By Louise Lazear
In the ED, “time is muscle”: proper triage of suspected myocardial infarction and congestive heart failure leads to optimizing treatment protocols, which ultimately reduces morbidity and mortality. The consequences of making the decision to undergo a costly patient admission for a resultant non-specific diagnosis, or conversely sending a patient home with an undiagnosed acute or pending myocardial infarction are tremendous. Cardiac markers continue to gain importance as key components in the triage scenario, and the IVD industry has responded with point-of-need systems and cardiac panels to complement immunoassay analysis in the central lab.
This year, the American Heart Association estimates that 1.1 million Americans will suffer from new or recurrent myocardial infarctions, and over 45 percent of those experiencing an MI will die. Close to 6.4 million Americans have angina pectoris, and 400,000 new cases of stable angina and 150,000 of unstable angina occur each year. The societal and economic costs associated with these diseases are staggering: CHD accounts for close to 20 percent of Social Security disability allowances, and tens of billions of healthcare dollars are spent every year to cover the costs of hospitalizations due to this disease. Of the five million people per year admitted for suspected cardiac disease, half are admitted inappropriately. Conversely, a large portion of ED patients that are sent home without further follow-up, are misdiagnosed with adverse sequelae including fatal cardiac events. Clearly, correctly diagnosing cardiac events is of paramount importance in both the ED and urgent care settings.
The availability of more sensitive and specific biomarkers in point-of-need applications and new therapeutic regimens led to a refinement of current clinical practice for triage of suspected cardiac disease. In 2000, a joint committee of the European Society of Cardiology and the American College of Cardiology (ESC/ACC) redefined the World Health Organization’s definition of myocardial infarction (two of the following three characteristics: typical symptoms, an increase in enzymes, and an ECG pattern with Q waves) to one that promotes this basic concept: any amount of myocardial necrosis is to be defined as an infarct. The ESC/ACC recognized the far-reaching implications of their recommendations: more patients would be identified as having suffered an MI, but with a decrease in the number of false-positive cases. Therefore, the joint committee further recommended that the diagnosis of MI must undergo further characterization, including the size of the infarct, whether the infarct was spontaneous or related to a diagnostic or interventional procedure, and the timing of the necrotic pathway relative to the time of observation (evolving, recovering, or healed).
Pivotal to the joint committee’s redefinition of an acute, evolving, or recent MI is the measurement of key biomarkers that peak at different, predictable times post onset. Consequently, recommendations for both early and late markers with turn around times of less than 30 minutes have been proposed by this and other organizations. The ECS/ACC identified cardiac troponin as the preferred biomarker for damage to myocardial tissue due to its high specificity for cardiac tissue, and its high sensitivity to detect microscopic areas of necrosis. Because assay sensitivities vary, the committee defined the decision limit as one exceeding the 99th percentile of a reference control group at least one time during the first 24 hours post index episode. For purposes of standardization, the committee recommends a coefficient of variation (CV) less than or equal to 10 percent. Cardiac troponin will typically appear in blood four to 12 hours post symptom onset, and will remain elevated for four to 12 days. Both cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are available for measurement in the central lab and at the point-of-care. Both analytes have their subtleties: cTnT was initially found to have high false-positive rates in patients with chronic renal failure, while cTnI can appear in as many as 14 different isoforms in the blood post-ischemic event. However, second and third generation ELISA assays and proprietary antibodies specific to myocardial cTnI isoforms have lead to the acceptance of either analyte as a biomarker of myocardial infarction. Most vendors offer assays for cTnI due to licensing issues related to the use of cTnT.
If cTn measurement is not available, the committee recommends assay for the creatine kinase-myocardial band (CKMB) with decision limits (positive for necrosis) at the 99th percentile of reference control groups, also with a CV of less than 10 percent. Although less tissue specific than cTn, CK-MB may be detected as little as six hours post MI, peaks at approximately 18 hours, and typically returns to normal levels at 24 to 36 hours. Many clinicians will request total CK to diagnose acute MI. Due to its lack of specificity, the ECS/ACC recommends that CK analysis should be performed in conjunction with either CK-MB or cTn to accurately diagnose acute MI.
