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Cardiac biomarkers and point-of-care testing

Paul Collinson
28 May, 2013  
Point-of-care testing has the potential to reduce admission rates, associated bed use and hospital costs for patients presenting with acute chest pain
 
Paul Collinson MA MB Bchir FRCPath MD
Consultant Chemical Pathologist and Professor of Cardiovascular Biomarkers
Departments of Clinical Blood Sciences and Cardiology
St George’s Hospital, London, UK
 
Chest pain is one of the most common presentations to the emergency department (ED), accounting for approximately 7000 (6%) of ED attendances and 4500 (27%) acute medical admissions annually at a typical hospital.(1) It is also one of the most difficult clinical conditions to diagnose reliably. An audit of 110 chest pain attendances found that 7% of patients who have been discharged had significant myocardial injury and had been inappropriately sent home.(2)
 
Conversely, approximately 42% of patients presenting with chest pain do not have cardiac disease or other medical conditions.(1) The challenge for the emergency physician is to rapidly rule in or rule out acute coronary syndromes (ACS) as the cause of chest pain. Patients with ACS require hospital admission with appropriate management. Patients without ACS require exclusion of ischaemic heart disease then discharge or medical management as appropriate. The challenge is to perform these tasks both rapidly and accurately.
 
Assessment
The assessment of patients presenting with chest pain has three components: clinical assessment; the electrocardiogram (ECG); and measurement of cardiac biomarkers. The role of clinical assessment is to determine if the patient has significant symptoms of or risk factors for coronary disease. It is also to exclude any alternative causes of chest pain. These may vary from the obvious, such as a penetrating chest wound, to more subtle, such as an underlying chest infection or pulmonary embolus. The ECG is an essential management tool.
 
Identification of the classic ECG finding for acute myocardial infarction (AMI), ST segment elevation, identifies a patient group where immediate revascularisation is life saving. A proportion of patients will have non-specific, but suspicious, features on their ECG, such as ST segment depression or T wave inversion. The majority of patients do not show ECG abnormalities that are diagnostic or indicative of underlying ischaemic heart disease. The combination of clinical assessment and initial ECG allows categorisation into low-, medium- or high-risk groups. Measurement of cardiac biomarkers is the key diagnostic test to confirm or exclude an acute myocardial injury and confirm the diagnosis of AMI.
 
Cardiac biomarkers
Traditionally, the cardiac biomarkers used were enzymes released from cardiac muscle following cell death in myocardial infarction. Examples include creatine kinase and its MB isoenzyme (CK-MB) and historically lactate dehydrogenase and aspartate transaminase. These have now been replaced by the measurement of components of the cardiac contractile apparatus, specifically proteins of the troponin–tropomyosin complex, the cardiac troponins, cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Measurement of these cardiac biomarkers is more sensitive, specific and prognostic than measurement of CK and CK-MB.
 
Release of cTnT or cTnI into the circulation where they can be measured in the blood is diagnostic of myocardial injury. The primacy of cardiac troponin measurement has been recognised by redefinition of AMI in the new universal definition of myocardial infarction.(3) This redefinition includes cardiac troponin elevation as one of the diagnostic criteria. The measurement of cardiac troponin renders the measurement of other cardiac biomarkers unnecessary. Early studies suggested that the optimal time to measure cardiac troponin was 10–12 hours from hospital presentation and this recommendation was incorporated into initial clinical guidelines. More recent evidence recommended that six-to-nine hours from presentation could be used.(4) The development of progressively more sensitive methods of troponin measurement has suggested that a much shorter interval, three-to-six hours from presentation, can be used.(5)
 
It has been recommended that the time taken from initial blood sampling to result availability to the clinician, usually referred to as turnaround time (TAT), should be as short as possible and typically less than 60 minutes. The premise is that the more rapidly a result is available, the more quickly it may be acted upon. When hospital protocols required a 12-hour stay before ruling out AMI, TAT was less significant in the timing of clinical decision-making. The use of more rapid protocols to rule out AMI within three-to-six hours of first hospital presentation means that the time taken for troponin measurement becomes a much more significant percentage of the total decision-making time. It is therefore an attractive option to use technological solutions to shorten the time taken for analysis. This can be done by utilising analytical methods that can be used at the point of care, that is, point-of-care testing (POCT).
 
POCT offers a number of advantages that will reduce TAT. Samples are measured in close proximity to the patient so do not have to be taken to the laboratory (which may cause a significant delay). The methods use whole blood, so samples do not require laboratory pre-processing before analysis. Finally, results are immediately available to the healthcare practitioner without having to be obtained elsewhere. 
 
POCT and cardiac markers
POCT for cardiac markers has been available in various forms since the 1980s but available technology to measure cardiac troponin is more recent. Currently, some of the available POCT systems are as good as contemporary laboratory methods for cardiac troponin measurement but none are as good as the new generation of high-sensitivity laboratory assays for cardiac troponin. The role of POCT cardiac marker testing in the management of patients presenting with chest pain has been examined in a number of studies, most comprehensively in a prospective multicentre randomised controlled trial: the Randomised Assessment Of Panel Assay Of Cardiac Markers (RATPAC) trial.(6,7)
 
RATPAC and ASPECT 
The RATPAC trial (ISRCTN378239293) randomised low-risk patients 18 years or older presenting with acute chest pain to ED of six participating hospitals to either diagnostic assessment where a cardiac panel, including cTnI, was measured by POCT on admission and at 90 minutes from admission, or to diagnosis when biomarker measurement was based on central laboratory testing (CLT). Only low-risk patients were enrolled. Exclusion criteria included ECG changes for myocardial infarction or high-risk acute coronary syndrome, known coronary heart disease presenting with prolonged (>one hour) or recurrent episodes of cardiac-type pain, proven or suspected serious non-coronary pathology (pulmonary embolus) or an obvious non-cardiac cause (pneumothorax or muscular pain).
 
