Technologies for cardiac biomarker pointofcare testing

Instruments, decision levels, and applications

Handheld, portable, and transportable instruments and devices available for cardiac biomarker POCT are summarized in Table 1 [18-38]. Test clusters, methods, analysis times, sample types, and other pertinent information are shown. Disposable qualitative test kits are shown also. For additional details of POC analytic principles, see Tang and colleagues [39] and for an earlier analysis of technology, see the University HealthSystem Consortium report by Cummings and colleagues [40]. Note that several of the devices and test kits in Table 1 may be used in near-patient laboratories or at the bedside. Before implementation, operators should check with manufacturers regarding regulatory constraints, decision thresholds, and test classifications. Currently, none of the tests listed qualify for so-called waived status under federal statutes governing diagnostic testing [41]. Thus, testing must be performed by licensed, certified, and validated personnel in accredited facilities with attention to required daily quality control, and should be supervised by POC coordinators who assure high-quality, satisfy inspection requirements, and incorporate proficiency testing (objective external performance review). Nurses and POCT coordinators and, often, experienced medical technologists, have become indispensable partners stitching these aspects of POCT together and maintaining the fabric of excellence in testing irrespective of where it is performed [42,43]. Chest pain centers should not attempt to implement and manage POCT without the assistance of an experienced POCT coordinator who provides valuable liaison with laboratory medicine and essential continuity of POCT throughout the hospital.

Several areas for potential improvement in the POC cardiac biomarker repertoire are identified in Table 1. Miniaturized bedside immunochemis-try has just passed its infancy and integrated mul-timarker test clusters have appeared only recently on portable and handheld devices. Despite over one decade of development [44], WBA times for immunochemistry remain prolonged, in the order of 15 minutes. Following the precedent set in other clinical applications, such as biosensor-based bedside glucose testing, analysis time should be reduced to just a few minutes while analytic sensitivity (minimum detection level) should be improved. These potentially conflicting goals may justify the use of novel nano- or microfluidics, microarray, or optical approaches heretofore not commonly present on POC devices. Complex manufacturing and funding hurdles stall efforts to combine cardiac biomarkers with other critical care analytes, such as electrolytes (eg, K+ and Ca++), blood gases, and pH. Currently, these analytes can be measured with exchangeable cartridge-based systems (eg, i-STAT) but should be fully integrated on other instruments for the evaluation, diagnosis, and monitoring of critically ill patients.

The inconsistency in qualitative and quantitative decision levels is emphasized in Table 2. In this phase of rapid growth, standardization of cardiac biomarker measurements and decision levels should occupy a position of high priority. Standardization, which demands consideration of subject reference levels and assay characteristics (eg, epitopes, antibodies, and matrices, all producing in the case of cTnI, varying specificities for different forms released), improves the consistency of diagnostic interpretation, reduces the potential for errors, and allows physicians to follow trends if different assays are used for testing after patients are admitted. Inadequate computer interfacing of devices and lack of critical results alerting represent two additional weaknesses. Full integration with hospital computerized systems is required for settings using an electronic medical record. As noted in later discussion of risk, missed diagnoses resulting from poor communication and other root causes can result in significant financial penalties. Examples of special situations where cardiac biomarker POCT is being developed or can help facilitate unusual clinical problem solving are presented in Table 3 [45-58]. Generally, per test cost for POCT exceeds that on larger mainframe chemistry analyzers found in clinical laboratories. Despite high costs, POCT can improve overall cost-effectiveness [3,6-9], discussed below.