Both the ESC/ACC and the National Academy of Biochemistry Standards of Laboratory Practice recognize the benefit of myoglobin as an early marker of acute MI. Myoglobin may increase as early as one to two hours after symptom onset, and has the potential to rule out acute MI. However, myoglobin is not cardiac specific and elevated levels can occur in renal failure, trauma, or skeletal muscle injury. Despite its poor specificity, many ED physicians use myoglobin because of its negative predictive value. At one point, isoforms of CK-MB were under evaluation as a more specific early marker than myoglobin. Since the assay for these isoforms involves a lengthy time-to-result electrophoresis procedure, use of these isoforms has lost momentum.
In order to test the effectiveness of a multianalyte assessment of patients using POC technology, U.S. researchers embarked on a study of 1,005 low-to-moderate risk patients in six chest pain units in emergency departments at various locations. Called CHECKMATE (for CK-MB, Myoglobin and troponin I), the aim of the study was to compare POC analysis of multiple markers within hours of presentation to single biomarker analysis at the central laboratory. ”There were two pieces that came together with CHECKMATE. First, we know that each of these markers… have different sensitivities, specificity profiles, and different time to positivity. …The second piece is that we also know that patients are not uniform in the way they present to the ED,” said L. Kristin Newby, M.D., associate professor of medicine and cardiologist at Duke University Medical Center. According to Newby, the primary investigator in the study, the researchers hypothesized that rather than test for a single marker multiple times over a period of hours, it may be better to simultaneously test for multiple makers with different time to positivity profiles, either once or multiple times over the course of diagnosis. Results from the study demonstrated that bedside quantification of the three markers identified more patients earlier than remote single marker analysis. Also, when myoglobin was used as part of the multi-marker scenario, more patients were identified as having a higher risk for an adverse outcome, and time to detection was significantly shortened. “Particularly when we had myoglobin in the multi-marker strategy, we picked up patients about an hour earlier than with a single marker, local laboratory test. Part of that was because we did POC testing, … and part of it was because we tested for myoglobin, ” she added.
In response to a push from ED caregivers, cardiologists, and hospital administrators concerned about cost and risk management issues, manufacturers are developing an ever-expanding list of POC systems with features that vary across the spectrum of technology, from test strips and non-instrument platforms to analyzers with expanded menus for broad applications. Technology selection and implementation is most often defined by the clinical objective of the process, and involves input from the laboratory, the ED caregivers, cardiologists, and administration.
“We take the view that the best and only way to truly implement these systems effectively within an institution is to involve (these) four key areas … to have an institutional buy-in,” said Robert O’Malley, VP of sales and marketing at First Medical, a manufacturer of the Alpha Dx point-of-need system. “It’s not a diminished role of the lab, it’s just a change in the role of the lab, “ he added. The focus at First Medical was to overcome the traditional barriers for POC, including issues of reliability and accuracy, economics and connectivity due to new regulatory issues for patient record transportability, security and electronic billing. Bi-level controls for each assay, low maintenance, ease of use and the availability to link to LIS were key system design features from inception. Despite clear recommendations from various professional organizations, “There is still a dynamic discourse in the market about what is the right combination of markers,” said Patrick Arensdorf, CEO of First Medical. Because of the difference in focus between ED clinicians and cardiologists, a POC device in this setting must be able to address both diagnostic as well as prognostic issues. With this product, the user can select from a set of various-combination assay discs for quantitative measurement of cTnI, myoglobin, CK and CK-MB in less than 18 minutes. The company has assays for bhCG and D-dimer for use on the Alpha Dx under development.
