Andrew R. MacRae

Analytic and Clinical Utility of a Next-Generation, Highly Sensitive Cardiac Troponin I Assay for Early Detection of Myocardial Injury

BACKGROUND Improvements in cardiac troponin (cTn) assays have increased the rapidity with which clinicians can identify patients with changing cTn concentrations (rise or fall) indicative of acute myocardial injury. The aim of the present study was to characterize a new, high-sensitivity cTnI (hs-cTnI) assay and examine whether increased sensitivity can result in still earlier detection of evolving injury. METHODS We determined the limit of detection, precision profiles, and preliminary estimates of the 99th percentile for the Beckman Coulter hs-cTnI assay in 125 healthy individuals (age <55 years, 54% male). We compared AccuTnI and hs-cTnI to assess whether change criteria for early concentration changes (i.e., > or =3SD for low concentrations and 20% difference for concentrations >0.10 microg/L) were exceeded in the first 2 specimens (median time between specimens, 1 h; 25th-75th percentile, 1-3 h) from subjects with symptoms suggestive of cardiac ischemia (n = 290). RESULTS The limit of detection for the hs-cTnI assay was 2.06 ng/L, and the 20% CV and 10% CV concentrations were 2.95 and 8.66 ng/L, respectively. The preliminary 99th percentile estimates in lithium heparin, serum, and EDTA plasma were 9.20, 8.00, and 8.60 ng/L, respectively. In 108 patients with myocardial injury based on the peak AccuTnI concentration, applying the change criteria on the 2 earliest specimens identified 81% (95% CI 73%-88%) of patients using the hs-cTnI assay compared to 62% (53%-71%) using the AccuTnI assay (P < 0.001). CONCLUSIONS Although more extensive validation studies are required, this Beckman Coulter hs-cTnI assay appears to detect patients with evolving myocardial injury earlier.

Short- and Long-Term Risk Stratification Using a Next-Generation, High-Sensitivity Research Cardiac Troponin I (hs-cTnI) Assay in an Emergency Department Chest Pain Population

BACKGROUND The next-generation, high-sensitivity cardiac troponin assays can measure quantifiable concentrations of cTn in a majority of individuals, but there are few studies assessing these assays for risk stratification. The present study was undertaken to determine if a research hs-cTnI assay can be useful for predicting death/myocardial infarction (MI), both short- and long-term, in an emergency department acute coronary syndrome (ACS) population. METHODS In a cohort of 383 subjects, originally recruited in 1996, presenting to the emergency department with symptoms suggestive of ACS, the heparin plasma obtained at initial presentation was thawed and measured in 2007 with a research hs-cTnI assay. AccuTnI (Beckman Coulter) measurements were made on these same samples in 2003. The population was divided into 4 groups by hs-cTnI: <5.00, 5.00-9.99, 10.00-40.00, and >40.00 ng/L. Kaplan-Meier, Cox proportional hazards, ROC curves, and logistic regression analyses were used to identify which hs-cTnI concentrations were predictive of death/MI within 10 years after presentation. RESULTS There were significant differences between the hs-cTnI groups for the probability of death/MI up to 10 years after presentation (P < 0.05). At 6 months, patients with hs-cTnI > or =10.00 ng/L were at higher risk for death/MI (hazard ratio >3.7; P < 0.05) compared with those having hs-cTnI <5.00 ng/L. ROC curve analysis for death/MI at 30 days with the hs-cTnI assay had an area under the curve of 0.74 (95% CI 0.65-0.82), with logistic models yielding an optimal assay threshold of 12.68 ng/L. CONCLUSIONS This research hs-cTnI assay appears useful for risk stratification for death/MI in an ACS population.

Increasing Cardiac Troponin Changes Measured by a Research High-Sensitivity Troponin I Assay: Absolute vs Percentage Changes and Long-Term Outcomes in a Chest Pain Cohort