Table 1

Cardiac Biomarker POCT

Test/Device name

Biomarker(s)

Device characteristics

Reference notes

Cardiac Reader

• NT-proBNP (Portable) Roche Diagnostics

TropT sensitive

(Handheld, disposable) Roche Diagnostics Indianapolis, IN www.roche.com Cardiac STATus

(Handheld, disposable) Spectral Diagnostics Toronto, Ontario, CAN www.spectraldx.com

i-Lynx

(Handheld, portable) Spectral Diagnostics Toronto, Ontario, CAN www.spectraldx.com

cTnT

Myoglobin

D-dimer

NT-proBNPa cTnT (QUAL)

Myo + cTnI

(test clusters) cTnI CK-MB

Sample: 150 ^L heparinized or

EDTA WB Analysis time: 12 min, TnT; 8 min, myoglobin; and 8 min, D-dimer Method: Immunoassay and photosensor Sample: 150 ^L heparinized or EDTA WB Analysis time: 15 min Method: Immunoassay

Sample: 150 ^L heparinized WB, heparinized plasma or serum Analysis time: 15 min Method: Lateral flow based immunoassay

The system consists of two interfaced components; a handheld electronic device to capture and analyze an image from the current Cardiac STATus rapid test strip, and a local area network compatible docking station to automate data capture communication

Cardiac Reader interprets Cardiac T/M/D rapid assay strips. Comparison between the rapid test and a established laboratory-based method showed sufficient agreement of results with a correlation of r = 0.89 for troponin T and r = 0.912 for myoglobin [18]. The Cardiac T exhibited Sn = 100% and Sp = 76.2% for MI [19]. See also [20].

Out of 34 patients who present with AMI, the TropT sensitive test showed positive quantitative results for 20 patients versus 29 patients when the Cardiac Reader was used [21]. At 3 hours after onset of symptoms for AMI, Sn = 50%, Sp = 96.3%, PPV = 80%, and NPV = 86.7% for AMI [22].

Qualitative results from CK-MB and myoglobin test cards were comparable diagnostically to quantitative results from the Ciba Corning ACS-180 and Dade Stratus IIntellect [23]. cTnI tests showed 98% concordance with ELISA [24]. In comparison with Roche TropT, the Cardiac STATus proved more effective in early diagnosis of AMI [25]. The Cardiac STATus had a sensitivity of 96% for the detection of AMI within 3 hours of presentation [26].

The i-Lynx is a connectivity solution with full QC functionality in open architecture, including system maintenance, user ID, QC log, lockout, passcode protection, universal barcode, and connectivity by way of TCP-IP for POC Coordinators (Chris Wayne, Spectral Diagnostics, e-mail communication.)

Cholestech LDX (Portable) Cholestech Corp. Hayward, CA www.cholestech.com

i-STAT 1 and PCA (Handheld) i-STAT

East Windsor, NJ www.i-stat.com

LifeSign MI

(Handheld, disposable) PBM

Princeton, NJ www.pbmc.com

NycoCard Reader II (Portable) Axis-Shield Oslo, Norway www.axis-shield.co.uk

Nexus Dx

(Handheld, disposable) Syn X Pharma Inc. Toronto, CAN www.synxpharma.com One-Step Marker Test (Handheld, disposable) ACON Labs San Diego, CA www.aconlabs.com

cTnI

(test clusters) MLC-1b NT-proBNPb CRP D-dimer cTnl + myoa cTnl + myo + CK-MBa

(test clusters) cTnIa

NT-proBNPa,b cTnl + myo + CK-MBa (test cluster)

Sample: 50 mL WB or

40-50 mL plasma Analysis time: 7 min Other analytes: Total cholesterol, HDL, triglycerides, ALT, and glucose. Method: Reflectance photometry, immunoassay Sample: 16 mL heparnized WB or plasma Analysis time: 10 min, cTnl Other analytes: Na+, K+, CP, Ca2+, glucose, creatinine, lactate, BUN, Hct, Hb, pH, pCO2, pO2, ACT, and PT Method: ELISA

Sample: 120 mL WB, plasma, or serum

Analysis time: 15 min

Method: Chromatographic immunoassay

Sample: 5 mL heparinized/EDTA/ citrated WB or serum (dilution to 50 mL required) Analysis time: 3 min Other analytes: HbA1c, microalbumin Method: Reflectometric immunoassay Sample: 120 mL WB, plasma or serum for cTnl Analysis time: 15 min, cTnI Method: Chromatographic immunoassay

Sample: 120 mL WB, plasma, or serum

Analysis time: 15 min

Method: Chromatographic immunoassay

WB and plasma samples showed a concordance rate of 94% and 90%, respectively, with results from Dade Behring BN100 [27].

cTnI test performance proved insensitive to hematocrits between 0 to 65%, but higher hematocrits produced imprecision [28].