Bio-Site Diagnostics has developed the Triage Cardiac System consisting of the Triage meter, a small-footprint instrument that provides simultaneous quantitative assessment of cTnI, myoglobin, and CK-MB in approximately 15 minutes. Test cartridges may be stored at room temperature for up to fourteen days prior to use. The system offers high throughput for multiple patient analysis: inoculated cartridges can incubate outside the reader while others are being read. Connectivity to LIS, ease of use, built in controls, and optional battery power portability are key features of the system. As with any POC diagnostic system, some users are concerned with the ability to standardize values with the central lab. According to Thomas Clark, senior product manager at Bio-site, hospitals address this issue in many ways. “Some hospitals use the system for triage in the ED, then reflex back to lab platforms if the patient is admitted. Some institutions will rebaseline admitted patients with their lab analyzer, others will use a correlation factor. Others look at relative ranges of the two systems, ” he said. The company has developed recommendations and can provide guidance during implementation of the technology. “In any case, we see the laboratory as having a pivotal role in POC testing as an extension of their services, ” he added.
In November 2000, Bio-Site received FDA 510K clearance for a B-type natriuretic peptide (BNP) assay for use with the Triage meter to aid in the diagnosis of congestive heart failure (CHF). BNP is released by heart muscle during ventricular dilation and pressure overload, a major component of the CHF disease cascade. Despite its high prevalence (estimates of more than 5 million people in the U.S. afflicted with the disease), CHF is often difficult to diagnose, especially at early onset when other lung disease may be suspected. In acute situations, CHF responds well to appropriate therapies, and therefore rapid diagnosis can impact morbidity and mortality. Research indicates that BNP levels may also be of prognostic value in risk stratification post ischemia, and may aid in targeting therapy in patients with advanced CHF.
Roche Diagnostics provides cardiac marker assays for both POC and central lab applications. Included in their product offerings is the ultra sensitive Cardiac T, available in both 9 and 18 minute assays for cTnT for use on the Elecsys platform. Also available are the Cardiac T rapid assay qualitative strip test, and the CardioCare system, which includes the Cardiac Reader and quantitative assays for cTnT and myoglobin. The Cardiac Reader reads the rapid assay strip and returns a qualitative value for cTnT. Roche has exclusive rights to the cTnT assay, which the company feels has advantages over assays for cTnI. “Troponin T is more stable in vivo than cTnI. Also, our antibodies recognize a very stable portion of the cTnT molecule, which reduces the impact of time-dependent changes,” said Theresa Ambrose, Ph.D., project manager for scientific affairs at Roche. According to Ambrose, the Cardiac Reader and Elecsys assays use the same sets of antibodies. Consequently, correlation of cut-offs, which is especially important when determining the proper therapeutic regimen based on troponin levels, is a non-issue. Roche is developing an assay for the N-terminal portion of the pro BNP molecule on the Elecsys platform for use in diagnosis of CHF. Pro BNP, which is released along with BNP during ventricular enlargement, is not expected to cross react with BNP-type drugs that are administered to treat CHF. The assay has been released as a product in Europe, but is still investigational at this point in the U.S.
Dade-Behring, which introduced the first automated troponin assay in 1995, also provides central lab and POC solutions for cardiac marker assays on its Dimension, Opus, BN-Series, and StratusCS platforms. The POC StratusCS, used by the researchers in the CHECKMATE study, provides quantitative measurement of CK-MB, myoglobin, and cTnI in under 30 minutes for all three analytes. Larger than most POC systems, the StratusCS features an on-board centrifuge and uses antibodies and calibrator anchors common to the Dimension platform. “What we are able to show is that samples run in the ED on the StratusCS and run on the Dimension analyzer in the central lab will provide you with the same clinical interpretation,” said Debbie Whitehair, MT, ASCP, SC, and marketing manager at Dade-Behring. Because the two platforms share the same reference ranges, there is a correlation between results on the two platforms, which allows for easier implementation into therapy protocols, patient management and LIS management.