To the Editor: With novel high-sensitivity cardiac troponin assays, there is great interest in determining the change needed between successive cardiac troponin measurements to inform the diagnosis of acute myocardial infarction (MI)1 (1). Recent publications have reported both short- and long-term reference change values (RCVs) in healthy populations for both high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT); thus, the RCV perhaps could be the metric used for determining the optimal clinical change value (2, 3). The RCVs for the hs-cTnT and hs-cTnI assays, however, are markedly different, possibly because of assay characteristics, differences in the biology of the 2 isoforms, or the healthy populations studied (1). The optimal clinical change for detecting patients with acute MI might be greater than the published RCVs. Two recent studies that used ROC curve analyses suggest exactly that. Giannitsis et al. (4) determined the optimal δ to be ≥243% for hs-cTnT, whereas we identified an optimal δ of >235% on the basis of MI or death at 30 days for a research hs-cTnI assay (5). Percentages may work well when values are low but may become impractical when more substantial increases occur. The 2 studies neither reported δ in terms of absolute concentration nor defined its role in long-term risk stratification. …

2007 Universal Myocardial Infarction Definition Change Criteria for Risk Stratification by Use of a High-Sensitivity Cardiac Troponin I Assay

Analytical sensitivity is an important determinant of the diagnostic power of cardiac troponin (cTn)1 for diagnosing myocardial infarction (1)(2). Increased cTn only partially fulfills the criteria to document acute injury, however, because a change (increase/decrease) in biomarker concentration is required (1). A recent study of a contemporary sensitive, guideline-acceptable cTnI assay suggested that change criteria improved risk stratification because it improved the specificity of cTnI in the study for acute coronary syndrome (ACS) (2). Data about the use of change criteria are only beginning to emerge (2). Furthermore, as assay performance improves and more diagnostic companies proceed to develop the second- and third-generation high-sensitivity (hs) assays (3), each must be validated with these criteria. Moreover, there remains no consensus on the criteria to define a changing pattern for cTn assays in clinical use, or for the new hs-cTn assays. One approach has been to use criteria for change obtained from the 2007 universal myocardial infarction (MI) definition (1). This was recently used in a comparison of a sensitive cTnI assay [AccuTnI; refer to Apple (3) for assay designation] against a research third-generation hs assay (hs-cTnI) for early detection of myocardial injury (4). In the present study, we assessed if the criteria for change used in the previous study (4) also add to risk stratification with this hs-cTnI assay. In a cohort of unique subjects (n = 257) presenting with chest pain to an emergency department at a community hospital in 1996, we obtained time of symptom onset, with …

PAPP-A as a marker of increased long-term risk in patients with chest pain

OBJECTIVES Long-term risk stratification in patients presenting with acute coronary syndromes (ACS) is possible by measuring cardiac troponin (cTn). The present study examined whether PAPP-A measured in an emergency department (ED) chest pain population in association with conventional and novel high sensitivity cTn (hs-cTnI) assays can predict long-term mortality. METHODS In 320 patients with cTn measurements the earliest heparinized plasma PAPP-A concentration after presentation was used for risk stratification for death by Kaplan-Meier and Cox analyses. Subgroup analyses using the earliest PAPP-A concentrations were also performed in a cohort of subjects with presentation cTnI < or = 99th percentile but with significantly changing cardiac troponin concentrations as measured by the AccuTnI assay and the hs-cTnI assay (n=45 and 120 subjects, respectively). RESULTS Subjects with PAPP-A concentrations in the highest tertile were at higher risk for death (HR > 2.00; p < or = 0.05 at 2 years) even after adjusting for cTnI at presentation. In the cohort with cTnI < or = 99th percentile but with changing hs-cTnI concentrations, subjects in the top PAPP-A tertile had a higher probability for death (p=0.02). CONCLUSION Early measurement of PAPP-A may identify chest pain patients at higher risk for long-term death. Additional prospective ACS studies are required to fully elucidate PAPP-As role.

Outcome validation of the Beckman Coulter access analyzer in a second-trimester Down syndrome serum screening application.