Each test cluster is equipped with a built in control for quality assurance [29].

NycoCard Reader II interprets CRP and D-dimer test strips.

NT-proBNP test was approved in Europe mid-2004 and is pending FDA approval in the United States. Other tests are available only in Canada and Europe [30].

Device is only available outside the United States. Quality controls are built into the test card.

(continued on next page)

Test/Device name

Biomarker(s)

Device characteristics

Reference notes

RAMP Reader

Myoglobin

Sample: 70 ^L WB

At 95% CI, Sn (cTnl) = 90%, Sp (cTnl) = 86%,

(Portable)

CK-MB

Analysis time: ~ 15 min

Sn (CK-MB) = 59%, and Sp (CK-Mb) = 90% for AMI [31].

Response Biomedical

cTnl

Other analytes: WNV antigen

British Columbia, CAN

Method: Fluorescence-based

www.responsebio.com

immunoassay

RAPICHEKb

H-FABP

Sample: 150 ^L WB

H-FABP panel test achieved 98.4% agreement with H-FABP

(Handheld, disposable)

Analysis time: 15 min

mass concentration ELISA [22,32]. At 3 hours following

Dainippon Pharmaceuticals

Method: Chromatographic

onset of symptoms of AMI, RAPICHEK had Sn = 100%,

Suita City, Osaka, Japan

immunoassay

Sp = 63%, PPV = 44%, and NPV = 100%. RAPICHEK

www.dainippon-pharm.co.jp

versus TropT sensitivity were 100% versus 50%, respectively.

Stratus CS STAT

CK-MB

Sample: 2.7 mL heparainzed WB or plasma

Device correlated well with cTnI tests performed in a central

(Transportable NPT)

Myoglobin

Analysis time: 14 min for first result, 4 min

laboratory; imprecision of troponin method has a CV of less

Dade Behring

cTnl

for each additional result

than 10% at the 99th percentile of the reference population

Deerfield, IL

D-dimera

Other analytes: P-hCG

[33,34].

www.dadebehring.com

Method: Fluorescence-based immunoassay

Triage Cardiac Panel

CK-MB + myo + cTnl

Sample: 225 ^L EDTA WB or plasma

Triage MeterPlus interprets Triage Cardiac Panels, includes

(Portable)

cTnl + CK-MB + myo +

Analysis time: ~ 15 min

built-in quality controls, and provides simultaneous analyses

Biosite Diagnostics

BNP (test clusters)

Other analytes: acetaminophen,

of multiple analytes. Study showed Triage Cardiac Panel

San Diego, CA

D-dimer

amphetamines, methamphetamines,

comparable to established methods for detection of AMI

www.biosite.com

cocaine, opiates, phencyclidine,

[35]. Sn for cTnI, CK-MB, and Myo were 98%, 95%, and

tetrahydrocannabinol, barbiturates,

81% respectively, and the Sp were 100%, 91%, and 92%

benzodiazepines, propoxyphen,

respectively for AMI [35,36].

tricyclic antidepressants

Method: Fluorescence-based immunoassay

TBA

Sample: fingerstick WB

A faster quantitative fingerstick-based test strip using whole

Analysis time: 2-5 min

blood is being developed (Julie Doyle, M.D., Biosite

Method: under development

Diagnostics, e-mail communication.).

