Biomedical subjects
Fred S Apple
Publications and source records attributed to Fred S Apple.
Toward standardization of cardiac troponin I measurements part II: assessing commutability of candidate reference materials and harmonization of cardiac troponin I assays.
BACKGROUND: Cardiac tropoin I (cTnI) measurements show an approximately 20- to 40-fold difference between assays, and better standardization and harmonization are needed. Toward this goal, the AACC cTnI Standardization Committee collaborated with the National Institute of Standards and Technology (NIST) in an earlier study to select 2 candidate reference materials (cRMs). METHODS: Two troponin cRMs, a troponin C-troponin I-troponin T (CIT) complex from human heart tissue and a CIT complex from recombinant technology, were supplied to NIST for assessment of composition and purity, and cTnI value assignment. These cRMs and 6 cTnI-positive human serum pools were shipped to manufacturers of 15 cTnI assays. Commutability of the materials was examined by determining the numerical relationship for the cRM preparations between each manufacturer-specified field method and each of the other 14 field methods. These relationships were then compared with the corresponding numerical relationships for the human serum pools. Harmonization of methods was accomplished by determining regression parameters relative to the analytical system yielding values closest to the median for each serum pool. These regression parameters were used to recalculate pool values to harmonize the assays. Interassay CVs before and after harmonization were determined. RESULTS: Characterization of the CIT and CI cRMs showed that these materials were of specified composition. The proportion of cTnI methods that demonstrated commutability for the CIT cRM was 45%; for the CI cRM, 39% of methods demonstrated commutability. Interassay cTnI variability for the field methods ranged from 82% to 97%, median 88%. After harmonization, variability of the serum pools for the cTnI methods was decreased to between 9.0% and 23%, median 15.5%. CONCLUSIONS: The proportion of methods demonstrating commutability was too low for use as a common calibrator for the cTnI field methods. However a simple strategy using serum pools can improve harmonization of field cTnI methods by more than 5-fold. The CIT cRM was selected by the AACC cTnI standardization committee, and a new lot has been classified as the cTnI certified reference material Standard Reference Material 2921 by NIST.
Biomarkers in acute cardiac disease: the present and the future.
The use of biomarkers to aid diagnosis and treatment is increasing rapidly as genomics and proteomics help us expand the number of markers we can use and as an improved understanding of the pathophysiology of cardiac disease guides their use. However, as with all rapidly expanding fields, there is the risk of excessive enthusiasm unless we are circumspect about the data that guide the clinical use of these new tools. This review focuses first on how to use troponin, which at present is the best validated of the new markers, and will hopefully provide insight into how to use this biomarker more productively by distinguishing subsets of patients and by providing an understanding of the meaning of elevations in various clinical situations. The review then discusses the use as well as the knowledge gaps associated with emerging biomarkers such as B-type natriuretic peptide and C-reactive protein, which are increasingly moving toward more productive clinical use. Finally, it reflects on some of the large number of markers that are still in development.
Letter regarding article by Khan et al, "prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease: a meta-analysis".
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Decreased patient charges following implementation of point-of-care cardiac troponin monitoring in acute coronary syndrome patients in a community hospital cardiology unit.
BACKGROUND: The need to rapidly evaluate patients presenting to emergency departments and cardiology services for ruling in and ruling out acute myocardial infarction (AMI) is widely recognized as a clinical challenge. We determined the impact of incorporating point-of-care (POC) cardiac troponin I (cTnI) testing into a cardiology service regarding assay turn around time (TAT), patient length of stay (LOS), financial matrixes and patient outcomes compared to central laboratory cTnI testing. METHODS: Patients presenting with symptoms suggestive of acute coronary syndrome (ACS) were enrolled pre-POC (PreCS, n=271) and post-POC (PostCS, n=274). POC cTnI determinations were performed at the bedside on the Dade Behring Stratus CS by nursing staff. Routine cTnI determinations were performed in the central laboratory (Dade Behring Dimension) by laboratory staff. Data were collected and analyzed on each patient per hospital stay by review of electronic medical and financial records. In addition, risk stratification outcomes for all cause death were determined at 30 days and 1 y following baseline sampling based on the 99th percentile cutoff concentrations of <0.1 microg/l for both assays. RESULTS: There was a decrease in time from blood draw to result to healthcare provider (PreCS mean 76 min; PostCS mean 19.5 min; p<0.001) as well as a decrease trend in charge per patient admission (4281 dollars savings) following implementation of POC testing. Total charges per patient admission decreased by 25% PostCS vs. PreCS (17,163 dollars vs. 12,882 dollars); a composite of lower charges for: boarding (-21%), other departments (-58%), pharmacy (-28%), labs (-22%), non-cardiac procedures (-28%), cardiac procedures (-14%). The mean LOS also decreased 8% (p=0.05) from PreCS (2.36 days) to PostCS (2.19 days). cTnI reagents charges to the laboratory were higher for the POC assay, 10.54 dollars, vs. the central lab assay, 3.83 dollars. One year survival was greater in the <0.1 microg/l patients (PreCS 96.2%, PostCS 97.2%) compared to the >0.1 microg/l patients (PreCS 77.7%, PostCS 75.5%); both p<0.001. Kaplan-Meier survival curves showed early separation by 30 days in each group. CONCLUSIONS: Our study demonstrates the cost effectiveness and clinical effectiveness of implementation of POC whole blood, cTnI testing for assisting clinicians with diagnostic and risk assessment of ACS patients.
