Imprecision of high-sensitivity cardiac troponin assays at the female 99th-percentile.

BACKGROUND: An analytical benchmark for high-sensitivity cardiac troponin (hs-cTn) assays is to achieve a coefficient of variation (CV) of ≤ 10.0 % at the 99th percentile upper reference limit (URL) used for the diagnosis of myocardial infarction. Few prospective multicenter studies have evaluated assay imprecision and none have determined precision at the female URL which is lower than the male URL for all cardiac troponin assays. METHODS: Human serum and plasma matrix samples were constructed to yield hs-cTn concentrations near the female URLs for the Abbott, Beckman, Roche, and Siemens hs-cTn assays. These materials were sent (on dry ice) to 35 Canadian hospital laboratories (n = 64 instruments evaluated) participating in a larger clinical trial, with instructions for storage, handling, and monthly testing over one year. The mean concentration, standard deviation, and CV for each instrument type and an overall pooled CV for each manufacturer were calculated. RESULTS: The CVs for all individual instruments and overall were ≤ 10.0 % for two manufacturers (Abbott CVpooled = 6.3 % and Beckman CVpooled = 7.0 %). One of four Siemens Atellica instruments yielded a CV > 10.0 % (CVpooled = 7.7 %), whereas 15 of 41 Roche instruments yielded CVs > 10.0 % at the female URL of 9 ng/L used worldwide (6 cobas e411, 1 cobas e601, 4 cobas e602, and 4 cobas e801) (CVpooled = 11.7 %). Four Roche instruments also yielded CVs > 10.0 % near the female URL of 14 ng/L used in the United States (CVpooled = 8.5 %). CONCLUSIONS: The number of instruments achieving a CV ≤ 10.0 % at the female 99th-percentile URL varies by manufacturer and by instrument. Monitoring assay precision at the female URL is necessary for some assays to ensure optimal use of this threshold in clinical practice.

The Clinical Validation of a Common Analytical Change Criteria for Cardiac Troponin for Ruling in an Acute Cardiovascular Outcome in Patients Presenting with Ischemic Chest Pain Symptoms.

Serial cardiac troponin (cTn) testing on patients with symptoms suggestive of acute coronary syndrome (ACS) is primarily to identify those patients with evolving myocardial injury. With the improved analytical performance of the high-sensitivity cTn (hs-cTn) assays, different change criteria have been proposed that are mostly assay dependent. Here, we developed and compared a new Common Change Criteria (3C for the combined criteria of >3 ng/L, >30%, or >15% based on the initial cTn concentration of <10 ng/L, 10 to 100 ng/L, or >100 ng/L, respectively) method, versus the 2 h assay-dependent absolute change criteria endorsed by the European Society of Cardiology (ESC), versus the common relative >20% change criterion. These different analytical change criteria were evaluated in 855 emergency department (ED) patients with symptoms of ACS and who had two samples collected 3 h apart. The cTn concentrations were measured with four different assays (Abbott hs-cTnI, Roche hs-cTnT, Ortho cTnI-ES, and Ortho hs-cTnI). The outcomes evaluated were myocardial infarction (MI) and a composite outcome (MI, unstable angina, ventricular arrhythmia, heart failure, or cardiovascular death) within 7 days of ED presentation. The combined change criteria (3C) method yielded higher specificities (range: 93.9 to 97.2%) as compared to the >20% criterion (range: 42.3 to 88.1%) for all four assays for MI. The 3C method only yielded a higher specificity estimate for MI for the cTnI-ES assay (95.9%) versus the absolute change criteria (71.7%). Similar estimates were obtained for the composite outcome. There was also substantial agreement between hs-cTnT and the different cTnI assays for MI with the 3C method, with the percent agreement being ≥95%. The Common Change Criteria (3C) method combining both absolute and different percent changes may be used with cTnI, hs-cTnT, and different hs-cTnI assays to yield similar high-specificity (rule-in) estimates for adverse cardiovascular events for patients presenting to the ED with ACS symptoms.

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.

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.

High-Sensitivity Cardiac Troponin I Thresholds to Identify Myocardial Injury After Noncardiac Surgery: A Cohort Study.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is common and associated with short- and long-term major cardiovascular events. Diagnostic criteria for MINS using Abbott high-sensitivity cardiac troponin I (hs-cTnI) are unknown. METHODS: We performed a prospective cohort study of adults who had in-patient noncardiac surgery and measured hs-cTnI (Abbott Laboratories) on postoperative serum samples collected up to postoperative day 3. The objective was to determine prognostically important hs-cTnI thresholds associated with major cardiac events and death at 30 days after noncardiac surgery. Using Cox proportional iterative analyses, we determined peak postoperative hs-cTnI thresholds associated with the occurrence of the 30-day composite of major cardiac events (ie, nonfatal myocardial infarction after 3 postoperative days, cardiac arrest, and congestive heart failure) and death. RESULTS: Of 3953 included patients, 66 (1.7%) experienced the primary outcome at 30 days. Peak hs-cTnI values and associated incidence of major cardiac events and death were as follows: < 60 ng/L: 1.0% (95% CI 0.7-1.3); 60 to < 700 ng/L: 8.6% (5.6-13.0); and ≥ 700 ng/L: 27.3% (16.4-41.9). Compared with peak hs-cTnI < 60 ng/L, adjusted hazard ratios were 7.54 (95% CI% 4.27-13.32) for hs-cTnI values of 60 to < 700 ng/L and 26.87 (13.27-54.41) for values ≥ 700 ng/L. CONCLUSIONS: Hs-cTnI elevation within the first 3 days after noncardiac surgery independently predicts major cardiac events and death at 30 days. A postoperative hs-cTnI ≥ 60 ng/L was associated with a > 7-fold increase in the risk of subsequent major cardiac events and mortality at 30 days.

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.

Storage conditions, sample integrity, interferences, and a decision tool for investigating unusual high-sensitivity cardiac troponin results.

The current definition of high-sensitivity cardiac troponin (hs-cTn) assays is laboratory-based and their analytical attributes and characteristics have drawn significant attention in the literature at least partly due to the lower concentration cut-offs and changes in concentrations (i.e., deltas) employed in different algorithms and pathways to manage patient care. We propose that pre-analytical conditions such as sample type, storage conditions, and other interferences may also have a significant impact on hs-cTn concentrations and clinical management. The purpose of this literature review is to provide a summary of important pre-analytical and interference studies affecting hs-cTn concentrations. A breakdown of the literature for the major diagnostic companies providing core laboratory instrumentation (i.e., Abbott, Beckman, Ortho, Roche, and Siemens) is also provided. Finally, three cases are highlighted where knowledge of pre-analytical factors aids the hs-cTn clinically discordant investigations. This review highlights the importance of pre-analytical variables, especially storage condition, sample handling, and blood tubes used (i.e., sample type) when interpreting hs-cTn assays. Additional studies are needed to further elaborate on pre-analytical variables (i.e., centrifugation, sample type, stability) and interferences for all hs-cTn assays in clinical use, as knowledge of these variables may aid in hs-cTn clinically discordant investigations.