Abbreviations: ACT, activated clotting time; ALT, alanine aminotransferase; P-hCG, P-human chorionic gonadotropin; BUN, blood urea nitrogen; ELISA, enzyme-linked immunoabsorbant assay; F, female; Hb, hemoglobin; Hct; hematocrit; HDL, high density lipoprotein; H-FABP, human-type fatty acid binding protein; M, male; MLC-1, myosin light chain-1; myo, myoglobin; NA, not available; NPT, near-patient testing; NPV, negative predictive value; PPV, positive predictive value; PT, prothombin time; QC, quality control; QUAL, qualitative; Sn, sensitivity; Sp, specificity; TBA, to be announced; Tnl, troponin I; WB, whole blood; and WNV, West Nile Virus.

Notes: a) Under development, b) Not available in US, +) Indicates test cluster. Methods were provided by manufacturers or their web sites. Reference 20 cited for completeness. No current information available for the First Medical Alpha Dx system [37,38]. Chemometrics data given for emergency room or early diagnostic applications. See Jaffe chapter for general information of sensitivity, specificity, and predictive values.

Table 2

Clinical decision levels for cardiac biomarker POCT

Table 2

Clinical decision levels for cardiac biomarker POCT

Biomarker

Device(s)

Qualitative

Quantitative

Decision level

BNP

Triage Cardiac Panel

X

100 pg/mL

CK-MB

Cardiac STATus

X

5.0 ng/mL

LifeSign MI

X

5.0 ng/mL

Nexus Dxa,b

X

Under development

One-Step Marker Test

X

5.0 ng/mL

RAMP Reader

X

5.0 ng/mL

Stratus CS STAT

X

3.5 ng/mL

Triage Cardiac Panel

X

4.3 ng/mL

CRP

Cholestech LDX

X

Under development

NycoCard CRP

X

Not available

cTnI

Cardiac STATus

X

0.5 ng/mL

i-STAT 1 and PCA

X

0.1 ng/mL

LifeSign MI

X

1.5 ng/mL

One-Step Marker Test

X

0.5 ng/mL

RAMP Reader

X

0.12 ng/mL

Stratus CS STAT

X

0.06 ng/mL

Triage Cardiac Panel

X

0.4 ng/mL

Nexus Dxa,b

X

Under development

cTnT

Cardiac Reader

X

0.1 ng/mL

TropT Sensitive

X

0.1 ng/mL

D-dimer

Cardiac Reader

X

0.5 mg/mL

NycoCard D-dimer

X

Not available

Triage Cardiac Panel

X

100 ng/mL

Stratus CS STATa

X

Under development

H-FABP

RAPICHECK

X

6.2 ng/mL

MLC-1

LifeSign MIb

X

Not available

Myoglobin

Cardiac Reader

X

76 ng/mL (M), 64 ng/mL (F)

Cardiac STATus

X

80 ng/mL

LifeSign MI

X

50 ng/mL

Nexus Dxa,b

X

Under development

One-Step Marker Test

X

50 ng/mL

RAMP Reader

X

99.3 ng/mL

Stratus CS STAT

X

98 ng/mL (M), 56 ng/mL (F)

Triage Cardiac Panel

X

107 ng/mL

NT-proBNP

Cardiac Readera

X

Under development

LifeSign MIb

X

Not available

Nexus Dxa'b

X

Under development

Abbreviations: CRP, C-reactive protein; cTnT, cardiac troponin T; F, female; H-FABP, human-type fatty acid binding protein; M, male; MI, myocardial infarction; MLC-1, myosin light chain-1; NT-proBNP, N-terminal proBNP; Tnl, troponin I; TnT, troponin T.

Notes: a) Under development; b) Not available in United States.

Disclaimer: Tables 1 through 3 were compiled from reliable sources including company web sites and cited literature. However, during evaluation before implementation users should update and verify all data directly from manufacturers and product inserts. Users also should verify decision levels and reference methods, as well as FDA-approved clinical applications of each cardiac biomarker.