B-type natriuretic peptide (BNP) and N-terminal pro-BNP in obese patients without heart failure: relationship to body mass index and gastric bypass surgery.
BACKGROUND: Further investigations are warranted to better characterize variables that may confound the clinical interpretation of plasma natriuretic peptide measurements, which are increasingly recognized to have diagnostic and predictive importance. METHODS: Blood samples (EDTA plasma) from patients (n = 206) attending clinics for the medical treatment and follow-up of obesity were analyzed for B-type natriuretic peptide (BNP; Bayer assay) and the N-terminal segment of its prohormone (NT-proBNP; Roche assay). Natriuretic peptide concentration ranges were evaluated in those without diagnosis of congestive heart failure (CHF) or chronic kidney disease (CKD). RESULTS: BNP and NT-proBNP were directly correlated (r = 0.87; P = 0.01), with NT-proBNP concentrations higher relative to BNP. Of obese patients without CHF or CKD, 21.6% (40 of 185) had NT-proBNP concentrations greater than the published assay upper reference limit. Concentrations of both natriuretic peptides were higher in patients currently exposed to beta blockers, patients with the diagnosis of hypertension or type 2 diabetes, and patients with a history of gastric bypass surgery. An inverse relationship between body mass index (BMI) and both BNP and NT-proBNP was evident. According to the National Institutes of Health, National Heart, Lung, and Blood Institute classification, more than 95% of the participants sampled in this study were either obesity class 2 (35 kg/m(2) < BMI < 39.9 kg/m(2)) or class 3 (BMI >or=40 kg/m(2)) CONCLUSIONS: A substantial proportion of obese patients without CHF or CKD have concentrations greater than the upper reference limit for NT-proBNP but not for simultaneously measured BNP. A history of gastric bypass surgery appeared to be a significant predictor of increased natriuretic peptide concentrations when assessed in a population of patients with class 2 or 3 obesity.
Clinical biomarkers of cardiac injury: cardiac troponins and natriuretic peptides.
Laboratory and clinical medicine groups are actively collaborating and optimizing their individual expertise to potentially prove standardized biomarker assays that will optimize patient care. It is critical as new biomarkers are discovered, that quality specifications be developed prior to approval by regulatory agencies that give supported endorsement for the worldwide marketplace. The laboratory medicine and clinical communities of scientists continues to challenge the biomarker field, working towards developing standard reference materials, and providing quality analytical specifications that, hopefully, will be endorsed by our clinical, in vitro diagnostic and pharmaceutical industry colleagues. This paper will specifically address cardiac troponins and natriuretic peptides.
Bovine polymerized hemoglobin (hemoglobin-based oxygen carrier-201) resuscitation in three swine models of hemorrhagic shock with militarily relevant delayed evacuation--effects on histopathology and organ function.
