomarkers is recommended.

Individual risk prediction of high grade prostate cancer based on the combination between total prostate-specific antigen (PSA) and free to total PSA ratio.

OBJECTIVES: Clinical practice guidelines endorse the stratification of prostate cancer (PCa) risk according to individual total prostate-specific antigen (tPSA) values and age to enhance the individual risk-benefit ratio. We defined two nomograms to predict the individual risk of high and low grade PCa by combining the assay of tPSA and %free/tPSA (%f/tPSA) in patients with a pre-biopsy tPSA between 2 and 10 µg/L. METHODS: The study cohort consisted of 662 patients that had fPSA, tPSA, and a biopsy performed (41.3% with a final diagnosis of PCa). Logistic regression including age, tPSA and %f/tPSA was used to model the probability of having high or low grade cancer by defining 3 outcome levels: no PCa, low grade (International Society of Urological Pathology grade, ISUP<3) and high grade PCa (ISUP≥3). RESULTS: The nomogram identifying patients with: (a) high vs. those with low grade PCa and without the disease showed a good discriminating capability (∼80%), but the calibration showed a risk of underestimation for predictive probabilities >30% (a considerable critical threshold of risk), (b) ISUP<3 vs. those without the disease showed a discriminating capability of 63% and overestimates predictive probabilities >50%. In ISUP 5 a possible loss of PSA immunoreactivity has been observed. CONCLUSIONS: The estimated risk of high or low grade PCa by the nomograms may be of aid in the decision-making process, in particular in the case of critical comorbidities and when the digital rectal examinations are inconclusive. The improved characterization of the risk of ISUP≥3 might enhance the use for magnetic resonance imaging in this setting.

Antibody-mediated interferences affecting cardiac troponin assays: recommendations from the IFCC Committee on Clinical Applications of Cardiac Biomarkers.

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

Performance of the European Society of Cardiology 0/1-Hour, 0/2-Hour, and 0/3-Hour Algorithms for Rapid Triage of Acute Myocardial Infarction : An International Collaborative Meta-analysis.

BACKGROUND: The 2020 European Society of Cardiology (ESC) guidelines recommend using the 0/1-hour and 0/2-hour algorithms over the 0/3-hour algorithm as the first and second choices of high-sensitivity cardiac troponin (hs-cTn)-based strategies for triage of patients with suspected acute myocardial infarction (AMI). PURPOSE: To evaluate the diagnostic accuracies of the ESC 0/1-hour, 0/2-hour, and 0/3-hour algorithms. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from 1 January 2011 to 31 December 2020. (PROSPERO: CRD42020216479). STUDY SELECTION: Prospective studies that evaluated the ESC 0/1-hour, 0/2-hour, or 0/3-hour algorithms in adult patients presenting with suspected AMI. DATA EXTRACTION: The primary outcome was index AMI. Twenty unique cohorts were identified. Primary data were obtained from investigators of 16 cohorts and aggregate data were extracted from 4 cohorts. Two independent authors assessed each study for methodological quality. DATA SYNTHESIS: A total of 32 studies (20 cohorts) with 30 066 patients were analyzed. The 0/1-hour algorithm had a pooled sensitivity of 99.1% (95% CI, 98.5% to 99.5%) and negative predictive value (NPV) of 99.8% (CI, 99.6% to 99.9%) for ruling out AMI. The 0/2-hour algorithm had a pooled sensitivity of 98.6% (CI, 97.2% to 99.3%) and NPV of 99.6% (CI, 99.4% to 99.8%). The 0/3-hour algorithm had a pooled sensitivity of 93.7% (CI, 87.4% to 97.0%) and NPV of 98.7% (CI, 97.7% to 99.3%). Sensitivity of the 0/3-hour algorithm was attenuated in studies that did not use clinical criteria (GRACE score <140 and pain-free) compared with studies that used clinical criteria (90.2% [CI, 82.9 to 94.6] vs. 98.4% [CI, 88.6 to 99.8]). All 3 algorithms had similar specificities and positive predictive values for ruling in AMI, but heterogeneity across studies was substantial. Diagnostic performance was similar across the hs-cTnT (Elecsys; Roche), hs-cTnI (Architect; Abbott), and hs-cTnI (Centaur/Atellica; Siemens) assays. LIMITATION: Diagnostic accuracy, inclusion and exclusion criteria, and cardiac troponin sampling time varied among studies. CONCLUSION: The ESC 0/1-hour and 0/2-hour algorithms have higher sensitivities and NPVs than the 0/3-hour algorithm for index AMI. PRIMARY FUNDING SOURCE: National Taiwan University Hospital.