Qualitative versus quantitative testing: the American College of Cardiology/American Heart Association guidelines

Cardiac biomarkers linked with efficient triage and treatment strategies can facilitate resource use, risk stratification, therapeutic management, and clinical outcomes [59-64]. The American

College of Cardiology/American Heart Association (ACC/AHA) 2002 guideline update [65] for patients who present with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) states that ''point-of-care assays at present are qualitative or, at best, semiquantitative. The evolution of technology

Table 3

Special applications of cardiac biomarker POCT

Special applications

Biomarker/concept

Device/index

Multivariate analysis

ACS. Rapid test for ACS risk stratification utilizing cMyo cardiac myoglobin and CAIII for early specificity and sensitivity (Chris Wayne, Spectral Diagnostics, e-mail communication).

CHF. Patients who died or were readmitted tend to have BNP an increase in BNP concentration during their hospitalization (+ 239 G 233 pg/mL). Patients who had successful treatment tend to have decreases in their BNP concentration during their hospitalization (—216 G 69 pg/mL). The difference between these two groups were significant (P < .05). Therefore, POCT of BNP may be an effective way to improve inhospital management of patients with decompensated CHF [45].

Correctional facility. When the Cardiac STATus is combined with EKG results and medical history, a positive result leads to early diagnosis and subsequently faster, more effective treatment. A negative result can provide the confidence needed to safely treat the inmate on premises. In the end the correctional facility saved substantial funds (Chris Wayne, Spectral Diagnostics, e-mail communication).

Diabetes risk. Bhalla and colleagues [46] state BNP to be BNP the most significant (P < .001) predictor of all-cause mortality in diabetic patients suspected of cardiac dysfunction.

Diagnostic synthesis. "MMX" combines multiple Multimarker index biomarker test results in a continuous parameter that shows potential to discriminate patients with ACS from those without ACS (Julie Doyle, M.D., Boisite Diagnostics, e-mail communication). From ROCs, MMX AUC appears to outperform individual analyte (cTnI, CK-MB, myoglobin, or BNP) AUCs in ACS versus non-ACS and in other comparisons, such as MI versus UA or non-ACS, including for subsets of patients within 6 hours after the onset of chest pain. MMX algorithms have the potential to aid in the differential diagnosis of other conditions, such as stroke. Independent multimarker analysis also can be used for risk stratification [47,48].

Early dysfunction. Mueller and colleagues [49] showed NT-proBNP

NT-proBNP comparable to BNP biomarkers for differential diagnosis in symptomatic and asymptomatic structural heart disease. However, results also suggested NT-proBNP was able to discern early cardiac dysfunction compared to BNP.

General practice environment. Dahler-Eriksen and CRP

colleagues [50] showed CRP testing in general practice identified significantly (P = .002) more new diseases (eg, infectious disease, inflammatory disease) compared to the control group. Additionally, cost-effectiveness analysis showed a reduction of $110,000 per year.

Spectral Dx cMyo Test (under development)

Triage BNP

Cardiac STATus

Triage BNP

MMX (Anderberg J. and colleagues. AACC Oak Ridge Conference, 2005;63)

(Roche Elecsys) POCT under development

NycoCard Reader

Special applications

Biomarker/concept

Device/index

Home testing. Each year, more than a million persons in the United States have a heart attack, and about 50% of them die [51]. About 50% who die do so within 1 hour of the start of symptoms, such as pre-infarction angina. Home testing could improve outcomes.

Military. Cardiac troponin T can help exclude myocardial damage in patients who experience an elevated CK caused by skeletal muscle trauma [52].

Military. The Cardiac STATus is available to every surface ship in the entire US Navy fleet (Chris Wayne, Spectral Diagnostics, e-mail communication).

Mobile intensive care unit. When used within 2 to 12 hours from the onset of symptoms, the CK-MB/ myoglobin multimarker test can prevent misdiagnosis of AMI or unnecessary hospitalization [53].

Paramedic use. Use of the cTnI test helps Onslow County paramedics to quickly diagnose chest pain, and confidently rule-in or rule-out heart attacks while patients are in transit to the hospital. In certain cases, if the paramedic or ED physician confirms the patient is having a heart attack they can, following a protocol, implement therapy before they reach the hospital doors (Chris Wayne, Spectral Diagnostics, e-mail communication).