OBJECTIVE: To test our hypothesis that hemoglobin-based oxygen carrier (HBOC)-201 resuscitation in hemorrhagic shock (HS) will not lead to increased organ injury and dysfunction. DESIGN: Three swine HS models simulating military-relevant delayed evacuation: a) moderate controlled HS, b) severe controlled HS, and c) severe uncontrolled HS. SETTING: Military research laboratory. SUBJECTS: Swine. INTERVENTIONS: Swine were anesthetized/intubated and instrumented. To induce HS, in two controlled hemorrhage experiments, 40% (moderate controlled HS) or 55% (severe controlled HS) of blood volume was withdrawn; in an uncontrolled HS experiment, the liver was crushed/lacerated. During a 4-hr "prehospital phase," pigs were resuscitated with HBOC-201 (HBOC) or Hextend (HEX) or were nonresuscitated (NON). Upon "hospital arrival," liver injury was repaired (severe uncontrolled HS), blood or saline was infused, hemodynamics were monitored, and blood was collected. Upon animal death and/or 72 hrs, necropsy was followed by histopathologic evaluation of organ injury (hematoxylin and eosin, electron microscopy) and immunohistochemistry of oxidative potential (3-nitrotyrosine). Significance (p < .05) was assessed by Kruskal-Wallis, analysis of variance/Bonferroni, and mixed procedure tests. MEASUREMENTS AND MAIN RESULTS: Survival was significantly higher with HBOC than HEX only with severe uncontrolled HS (p = .002). Myocardial necrosis/fibroplasia, fluid requirements, cardiac output, and cardiac enzymes were generally similar or lower in HBOC than HEX pigs, but creatine kinase-MB (but not creatine kinase-MB/creatine kinase ratio) was higher with HBOC in moderate controlled HS. Alveolar/interstitial pulmonary edema was similar with HBOC and HEX, but Po2 was higher with HBOC in severe uncontrolled HS. Jejunal villar epithelial and hepatocellular necrosis were similarly minimal to moderate in all groups. Minimal biliary changes occurred exclusively with HBOC. Aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase were generally higher with HBOC than HEX. Mild renal papillary injury occurred more frequently with HBOC, but consistent patterns for urine output, blood urea nitrogen, and creatinine, were not seen. The 3-nitrotyrosine staining intensity was not different. CONCLUSIONS: In comparison with hetastarch, HBOC-201 resuscitation of swine with HS increased survival (with severe HS), did not increase evidence of oxidative potential, and had histopathologic and/or functional effects on organs that were clinically equivocal (myocardium, lungs, hepatic parenchyma, jejunum, and renal cortex/medulla) and potentially adverse (hepatobiliary and renal papilla). The effects of HBOC-201-resuscitation in HS should be corroborated in controlled clinical trials.
Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS).
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Point-of-care i-STAT cardiac troponin I for assessment of patients with symptoms suggestive of acute coronary syndrome.
BACKGROUND: Few studies have investigated the role of cardiac troponin point-of-care (POC) testing for predicting adverse outcomes in acute coronary syndrome (ACS) patients. We investigated the use of a POC cTnI assay in ACS patients. METHODS: We studied consecutive patients (n = 367) presenting with symptoms suggestive of ACS who were admitted through the emergency department. We measured plasma cTnI with the i-STAT assay. Patients were risk-stratified based on cTnI concentrations defined by the predetermined 99th percentile reference limit for plasma (0.04 microg/L). Patients were followed for 60 days. We computed survival and event curves with the Kaplan-Meier method and compared risk stratification groups with the log-rank test. RESULTS: Acute myocardial infarction (MI) was diagnosed in 8.1% of patients. Odds ratios and 95% confidence intervals for all-cause death (ACD), MI or ACD, MI or cardiac death, and cardiac death at 60 days were all statistically significant after adjustment for age, diabetes, hypertension, and history of renal failure as follows: 2.54 (1.24-5.20), P = 0.009; 2.76 (1.37-5.58), P = 0.003; 5.98 (1.65-21.7), P = 0.008; and 2.54 (1.24-5.20), P = 0.009. Kaplan-Meier curves showed early separation between patients with increased vs. reference concentrations before 30 days for ACD, MI or ACD, and MI or cardiac death. CONCLUSION: The i-STAT POC cTnI assay can be added to the list of assays for risk stratification.
Use of B-type natriuretic peptide testing in a community teaching hospital 4 years after implementation and agreement of results with discharge diagnoses.
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Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome.
BACKGROUND: Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event. APPROACH AND CONTENT: The purpose of this review is to provide an overview of the pathophysiology and clinical and analytical characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. These biomarkers (myeloperoxidase, metalloproteinase-9, soluble CD40 ligand, pregnancy-associated plasma protein A, choline, ischemia-modified albumin, unbound free fatty acids, glycogen phosphorylase isoenzyme BB, and placental growth factor) have demonstrated promise and need to be more thoroughly evaluated for commercial development for implementation into routine clinical and laboratory practice. SUMMARY: Specifications that have been addressed for cardiac troponins and natriuretic peptides will need to be addressed with the same scrutiny for the biomarkers discussed in this review. They include validating analytical imprecision and detection limits, calibrator characterization, assay specificity and standardization, pre-analytical issues, and appropriate reference interval studies. Crossing boundaries from research to clinical application will require replication in multiple settings and experimental evidence supporting a pathophysiologic role and, ideally, interventional trials demonstrating that monitoring single or multiple biomarkers improves outcomes.
