Future developments in the point-of-care testing of cardiac biomarkers suggest that handheld technology is the preferred option and that methods will soon match laboratory high-sensitivity assays
Paul Collinson MD FRCPath FRCP
Departments of Clinical Blood Sciences and Cardiology, St George’s Hospital and Medical School, London, UK
The evolution of point-of-care testing (POCT) systems has been from two directions. POCT traditionally has a long history based on urine testing. Indeed, one of the first descriptions of this was by the Byzantine physician, Theophilus Protospatharios in the 7th century, and the discipline of urine testing was codified in the UK in the 16th century in the Seynge of Urines.(1) Techniques then included tasting the urine, which would now be considered unacceptable from a health and safety perspective (although undoubtedly very cost effective). The evolution of strip-based testing has resulted in POCT instruments that measured early cardiac biomarkers, such as creatine kinase (CK)(2,3) and its MB isoenzyme (CK-MB).(4)
However, the benchmark for portable handheld instrumentation is set by blood glucose meters. These are now very compact indeed, although the modern generation of devices, which includes the appropriate degree of functionality such as wireless connectivity, barcode scanning, positive patient ID, remote operator management and quality assurance (QA) checking, are slightly less so. However, they are definitely hand portable. The criterion for a portable handheld device is, of course, arbitrary, but shoe-sized is not unreasonable (this is a personal view).
Evolution
The second evolutionary direction has been to take laboratory instruments and make them more compact and more suitable for use outside the laboratory environment. This initially started with blood gas analysers and has resulted in the current generation of equipment, which is auto-calibrating, has IT connectivity and all of the operator and QA checking capability discussed above. The functionality has been extended beyond blood gasses to a range of other analytes, including electrolytes and renal function. In an attempt to avoid some of the problems of inappropriate samples, single-use, cartridge-based systems have been developed. However, truly handheld systems based on traditional laboratory style instruments do not currently exist, although laboratory instruments suitable for POC whole blood analysis are available.(5,6) And, as every point-of-care coordinator will agree, every time a system is developed into the next generation to make it more operator-friendly and ‘idiot proof’, someone invents a ‘better idiot’.
A truly innovative approach
The only truly innovative approach to the situation of needing both a handheld instrument and the ability to measure a range of analytes across both the chemistry and blood gas range is the development of the i-STAT system.(7) This type of technology combines the concept of a handheld device with disposable cartridges for analyte measurement, conceptually like having disposable reagent strips. The i-STAT effectively provides a small portable laboratory, which has been used in a diverse range of different environments where portability is important. We have used this technology for monitoring sporting events, such as the London Marathon. A more common use is in the emergency department, to provide laboratory testing facilities for a rural environment, and its potential for use in disaster medicine.
Cardiac troponin measurement
The development of cardiac troponin measurement for the diagnosis and risk stratification of patients presenting with chest pain has presented further challenges to the ability to deliver POC-based testing solutions. The development of lateral flow and immunochromatographic techniques was the first serious step to developing compact handheld cardiac marker technology. A range of handheld, visually read devices were developed that measured a range of cardiac biomarkers, typically focusing on a combination of myoglobin, creatine kinase MB fraction (CK-MB)(8) and cardiac troponin, either cardiac troponin T (cTnT)(9,10) or cardiac troponin I (cTnI).
These were often referred to as ‘dipstick’ tests although this was inaccurate because they required the application of a small volume of whole blood from a transfer device. The analytical performance of these devices was considered comparable to that obtainable from laboratory measurements at the time. The reason for using a panel of markers was the perceived period of ‘troponin blindness’. This reflected the relative insensitivity of cardiac troponin measurements at this point in the evolution of cardiac troponin assays. The logic was that myoglobin and CK-MB would provide early diagnostic sensitivity whereas the troponin would provide diagnostic specificity. The technology utilised was gold labelled, optically read immunoassay (GLORIA). These devices were qualitative, providing an answer on biomarker presence or absence. An early prospective randomised, controlled, trial showed not only were these devices accurate but also that their use shortened length of stay.(11)
Experienced readers could give a semi-quantitative estimation of the degree of positivity by the time taken to become positive and intensity of colour and could estimate the degree of marker elevation.(12) However, quantitation was preferable and hand portable devices were developed that allowed accurate quantitation utilising the same GLORIA technology. These systems could be used for both diagnosis and risk stratification. In addition to optically read strips, methods that utilised fluorescence detection were also developed.(13) Immunoassay technology suitable for cartridge-based systems was also developed for the i-STAT and measurement of cTnI developed. Evaluation of the analytical and clinical performance of this system showed that results comparable to laboratory-based measurements could be produced and results were obtained much faster.(14)
Role of cardiac biomarkers
The role of cardiac biomarkers in the diagnosis and management of patients presenting with chest pain underwent a paradigm shift with the proposed redefinition of acute myocardial infarction with cTnT or cTnI as preferred biomarkers, and the inclusion of cTnT and cTnI in the guidelines for management of patients with suspected non-ST elevation myocardial infarction. The redefinition and subsequent universal definition of myocardial infarction stipulated that the 99th percentile of a reference population was the diagnostic discriminant, and also specified high-performance characteristics for the assays used. There was a requirement for a 10% CV below the 99th percentile. This requirement resulted in pressure on the diagnostic industry and produced a progressive improvement in the sensitivity of laboratory assays. When comparing modern generations of cTnT or cTnI to current POCT instrumentation for measurement of troponin, there is lower diagnostic sensitivity for the current POCT devices.(15)
Does this mean that current handheld POCT for much of cardiac biomarkers is redundant? No, but it does mean that users of technology need to be aware that there are limitations. Currently, POCT measurement of cardiac troponin with the majority of the devices on the market will not achieve the same degree of sensitivity as high-sensitivity, current generation, laboratory-based assays. However, POCT troponin assays can still be used for rapid ruling in acute myocardial infarction, for example for decisions on transporting patients to primary intervention sites or for immediate patient disposition. Failure to detect troponin by POCT means that either it is necessary to wait for a more sensitive laboratory result or to repeat the measurement. Providing the relative diagnostic sensitivity of the POCT troponin measurement compared with the central laboratory measurement is known, decision-making can be tempered according.
Future developments
Future developments in the POCT of cardiac biomarkers suggest that handheld technology is the preferred option and continued assay improvement will result in development of instrumentation and methods that will match laboratory high-sensitivity assays. The current gap between central laboratory troponin measurements and POCT will be closed again. We will then be back to where we were originally, that is, that POCT cardiac biomarker measurement has the potential for significant impact in clinical decision making but only when incorporated within an appropriate clinical decision-making protocol.
References
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- Ramhamadany EM et al. Reliability of the Ames Seralyser for creatine kinase measurement in the coronary care unit. Clin Chem 1988; 34(9):1914.
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- Antman EM et al. Time to positivity of a rapid bedside assay for cardiac-specific troponin T predicts prognosis in acute coronary syndromes: a Thrombolysis in Myocardial Infarction (TIMI) 11A substudy. J Am Coll Cardiol 1998;31(2):326–30.
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