ESAIC focused guideline for the use of cardiac biomarkers in perioperative risk evaluation.

BACKGROUND: In recent years, there has been increasing focus on the use of cardiac biomarkers in patients undergoing noncardiac surgery. AIMS: The aim of this focused guideline was to provide updated guidance regarding the pre-, post- and combined pre-and postoperative use of cardiac troponin and B-type natriuretic peptides in adult patients undergoing noncardiac surgery. METHODS: The guidelines were prepared using Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology. This included the definition of critical outcomes, a systematic literature search, appraisal of certainty of evidence, evaluation of biomarker measurement in terms of the balance of desirable and undesirable effects including clinical outcomes, resource use, health inequality, stakeholder acceptance, and implementation. The panel differentiated between three different scopes of applications: cardiac biomarkers as prognostic factors, as tools for risk prediction, and for biomarker-enhanced management strategies. RESULTS: In a modified Delphi process, the task force defined 12 critical outcomes. The systematic literature search resulted in over 25,000 hits, of which 115 full-text articles formed the body of evidence for recommendations. The evidence appraisal indicated heterogeneity in the certainty of evidence across critical outcomes. Further, there was relevant gradient in the certainty of evidence across the three scopes of application. Recommendations were issued and if this was not possible due to limited evidence, clinical practice statements were produced. CONCLUSION: The ESAIC focused guidelines provide guidance on the perioperative use of cardiac troponin and B-type natriuretic peptides in patients undergoing noncardiac surgery, for three different scopes of application.

Application of High-Sensitivity Troponin in Suspected Myocardial Infarction.

BACKGROUND: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. METHODS: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. RESULTS: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. CONCLUSIONS: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.).

Sex-Specific Absolute Delta Thresholds for High-Sensitivity Cardiac Troponin T.

BACKGROUND: Sex differences in high-sensitivity cardiac troponin (hs-cTn) concentrations from healthy populations have led to the establishment of sex-specific upper reference limits for hs-cTn assays. This study assessed the performance of sex-specific delta (i.e., changes in concentrations) thresholds for the hs-cTnT assay for ruling in acute myocardial infarction (AMI) in different emergency department (ED) populations. METHODS: This retrospective study consisted of 2 cohorts (Cohort 1 derivation and Cohort 2 validation). Cohort 1 consisted of 18 056 ED patients who had serial hs-cTnT measured using a 0-h/3-h algorithm at a US medical center, with Cohort 2 consisting of 1137 ED patients with 0-h/3-h sampling at a Canadian medical center. The primary outcome was AMI diagnosis with sex-specific deltas derived based on the Youden index and specificity estimates (i.e., ≥90%) in Cohort 1 and validated in Cohort 2. RESULTS: In Cohort 1, 42% of all patients had 0-h hs-cTnT above the sex-specific 99th percentile. Males had higher 0-h hs-cTnT (median 17 ng/L) and absolute deltas (median 2 ng/L) than females (0-h median 11 ng/L, P < 0.0001; deltas median 1 ng/L, P < 0.0001) in non-AMI patients but not in patients with AMI. For ruling in AMI, the sex-specific delta thresholds based on 90% specificity (14 ng/L for males, 11 ng/L for females) performed best and resulted in 91% diagnostic accuracy in both males and females. The sex-specific delta thresholds yielding high specificity estimates were confirmed in the validation data set. CONCLUSIONS: Sex-specific absolute delta thresholds can be used to rule in AMI and are robust across different study populations.

Cardiac Troponin Testing in Patients with COVID-19: A Strategy for Testing and Reporting Results.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged late in 2019 causing COVID-19 (coronavirus disease-2019) may adversely affect the cardiovascular system. Publications from Asia, Europe, and North America have identified cardiac troponin as an important prognostic indicator for patients hospitalized with COVID-19. We recognized from publications within the first 6 months of the pandemic that there has been much uncertainty on the reporting, interpretation, and pathophysiology of an increased cardiac troponin concentration in this setting. CONTENT: The purpose of this mini-review is: a) to review the pathophysiology of SARS-CoV-2 and the cardiovascular system, b) to overview the strengths and weaknesses of selected studies evaluating cardiac troponin in patients with COVID-19, and c) to recommend testing strategies in the acute period, in the convalescence period and in long-term care for patients who have become ill with COVID-19. SUMMARY: This review provides important educational information and identifies gaps in understanding the role of cardiac troponin and COVID-19. Future, properly designed studies will hopefully provide the much-needed evidence on the path forward in testing cardiac troponin in patients with COVID-19.

