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

OBJECTIVES: Document patient choices and screening performance (false positive and detection rates) when three improved Down syndrome screening protocols were introduced coincidentally. METHOD: Second-trimester 'triple marker' screening was expanded by adding second-trimester dimeric inhibin-A (four-marker), with or without first-trimester pregnancy-associated plasma protein-A (five-marker). Nuchal translucency (NT) measurements were included when available from accredited sonographers (six-marker). For assigning risk, two sets of marker distribution parameters were evaluated. RESULTS: Over 3.5 years, 8571 women enrolled (median age 30.6 years). Uptake of the four-, five- and six-marker protocols was 18%, 46% and 36%, respectively. Of those selecting an integrated test (five or six markers), 9.7% did not provide the second trimester serum sample. False positive rates decreased with added markers (5.2%, 5.1% and 2.5%, respectively) and varied between the two parameter sets, while detection remained high. Overall, 21 of 23 cases were detected (91%, 95% CI 73-98%) at a 4.2% false positive rate (95% CI 3.3-5.1%). CONCLUSIONS: Integrated screening protocols were chosen 4.6 times more often than four-marker screening (82% vs. 18% uptake). Overall detection was higher and false positives lower, consistent with recent guidelines. Important performance factors include gestational dating method, risk cut-off, and the parameter set used to assign risk.

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.

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.

"Upstream markers" provide for early identification of patients at high risk for myocardial necrosis and adverse outcomes.

BACKGROUND: For patients presenting with acute coronary syndrome (ACS) to the emergency department, early identification of those that are at high risk for subsequent myocardial necrosis or adverse outcomes would allow earlier or more aggressive treatment. We determined if a panel of biomarkers can be used to identify high risk patients. METHODS: A cohort (84 females/132 males) from our 1996 ACS study population that had EDTA specimens stored (-70 degrees C) was selected and the earliest available specimen was analyzed for 11 biomarkers (IL-6, IL-8, MCP-1, VEGF, L-selectin, P-selectin, E-selectin, ICAM-1, VCAM-1, NT-proBNP, cTnT). These data were linked to the existing cTnI and health outcome databases for this population. ROC curve analysis for myocardial necrosis (i.e., peak cTnI >0.04 microg/l) identified 3 candidate biomarkers. These 3 biomarkers were applied together to generate a panel test (2 of the 3 biomarkers increased for a positive result) and assessed for its ability to identify patients at risk for myocardial necrosis and the combined endpoint of death, myocardial infarction (MI) and heart failure (HF). RESULTS: The panel test (IL-6, NT-proBNP, E-selectin) alone detected 60% (95% CI: 49-69; false positive rate: 26%) of subjects that would be classified with myocardial necrosis. Kaplan-Meier and Cox proportional analyses indicated that patients positive by the biomarker panel (including those with cTnI < or =0.04 microg/l) had significantly worse outcomes (death/MI/HF) as compared to those negative by both cTnI and the panel test. CONCLUSION: A biomarker panel analyzed early after pain onset can identify individuals at risk for both myocardial necrosis and the combined endpoint of death/MI/HF. Additional prospective studies are required to assess this panel for both early MI detection and to further refine which health outcomes (death, MI, HF) are associated with positive panel results.

Elevated C-reactive protein in acute coronary syndrome presentation is an independent predictor of long-term mortality and heart failure.

OBJECTIVES: To assess the ability of C-reactive protein (CRP) to predict long-term outcomes in a chest pain population. DESIGN AND METHODS: CRP was measured at presentation in 446 emergency department patients with acute coronary syndromes. All-cause mortality and hospital discharges for acute myocardial infarction (AMI) and congestive heart failure (CHF) were obtained for up to 8 years following the event. RESULTS: Kaplan-Meier analyses indicated that patients with CRP concentrations above the American Heart Association scientific statement cut-off had a higher rate for death and CHF admissions. After adjusting for troponin concentrations, in a Cox proportional hazard model, only CRP concentrations indicative of an acute phase response (i.e., >7.44 mg/L) were associated with a significant risk for death after 5 years and CHF readmission after 2 years. CONCLUSIONS: Patients presenting early with chest pain with elevated CRP concentrations have a greater long-term risk for death and heart failure.

Effects of contemporary troponin assay sensitivity on the utility of the early markers myoglobin and CKMB isoforms in evaluating patients with possible acute myocardial infarction.