The use of cardiac markers in the urgent care setting is also gaining importance. Despite typically poor reimbursement, urgent care centers often use markers to identify “hot” patients that are consequently medicated, stabilized, and transported to nearby medical facilities. At Urgent Medical Care in Smithfield, Rhode Island, a free-standing ACLS-certified facility which sees about 72 chest pain cases per year, clinicians have developed chest pain protocols that include an electrolyte panel and a total CK performed on the Abaxis Piccolo POC analyzer. “Depending upon the clinical presentation, we may send a sample to the lab for CK-MB fractionation and troponin levels,” said Jennifer Zuba, R.N. and nurse manager at the center. Abaxis is developing assays for CK-MB and troponin, which Zuba expects to be clinically available within the next few months. Until then, the facility is looking into implementing a cTnT rapid strip test, despite reimbursement levels of only 36 percent of the cost of the assay. The issue of standardization with hospital-based marker platforms is not an over riding concern for this front-line facility. However, Zuba would like to see more a coordinated effort between these settings. “Hospitals need to place more trust in the urgent care center. We have the data, and we need to get to the point where we move forward instead of repeating tests all over again,” she added.
To address this market, some vendors offer a slightly different approach. Spectral Diagnostics, Inc. has developed the CARDIAC STATus CARDIAC Panel, a moderately complex non-instrument based qualitative assay for CK-MB, myoglobin, and cTnI, with sensitivities of 5 ng/ml, 50 ng/ml, and 1.5 ng/ml respectively. The system, about the size of a Band-Aid, uses lateral flow immunoassay technology to provide positive results in about three to five minutes (confirmed negative in 15 minutes). The ability to provide qualitative analysis of these markers is a valuable tool with applications not just in emergency departments and labs but also in urgent care centers, ambulances, and other less traditional venues like correctional healthcare facilities and cruise ships, according to Christopher Wayne, director of marketing at Spectral. “Most clinicians ultimately just want to know if they are positive or not, so a disposition decision can be made, “ he said.
Small footprint, an expandable menu and an affordable projected retail cost of $1000 per system are the features of the newly FDA 510(k) cleared RAMP Reader and myoglobin assay from Response Biomedical Corp. The system provides quantitative results for myoglobin in fifteen minutes, and assays for cTnI and CK-MB are under development. The company expects to be able to offer a complete cardiac panel in early 2003. Our longer-term vision includes minaturizing the instrument to hand-held size,” said Bill Radvak, president and CEO.
While much of the focus to date concerns use of cTn, CK-MB and myoglobin in triage, new biomarkers to diagnose myocardial infarction are being investigated. In Europe, Ischemia Technologies has received approval to market an assay for Ischemia Modified Albumin (IMA), to be used with cTn to diagnose myocardial infarction. In the U.S., researchers in a multi-center study are investigating the use of IMA levels to replace acute perfusion imaging in patients presenting with chest pain and to aid in risk assessment for pending MI. “In the ED, about five percent of the people who present with MIs are going to inadvertently be sent home. The ideal situation is to have a blood test that answers one simple question – is it safe to send this person home until I can do more definitive studies, and know that within the next 72 hours they won’t suffer from a heart attack,” said Robert Cook, M.D., Ph.D. at Virginia Commonwealth University Health System In Richmond. The role of this marker as a potential screen for coronary heart disease is yet to unfold. “This research represents an interesting piece of diagnostics, prognostics, and epidemiology that needs to be sorted out. Right now, we are hoping that these studies will demonstrate its use as an event marker with predictive value as an acute tool rather than disease state tool, ” he added. The IMA assay currently does not have FDA clearance.
As diagnostic testing moves closer to the bedside, the role of the laboratory is more important than ever. Because almost all of the POC assays for cardiac assessment are moderately complex, the lab is the entity responsible for regulatory aspects of their use. Virtually every vendor contacted for this article was emphatic about one point: the lab is a key player in POC system selection and implementation, and should be involved in every step of the process. Use of near patient strategies for diagnosis is an important opportunity for laboratorians to be involved with their colleagues throughout the healthcare continuum to achieve the common goal of improving access to and quality of healthcare.
Louise Lazear is a freelance writer in Charlotte, N.C.