Variability in Cardiac Biomarkers during Hemodialysis: A Prospective Cohort Study.

BACKGROUND: The effect of hemodialysis on cardiac biomarkers is unclear. We sought to evaluate the degree and causes of intradialytic variability of high sensitivity troponin I (hs-TnI), galectin-3 (gal-3), and heart-type fatty acid binding protein (hFABP). METHODS: hs-TnI, gal-3, and hFABP were prospectively measured pre-dialysis and post-dialysis for 1 week every month for 6 months in 178 prevalent adult hemodialysis patients at a single center in Hamilton, Canada. The degree of change from pre-dialysis to post-dialysis for each cardiac biomarker was estimated with multilevel linear regression models. RESULTS: The median change in the concentration of hs-TnI during hemodialysis was -1 ng/L (interquartile range [IQR] -1 to 2 ng/L) while gal-3 and hFABP changed by -36.3 ng/mL (IQR -27.7 to -46.8 ng/mL) and -19.41 ng/mL (IQR -13.61 to -26.87 ng/mL), respectively. The median (IQR) percentage intradialytic changes for hs-TnI, gal-3, and hFABP were 2.6% (-4.4% to 12.5%), -59.8% (-54.7% to -64.8%) and -35.3% (-28.4% to -42.1%), respectively. Ultrafiltration was associated with an increase in concentration of hs-TnI, gal-3, and hFABP (mean 0.99 ng/L, 1.05 ng/mL, and 1.9 ng/mL per L ultrafiltration, respectively, P < 0.001). Both gal-3 and hFABP concentrations decreased in association with the volume of blood processed (P < 0.001) and with hemodialysis treatment time (P = 0.02 and P = 0.04) while hs-TnI concentration decreased only in association with hemodialysis treatment time (P < 0.001). CONCLUSIONS: Ultrafiltration volume and hemodialysis treatment time influenced hs-TnI, gal-3, and hFABP concentrations during hemodialysis and should be considered when interpreting their measurement.

Independent and combined effects of biotin and hemolysis on high-sensitivity cardiac troponin assays.

OBJECTIVES: This study compared the independent and combined effects of hemolysis and biotin on cardiac troponin measurements across nine high-sensitivity cardiac troponin (hs-cTn) assays. METHODS: Parallel cTn measurements were made in pooled lithium heparin plasma spiked with hemolysate and/or biotin using nine hs-cTn assays: Abbott Alinity, Abbott ARCHITECT i2000, Beckman Access 2, Ortho VITROS XT 7600, Siemens Atellica, Siemens Centaur, Siemens Dimension EXL cTnI, and two Roche Cobas e 411 Elecsys Troponin T-hs cTnT assays (outside US versions, with and without increased biotin tolerance). Absolute and percent cTn recovery relative to two baseline concentrations were determined in spiked samples and compared to manufacturer's claims. RESULTS: All assays except the Ortho VITROS XT 7600 showed hemolysis and biotin interference thresholds equivalent to or greater than manufacturer's claims. While imprecision confounded analysis of Ortho VITROS XT 7600 data, evidence of biotin interference was lacking. Increasing biotin concentration led to decreasing cTn recovery in three assays, specifically both Roche Cobas e 411 Elecsys Troponin T-hs assays and the Siemens Dimension EXL. While one of the Roche assays was the most susceptible to biotin among the nine studied, a new version showed reduced biotin interference by approximately 100-fold compared to its predecessor. Increasing hemolysis also generally led to decreasing cTn recovery for susceptible assays, specifically the Beckman Access 2, Ortho VITROS XT 7600, and both Roche Cobas e 411 Elecsys assays. Equivalent biotin and hemolysis interference thresholds were observed at the two cTn concentrations considered for all but two assays (Beckman Access 2 and Ortho VITROS XT 7600). When biotin and hemolysis were present in combination, biotin interference thresholds decreased with increasing hemolysis for two susceptible assays (Roche Cobas e 411 Elecsys and Siemens Dimension EXL). CONCLUSIONS: Both Roche Cobas e 411 Elecsys as well as Ortho VITROS XT assays were susceptible to interference from in vitro hemolysis at levels routinely encountered in clinical laboratory samples (0-3 g/L free hemoglobin), leading to falsely low cTn recovery up to 3 ng/L or 13%. While most assays are not susceptible to biotin at levels expected with over-the-counter supplementation, severely reduced cTn recovery is possible at biotin levels of 10-2000 ng/mL (41-8,180 nmol/L) for some assays. Due to potential additive effects, analytical interferences should not be considered in isolation.