BACKGROUND: The 2003 American Heart Association (AHA) definition for myocardial infarction (MI) requires an "adequate set" (i.e. at least 6 h between measurements) of biomarkers and specifically troponin for the diagnosis of MI. The aim of the present study was to assess the performance of myoglobin, the CKMB isoforms, and cardiac troponin I (cTnI) in specimens earlier than the requisite 6 h after presentation, in a population originally characterized using World Health Organization (WHO) criteria. METHODS: In 1996, 228 acute coronary syndrome patients with an "adequate sample set" had their specimens assayed for CKMB isoforms and myoglobin. In 2003, the same specimens were analyzed with the AccuTnI troponin I assay and myoglobin (Beckman Coulter Access immunoassay). RESULTS: The clinical sensitivities for both myoglobin and the CKMB isoforms were >90% when the population was classified by WHO criteria. However the sensitivities were <70% when the ESC/ACC MI definition was used. Analyzing cTnI at earlier time points as long as there was at least 3 h between specimens or at least 1 specimen 6 h from pain onset did not misclassify subjects based on adverse outcomes in the year following their presentation. CONCLUSION: Contemporary assays for cTnI with increased analytical sensitivity reduce the utility of myoglobin and CKMB isoforms to rule-out an AMI.

The relationship between managed competition in home care nursing services and nurse outcomes.

The objective of this study was to investigate the relationship between the characteristics of home-care contracts, as indicators of employment relationships, and nurses'job satisfaction and perceived job security. A cross-sectional design was used to collect data on the study variables.The setting was 11 Community Care Access Centres and 11 nursing provider agencies in the Canadian province of Ontario. The sample included 700 nurses. A mailed survey was used to collect data from CCACs on length of contract awarded to provider agencies, potential for renewal, volume of service awarded, and profit status of the agency. Data were collected, via a mailed survey, on nurses' age, gender, work status, and years of employment in the community and at the current agency. The Nursing Job Satisfaction Scale was used to collect data on nurses'job satisfaction. Perceived job security was assessed using a single item measured on a 5-point Likert scale. Significant differences were found among provider agencies in nurses' perception of the quality of care, work enjoyment, satisfaction with time for care, and job security. Older nurses rated work enjoyment higher than younger nurses. Nurses paid on an hourly basis were more satisfied with their time for care than those paid on a per-visit basis. Nurses employed on a casual basis were less satisfied with job security than those employed on a full-time basis. Differences in nurse outcomes were observed among nursing provider agencies, but these were not related to the profit status of the agency. Further research is needed on the best practices within agencies that result in more satisfied staff.

Analytical comparison of three different versions of a high-sensitivity cardiac troponin I assay over 10years.

BACKGROUND: Concerns have been raised on the long-term analytical performance of high-sensitivity cardiac troponin (hs-cTn) assays with respect to different reagent formulations, lots and instrumentation. Our goal for the present study was to compare three different versions of an hs-cTnI assay in two different study populations to evaluate if assay re-formulation over 10years has also affected the analytical results. METHODS: Beckman Coulter's CE marked hs-cTnI assay (Access hsTnI, 2017) was tested in 100 lithium heparin plasma samples first tested in 2007 with their prototype hs-cTnI assay and in 100 serum samples tested with their enhanced hs-cTnI assay in 2011 with comparison performed by Passing-Bablok regression. The Beckman Coulter hs-cTnI results from 2017 and 2011 from the serum samples were also compared to the Abbott ARCHITECT i1000 hs-cTnI results (2013) with 3-fold differences used to identify possible outliers. Freeze/thaw stability testing (-20°C) was also performed on normal cTnI (Beckman=4.0ng/L; Abbott=5.3ng/L) and high cTnI concentration (Beckman=77.6ng/L; Abbott=126.1ng/L) lithium heparin plasma pools for both hs-cTnI assays. RESULTS: After 3 freeze-thaws the Beckman hs-cTnI assay yielded minor decreases in concentrations (normal pool -0.7ng/L and high pool -12.6ng/L lower). Regression analyses yielded the following relationship between the Beckman hs-cTnI versions: 2017 hs-cTnI=2.0*(2007 prototype hs-cTnI)-5.1ng/L and 2017 hs-cTnI=1.04∗(2011 enhanced hs-cTnI)-2.5ng/L. Compared to the Abbott 2013 hs-cTnI results, the 2011 Beckman enhanced version had 8 results 3-fold higher, with the 2017 Beckman version yielding 6 results 3-fold lower. CONCLUSIONS: The 2017 Beckman hs-cTnI version (Access hsTnI) is closely aligned with the previous enhanced hs-cTnI assay and appears to have reduced the frequency of aberrantly high results.

The impact of the ESC/ACC redefinition of myocardial infarction and new sensitive troponin assays on the frequency of acute myocardial infarction.