Potential new biomarker. For the diagnosis of AMI, quantitative ELISA-based measurement of H-FABP has been shown to be more sensitive than myoglobin or CK-MB, and more specific than myoglobin [22]. However, the ELISA process takes R 90 minutes whereas the RAPICHEK takes 15 minutes. Additionally, the RAPICHEK test exhibited superior negative predictive values, which reached nearly 100% for patients in all time frames. Seino and colleagues [22] concluded that the H-FABP could be useful for emergencies.

Prehospital admission. Prehospital cTnT testing appears to be an objective marker for patients with poor outcomes [54].

Renal dysfunction. McCullough and colleagues [55] showed myoglobin and CK-MB correlated with corrected creatinine clearance (r = —0.36, P < 0.01, and r = —0.10, P = .01, respectively), while cTnI did not (r = —0.10, P = .12). Multiple receiver operating characteristic curve testing showed cTnI to be the most consistent marker of myocardial injury over all strata of renal dysfunction including end-stage renal disease on dialysis [56]. Therefore, cTnI is applicable and superior to myoglobin or CK-MB in the evaluation of chest pain in patients with renal dysfunction [55].

Renal failure. In patients with severe renal failure, cTnT could not be broken down and cleared by the kidneys, resulting in high serum cTnT levels [56].

Various cardiac biomarkers Waived tests (to be developed)

cTnT

Multimarker Analysis Multimarker Analysis cTnI

TropT Sensitive and Cardiac T

Cardiac STATus

Cardiac STATus

Cardiac STATus

H-FABP

RAPICHEK

cTnT

cTnI

TropT Sensitive and Cardiac T

Triage Cardiac Panel cTnT

TropT Sensitive and Cardiac T

(continued on next page)

Special applications Biomarker/concept Device/index

Secondary referral. European Society of Cardiology BNP BNP

recommendations include BNP testing to refer patients to secondary care. Thrombosis. As a cardiac biomarker, Dempfle and D-dimer Cardiac D

colleagues [57] found the Roche Cardiac D Rapid Assay was also useful as a rule-out diagnostic tool for patients with suspected acute thrombosis [58]. The Roche Cardiac D Rapid Assay also can be used for diagnostic work-up for deep vein thrombosis [57].

Abbreviations: AUC, area under curve; CAIII, cardiac anhydrase III; cMyo, cardiac myoglobin; CorrCrCl, corrected creatinine clearance; CRP, C-reactive protein; cTnT, cardiac troponin T; ELISA, enzyme-linked immunoabsorbant assay; F, female; H-FABP, human-type fatty acid binding protein; M, male; MI, myocardial infarction; MMX, multi-marker index; NA, not available; NT-proBNP, N-terminal pro B-type natriuretic peptide; ROC, receiver operator curve; and UA, unstable angina.

that will provide quantitative assays of multiple markers that are simple to use will improve the diagnosis and management of patients with suspected acute coronary syndrome (ACS) in the ED''. The 2004 ACC/AHA guidelines [66] for the management of patients with STEMI stated, ''Although handheld bedside (point-of-care) assays may be used for a qualitative assessment of the presence of an elevated level of a serum cardiac bio-marker, subsequent measurements of cardiac biomarker levels should be performed with a quantitative test.. in general, bedside assays are less sensitive and less precise than quantitative assays''. Further, ''A positive bedside test should be confirmed by a conventional quantitative test'' [66]. These guidelines statements regarding qualitative assays allude to the various types of handheld formats and disposable test kits noted for convenience [67] and listed in Table 1. Qualitative versus quantitative assays are identified in Table 2. Much room for improvement exists in the detection of minor myocardial damage. The sensitivity and precision at the cutoff concentrations of qualitative and quantitative assays should be checked and deemed clinically appropriate before implementation [68] in chest pain centers.