Analytical assessment of ortho clinical diagnostics high-sensitivity cardiac troponin I assay.

OBJECTIVES: To analytically evaluate Ortho Clinical Diagnostics VITROS high-sensitivity cardiac troponin I (hs-cTnI) assay in specific matrices with comparison to other hs-cTn assays. METHODS: The limit of detection (LoD), imprecision, interference and stability testing for both serum and lithium heparin (Li-Hep) plasma for the VITROS hs-cTnI assay was determined. We performed Passing-Bablok regression analyses between sample types for the VITROS hs-cTnI assay and compared them to the Abbott ARCHITECT, Beckman Access and the Siemens ADVIA Centaur hs-cTnI assays. We also performed Receiver-operating characteristic curve analyses with the area under the curve (AUC) determined in an emergency department (ED)-study population (n=131) for myocardial infarction (MI). RESULTS: The VITROS hs-cTnI LoD was 0.73 ng/L (serum) and 1.4 ng/L (Li-Hep). Stability up to five freeze-thaws was observed for the Ortho hs-cTnI assay, with the analyte stability at room temperature in serum superior to Li-Hep with gross hemolysis also affecting Li-Hep plasma hs-cTnI results. Comparison of Li-Hep to serum concentrations (n=202), yielded proportionally lower concentrations in plasma with the VITROS hs-cTnI assay (slope=0.85; 95% confidence interval [CI]:0.83-0.88). In serum, the VITROS hs-cTnI concentrations were proportionally lower compared to other hs-cTnI assays, with similar slopes observed between assays in samples frozen <-70 °C for 17 years (ED-study) or in 2020. In the ED-study, the VITROS hs-cTnI assay had an AUC of 0.974 (95%CI:0.929-0.994) for MI, similar to the AUCs of other hs-cTn assays. CONCLUSIONS: Lack of standardization of hs-cTnI assays across manufacturers is evident. The VITROS hs-cTnI assay yields lower concentrations compared to other hs-cTnI assays. Important differences exist between Li-Hep plasma and serum, with evidence of stability and excellent clinical performance comparable to other hs-cTn assays.

Preoperative prediction of Bleeding Independently associated with Mortality after noncardiac Surgery (BIMS): an international prospective cohort study.

BACKGROUND: Diagnostic criteria for Bleeding Independently associated with Mortality after noncardiac Surgery (BIMS) have been defined as bleeding that leads to a postoperative haemoglobin <70 g L-1, leads to blood transfusion, or is judged to be the direct cause of death. Preoperative prediction guides for BIMS can facilitate informed consent and planning of perioperative care. METHODS: In a prospective cohort study of 16 079 participants aged ≥45 yr having inpatient noncardiac surgery at 12 academic hospitals in eight countries between 2007 and 2011, 17.3% (2782) experienced BIMS. An electronic risk calculator for BIMS was developed and internally validated by logistic regression with bootstrapping, and further simplified to a risk index. Decision curve analysis assessed the potential utility of each prediction guide compared with a strategy of identifying risk of BIMS based on preoperative haemoglobin <120 g L-1. RESULTS: With information about the type of surgery, preoperative haemoglobin, age, sex, functional status, kidney function, history of high-risk coronary artery disease, and active cancer, the risk calculator accurately predicted BIMS (bias-corrected C-statistic, 0.84; 95% confidence interval, 0.837-0.852). A simplified index based on preoperative haemoglobin <120 g L-1, open surgery, and high-risk surgery also predicted BIMS, but less accurately (C-statistic, 0.787; 95% confidence interval, 0.779-0.796). Both prediction guides could improve decision making compared with knowledge of haemoglobin <120 g L-1 alone. CONCLUSIONS: BIMS, defined as bleeding that leads to a postoperative haemoglobin <70 g L-1, leads to blood transfusion, or that is judged to be the direct cause of death, can be predicted by a simple risk index before surgery. CLINICAL TRIAL REGISTRATION: NCT00512109.