BACKGROUND: The prevalence of acute myocardial infarction (AMI) has increased due to the recent definitions, but the magnitude of this effect using contemporary highly sensitive troponin assays is unclear. The objective of this study is to compare the diagnosis of AMI using a contemporary troponin I (cTnI) biomarker and the 2003 American Heart Association (AHA) case definition with diagnoses made using the 1994 World Health Organization MONICA definition. METHODS: Contemporary troponin I measurements were performed with the Beckman Coulter AccuTnI assay (Chaska, MN) on plasma specimens originally assayed in 1996 for creatine kinase (CK)-MB mass from 486 emergency department patients presenting within 24 hours of onset of symptoms suggestive of cardiac ischemia. RESULTS: In a subgroup of 258 patients with 2 specimens drawn at least 6 hours apart (the AHA "adequate set of biomarkers"), AMI prevalence using CK-MB was 19.4% (95% CI 15.0-24.7) based on MONICA and 19.8% (15.4-25.1) based on the AHA case definition using the criterion for change of > or = 20% between specimens. Using cTnI as the biomarker of choice, under the AHA definition, the prevalence increased to as high as 35.7% (30.1-41.7, a relative increase of 84%, P < .001) using the 99th percentile cutoff. In 121 patients with a lower index of suspicion and without the requisite 6-hour interval between measurements, positivity increased from 5% with CK-MB by MONICA up to 12% to 16% with cTnI by AHA. CONCLUSIONS: A highly sensitive contemporary cTnI assay used with the AHA case definition results in a 62% to 84% increase in the frequency of AMI diagnosis compared with MONICA criteria.

Second trimester serum markers.

Prenatal screening for Down syndrome in the early second trimester with multiple maternal serum markers has been available for more than 15 years. The multiple marker combination with the highest screening performance currently available is alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A, together with maternal age (so-called quad marker test). With this combination, a detection rate of 80% at a 5% false positive rate is achieved. Inhibin A, the newest addition to second trimester serum screening, is an alpha-beta subunit hormone of placental origin, and is measured using a monoclonal two-site ELISA validated for use in prenatal screening. Quality control parameters for inhibin A measurement are acceptable and are monitored through the proficiency testing program administered by the College of American Pathologists. Research into other possible second trimester screening markers has included studies on the maternal urine and serum levels of an hCG variant, hyperglosylated hCG (h-hCG; invasive trophoblast antigen). Recent data indicate that h-hCG is similar to hCG itself, although its measurement in maternal urine may improve the performance of the established serum marker combinations. With the introduction of first trimester screening markers and their use in an integrated first and second trimester marker approach to screening, and with the fact that many women do not seek prenatal care until the early second trimester, prenatal screening for Down syndrome using second trimester serum markers remains a major resource in obstetrical care.

The use of a cytokine panel to define the long-term risk stratification of heart failure/death in patients presenting with chest pain to the emergency department.

OBJECTIVE: To determine if a cytokine panel could be informative regarding subsequent heart failure(HF)/death. DESIGN AND METHODS: In 216 subjects presenting with chest pain to an emergency department in 1996, EDTA plasma (-70 degrees C) was thawed for IL-6, MCP-1, IL-10, VEGF, EGF measurement. RESULTS: Subjects with any three cytokines elevated were at higher risk for HF/death compared to those with < or = two cytokines elevated. DISCUSSION: A cytokine panel might be useful for risk stratification for HF/death.

Identification of myocardial injury in the emergency setting.

Within the past decade, the use of biomarkers to detect myocardial injury in the emergency department (ED) has been given increasing prominence as evident by the numerous studies and guidelines documenting their use. This review details the scope of the clinical problem, the history of changes in the definition of myocardial infarction (MI) and the new approaches, as well as suggestions for using laboratory biomarkers in the early detection of MI in the ED.

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-A's role.

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.

Risk stratification for heart failure and death in an acute coronary syndrome population using inflammatory cytokines and N-terminal pro-brain natriuretic peptide.

BACKGROUND: Inflammation in acute coronary syndrome (ACS) can identify those at greater long-term risks for heart failure (HF) and death. The present study assessed the performance of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) (cytokines involved in the activation and recruitment of leukocytes) in addition to known biomarkers [e.g., N-terminal pro-brain natriuretic peptide (NT-proBNP)] for predicting HF and death in an ACS population. METHODS: In a cohort of 216 ACS patients, NT-proBNP (Elecsys; Roche) and IL-6, IL-8, and MCP-1 (evidence investigator; Randox) were measured in serial specimens collected early after symptom onset (n = 723). We collected at least 2 specimens from each participant: an early specimen (median 2 h; interquartile range 2-4 h) and a later specimen (9 h; 9-9 h), and used the later specimens' biomarker concentrations for risk stratification. RESULTS: An increase in both IL-6 and NT-proBNP was observed but not for IL-8 or MCP-1 early after pain onset. Kaplan-Meier analysis demonstrated that individuals with increased NT-proBNP (>183 ng/L) or cytokines (IL-6 > 6.4 ng/L; above upper limit of normal for IL-8 or MCP-1) had a greater probability of death or HF in the following 8 years (P <0.05). In a Cox proportional hazard model adjusted for both CRP and troponin I, increased IL-6, MCP-1, and NT-proBNP remained significant risk factors. Combining all 3 biomarkers resulted in a higher likelihood ratio for death or HF than models restricted to any 2 of these biomarkers. CONCLUSION: IL-6, MCP-1, and NT-proBNP are independent predictors of long-term risk of death or HF, highlighting the importance of identifying leukocyte activation and recruitment in ACS patients.