A total of 2263 participants were recruited, of which 1132 were randomised to POCT and 1131 to central laboratory testing. The principal finding of the study was a significant reduction in the length of stay in the ED. There was no significant difference in the rate of major adverse events measured at three months follow up from first presentation to the ED between the POCT arm and conventional management. Hence, the study showed that a rapid diagnostic protocol was safe and effective in a low-risk patient population.
 
Similar findings for safety and efficacy were demonstrated in a large multicentre prospective observational study, the ASia-Pacific Evaluation of Chest pain Trial (ASPECT), using a rapid rule-out protocol including biochemical testing on ED admission and two hours from admission.(8) There is therefore strong evidence that POCT can be used to shorten length of stay and potentially reduce hospital admissions. In a secondary study of the RATPAC data, it was demonstrated that measurement of cardiac troponin alone was sufficient for diagnosis,(9) a finding also confirmed by the ASPECT study.(8)
 
It is important to review these studies in context. The first consideration is the patient population undergoing evaluation. Rapid protocols involving the measurement of cardiac troponin are not useful in patients presenting with characteristic ECG changes, typically 8% of hospital admissions with chest pain.(10) In such patients, the role of cardiac troponin is for retrospective confirmation of the diagnosis.
 
Patients considered likely to be at high risk because of dynamic ECG changes or significant risk factors for heart disease (approximately 20% of admissions) require a more intensive investigation regime. It is only the low-risk patients who are suitable for rapid rule out protocols. Fortunately, this is a significant proportion (40–70%)of those who attend the ED with chest pain or are admitted.(9,10) The second, and probably the most important, consideration is the process flow within the chest pain evaluation pathway. An analysis of the data from the RATPAC study showed marked differences within the individual sites with some showing no reduction in length of stay and others a very marked reduction.(11)
 
This was entirely attributable to the pathway within the emergency department. In a previous randomised controlled trial set on the coronary care unit, only those with a pre-specified decision based on cTnT measurement had a significantly reduced length of stay.(12) Other studies have demonstrated that POCT cardiac marker measurement can reduce length of stay but both specifically commented that the impact was critically dependent on the ED process and pathway.(13,14) Indeed, in the multicentre American study, the specific conclusions were: “The effect of POCT on length of stay in the ED varies between settings. At one site, POCT decreased time to admission, whereas at another, POCT increased time to discharge. Potential effects of point-of-care testing on patient throughput should be considered in the full context of ED operations.”(14)
 
Finally, overall cost-effectiveness needs to be assessed. In the RATPAC trial, overall costs were higher in the POCT arm but there was considerable variation between hospital sites. The increase in cost was associated with more appropriate admission to the CCU and a lower rate of missed myocardial infarction. However, the costings will be influenced heavily by the health systems in which they operate.
 
Conclusions
In conclusion, POCT measurement of cardiac troponin has the potential to significantly reduce length of stay in the ED but only within the context of an integrated clinical pathway that is audited and adhered to.
 
References
  1. Goodacre S et al. The health care burden of acute chest pain. Heart 2005;91:229–30.
  2. Collinson PO, Premachandram S, Hashemi K. Prospective audit of incidence of prognostically important myocardial damage in patients discharged from emergency department. BMJ 2000;320:1702–5.
  3. Thygesen K et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33, 2551–67.
  4. Bassand JP et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 2007;28:1598–660.
  5. Hamm CW et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054.
  6. Goodacre S et al. The RATPAC (Randomised Assessment of Treatment using Panel Assay of Cardiac markers) trial: a randomised controlled trial of point-of-care cardiac markers in the emergency department. Health Technol Assess 2011;15:iii-102.
  7. Goodacre SW et al. The Randomised Assessment of Treatment using Panel Assay of Cardiac Markers (RATPAC) trial: a randomised controlled trial of point-of-care cardiac markers in the emergency department. Heart 2011;97:190-6.
  8. Than M et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet 2011;377:1077-84.
  9. Collinson P et al. Very early diagnosis of chest pain by point-of-care testing: comparison of the diagnostic efficiency of a panel of cardiac biomarkers compared with troponin measurement alone in the RATPAC trial. Heart 2012;98:312–8.
  10. Collinson PO et al. Impact of European Society of Cardiology/American College of Cardiology guidelines on diagnostic classification of patients with suspected acute coronary syndromes. Ann Clin Biochem 2003;40:156-60.
  11. Bradburn M et al. Interhospital variation in the RATPAC Trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers). Emerg Med J 2012;29:233–8.
  12. Collinson PO et al. A prospective randomized controlled trial of point-of-care testing on the coronary care unit. Ann Clin Bioche. 2004;41:397–404.
  13. Loten C et al. Point of care troponin decreases time in the emergency department for patients with possible acute coronary syndrome: a randomised controlled trial. Emerg Med J 2010;27:94–8.
  14. Ryan RJ et al. A multicenter randomized controlled trial comparing central laboratory and point-of-care cardiac marker testing strategies: the Disposition Impacted by Serial Point of Care Markers in Acute Coronary Syndromes (DISPO-ACS) trial. Ann Emerg Med 2009;53:321–8.