Clinical and analytical review of ischemia-modified albumin measured by the albumin cobalt binding test.
IMA measured by the ACB test is proposed as a novel marker that appears sensitive to cardiac ischemia. It has the potential to become a triage tool in suspected ACS patients, especially to rule out ACS, and might also find utility in stroke, stress testing, nuclear imaging, and states of noncardiac ischemia and oxidative stress. Rapid-testing platforms will be necessary to achieve the optimal goal of assisting in the triage of chest (ACS) patients that present to EDs. However, it does not appear to be highly tissue or clinically specific. There is a continued need to improve the clinical and analytical evidence base of IMA to substantiate its clinical use in diagnostics and outcomes assessment. The search for a marker, whether IMA or another marker that establishes an evidence base, that would effectively rule in as well as rule out early cardiac ischemia continues. The ACB test has barely begun the exploration of the exciting challenges and discoveries that lie ahead in assisting clinicians in the early detection of myocardial ischemia to assist and improve patient triage, therapy, and management.
The diagnostic utility of cardiac biomarkers in detecting myocardial infarction.
Cardiac biomarkers, eg, cardiac troponin, have become the standard test in combination with clinical and electrocardiographic findings for physicians to conduct prompt and effective triage of patients presenting with chest pain. Cardiac biomarkers are protein components of cell structures that are released into circulation when myocardial injury occurs. The purpose of this article is multifold. First, to identify specific cardiac biomarkers and review current guidelines based on study findings on the diagnostic utility of cardiac biomarkers in detecting myocardial infarction. Recent guidelines of the European Society of Cardiology, the American College of Cardiology, the American Heart Association, and the National Academy of Clinical Biochemistry were examined, as well as relevant studies relating to the development of these guidelines. Second, to analyze the clinical significance of cardiac biomarker measurements and the challenges with existing cardiac biomarker assays. Third, to discuss our findings regarding our evaluation of the analytical performance of a chemiluminescent microparticle immunoassay for the quantitative determination of cardiac troponin I in human serum and plasma on an automated immunoassay instrument system (ARCHITECT) to aid in the diagnosis of myocardial infarction.
Standardization of cardiac markers.
Developing primary reference materials to standard cardiac biomarker assays, specifically cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), as well as develop quality specifications for immunoassays to optimize clinical use, whether for diagnostics or risk assessment, have been primary goals of the IFCC Committee on Standardization of Markers of Cardiac Damage (C-SMCD). The purpose of this paper is to review the current status of standardization issues for myoglobin, creatine kinase MB, cardiac troponin I and natriuretic peptides (BNP and NT-proBNP) and quality specifications for analytical immunoassays for the worldwide, consistent clinical utilization of these and future cardiac biomarkers.
Quality specifications for B-type natriuretic peptide assays.
BACKGROUND: The objective of this report is to improve the quality of immunochemical measurements of B-type natriuretic peptide (BNP) and its N-terminal propeptide (NT-proBNP). The recommendations proposed are intended for use by manufacturers of commercial assays, by clinical laboratories using those assays, by clinical trial groups and research investigators, and by regulatory agencies, such as the United States Food and Drug Administration. METHODS: A group of cardiac biomarker experts reviewed and abstracted the scientific literature to provide recommendations pertaining to the quality specifications for BNP/NT-proBNP assays. RESULTS: The evidence-based recommendations encourage manufacturers to endorse and consistently follow the proposed recommendations; encourage that all package inserts for BNP/NT-proBNP immunoassays include uniform information on assay design, preanalytical performance characteristics, analytical performance characteristics, and clinical performance; and encourage regulatory agencies to adopt a minimal and uniform set of criteria for manufacturers to provide when seeking clearance for new and/or improved assays. CONCLUSIONS: These recommendations address the use of BNP and NT-proBNP as cardiac biomarkers and not their physiologic and/or pathophysiologic relevance.
Validation of the 99th percentile cutoff independent of assay imprecision (CV) for cardiac troponin monitoring for ruling out myocardial infarction.
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What is the IMA assay really saying?
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