Assay types, clinical applications, and testing sites create many alternatives, and the relevance of published studies will depend in part on the configuration and staffing of individual chest pain centers. Hamm and colleagues [69] found qualitative POC cardiac troponin T (cTnT) and cTnI tests to be sensitive and useful for ED triage. Schwartz and colleagues [70] documented diag-nostically similar results from CK-MB and myo-globin qualitative testing in the ED and quantitative testing in the laboratory. Panteghini and colleagues [25] studied the potential usefulness of rapid bedside qualitative myoglobin/CK-MB and cTnT tests in initiating revascularization therapy. James and colleagues [48] found rapid qualitative cTnI suboptimal for prediction of subsequent cardiac events at suspicion of unstable coronary syndromes. Hirschl and colleagues [71] found reliable clinical performance of qualitative cTnT testing, whether performed in laboratories or by nurses and physicians in critical care units. For ''patients with suspicious AMI,'' Seino and colleagues [22] showed improved early sensitivity with a rapid whole-blood quantitative assay for heart-type fatty acid binding protein versus qualitative cTnT testing. Wu and colleagues [31] reported equivalent results for quantitative cardiac biomarker POCT and laboratory testing. Other studies [21,72] address quantitative bedside testing. Additionally, POCT encompasses near-patient testing (NPT), such as in ED satellite laboratories, where automated analyzers that provide quantitative testing (eg, Stratus CS STAT) often are placed.

In the ED, analytically sensitive quantitative cTn assays have blurred the distinction between patients who present with and without classically defined acute myocardial infarction (AMI) and have focused attention on the continuum of ACS from angina to transmural Q-wave myocardial infarcation (MI) [73,74]. With first-draw specimens in the ED and qualitative POCT, Kratz and colleagues [75] showed that triple cardiac bio-markers (ie, a test cluster) may be needed to avoid weak positive predictive values for individual tests, and quantitative confirmation in the clinical laboratory yields additional improvement. In a five-hospital study of acute chest pain patients, Goldman and colleagues [18] reported equivalent results for quantitative POC cTnT and myoglobin testing in the ED versus testing in the clinical laboratory and stated that POC cTnT proved advantageous for rapid decision making. In the ED, optimal clinical sensitivity for ACS on first-draw specimens derives from myoglobin, a better adjunct test than CK-MB [76]. Although qualitative POC methods appear in routine and also several special settings (see Table 3), to expedite clinical assessment without missing cases of AMI, quantitative and highly sensitive POC assays are needed. POC assays also allow monitoring of release and clearance dynamics in the form of bedside changes (A, ''delta values'') [65]. A conservative approach, the evidence to date, and the guidelines above indicate a need for highly sensitive and quantitative cardiac biomarker POCT, and given a choice, chest pain centers should implement quantitative assays.

Ischemia markers: critical need

Any ischemia biomarker that works well clinically, that is, can detect ischemia in the absence of necrosis, would be an immediate success if used for POCT. Aggressive early triaging demands improved cardiac biomarkers for that purpose. A new biomarker, ischemia-modified albumin (IMA) (ACB, albumin Cobalt binding test; Ischemia Technologies, Denver, Colorado), has been approved and licensed by the Food and Drug Administration (FDA). Unfortunately, clinical data show that the current generation of the IMA assay lacks requisite specificity [77-87] like that possibly afforded, for example, by ultrahigh-sensi-tivity assays for troponins. In addition, IMA has not been implemented on any of the POC platforms listed in Table 1. Biomarkers of ischemia under evaluation include free fatty acid, glycogen phosphorylase isoenzyme BB, myeloperoxidase, nourin-1, pregnancy-associated plasma protein A, sphingosine-1-phosphate, soluble CD40L, and whole-blood choline. Future clinical studies of ischemia biomarkers should target low-risk patients in whom quick evaluation in the chest pain center can exclude AMI, and then attention can turn to the underlying cause of the chest pain.

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