BACKGROUND Mid-trimester maternal serum alpha-fetoprotein (AFP) and unconjugated estriol (uE3) are 30% lower and human chorionic gonadotropin (hCG) is twofold higher in Down syndrome pregnancies compared with unaffected pregnancies. In maternal serum screening, patient-specific risks are calculated using published gaussian frequency distribution parameters for these three markers obtained with previously available immunoassays. New immunoassays must generate similar distribution parameters if the accuracy of assigned risks and overall performance of prenatal screening are to be maintained. METHODS Agreement between the Beckman Coulter Access and the Bayer Immuno 1 assays for AFP and hCG and the Amersham Amerlex-M RIA for uE3 was assessed in 558 fresh sera. Precision was measured over 6 weeks. Median concentrations were calculated by regression of 568 Caucasian singleton pregnancy samples against gestational age in days. Frozen mid-trimester sera from 44 confirmed Down syndrome singleton pregnancies (cases) were selected without conscious bias for reanalysis, and each case was matched with five control specimens from unaffected pregnancies. Serum markers were expressed as the multiple of the median (MoM) concentration derived from the control samples, corrected for maternal weight and converted to their log-equivalent values. Normality was assessed using probability plots and the Shapiro-Wilk W-test. Gaussian distribution parameters were compared with established values, and Down syndrome risk calculations were assessed with a commonly used risk algorithm. RESULTS The Access AFP and hCG assays had consistent proportional agreement with the established assays, whereas agreement between the uE3 methods was less consistent. Analytical imprecision was 3-6% at mid-trimester concentrations. Normal distributions were obtained for the log MoM values of all three markers in both the Down syndrome and unaffected populations, and their gaussian distribution parameters compared well with established values. The performance of the Access assays in an established trivariate risk algorithm for Down syndrome was equal to the performance exhibited by traditional methods. CONCLUSION The Beckman Coulter Access analyzer provides valid mid-trimester serum AFP, uE3, and hCG results and risk assessments when applied in a prenatal Down syndrome screening service.

Biparietal diameter and crown‐rump length in fetuses with Down's syndrome: implications for antenatal serum screening for Down's syndrome

Objectives 1. To compare the ultrasound biparietal diameter and crown‐rump length of fetuses with and without Downs syndrome in the first half of pregnancy; 2. To investigate the effect of estimation of gestational age using either measure on the detection rate of serum screening for Downs syndrome.

Is a Pattern of Increasing Biomarker Concentrations Important for Long-Term Risk Stratification in Acute Coronary Syndrome Patients Presenting Early after the Onset of Symptoms?

BACKGROUND Guidelines for treatment of acute coronary syndrome (ACS) recommend observing a rise or fall in cardiac troponin (cTn) concentrations for assessing acute injury. It is unknown whether a rising pattern presages a more adverse long-term prognosis than elevations that do not change. The present study assessed whether a rising pattern of cardiac biomarkers was more prognostic than simple elevations. METHODS We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) (Roche), cTnT (Roche) and cTnI (Beckman Coulter) in 212 ACS patients. These biomarkers were measured in coincident EDTA and heparin plasma samples available from at least 2 different time points, an early first specimen obtained a median of 2 hours after onset of symptoms, interquartile range (IQR) 2-4 hours, and a later second specimen obtained at 9 hours, IQR 9-9 hours. The cTn concentration in the second specimen was used to classify myocardial necrosis (cTnI >0.04 ug/L; cTnT >0.01 ug/L). Outcomes [death, myocardial infarction (MI), heart failure (HF)] were obtained >8 years after the initial presentation. For patients with myocardial necrosis and a cTn concentration ratio (second/first measured concentrations) > or =1.00, the concentration ratios and the absolute concentrations in the second specimen were used to assess prognosis after 4 years. RESULTS In myocardial necrosis, the relative change (cTn2/cTn1) was greater for cTnI than for cTnT (P <0.01), whereas the relative change in NT-proBNP was the same regardless of which troponin was used to classify necrosis (P = 0.71). The concentration ratio for cTnI, cTnT, and NT-proBNP was not useful for risk stratification (i.e., death/MI/HF; P > or =0.15). CONCLUSIONS A rise in cardiac troponin or NT-proBNP concentration in ACS patients presenting early after onset of pain is not helpful for long-term prognosis.

Second and first trimester estimation of risk for Down syndrome: implementation and performance in the SAFER study.

Document patient choices and screening performance (false positive and detection rates) when three improved Down syndrome screening protocols were introduced coincidentally.

Vascular versus myocardial dysfunction in acute coronary syndrome: Are the adhesion molecules as powerful as NT-proBNP for long-term risk stratification?

OBJECTIVES To determine if elevations of adhesion molecules in acute coronary syndrome (ACS) are useful for risk stratification. DESIGN AND METHODS A cell adhesion array (Randox Ltd.) and NT-proBNP were measured in 216 ACS patients. RESULTS Kaplan-Meier and Cox models indicate early elevations of NT-proBNP but not the adhesion molecules are predictive of future death/myocardial infarction. DISCUSSION Elevations of adhesion molecules early after pain onset in ACS are not useful for long-term risk stratification.