The association between Point-of-Care testing of Troponin and the management of patients with chest pain suspected of acute coronary syndrome: a systematic review protocol

Review question/objective The objective of this review is to investigate the association between Point-of-Care testing of Troponin (PoCT-cTn) and the management of chest pain patients suspected of Acute Coronary Syndrome (ACS), including timely diagnosis and triage, time to percutaneous coronary intervention (PCI) or fibrinolysis, and length of stay in the Emergency Department (ED). Background Cardiovascular diseases are defined by the World Health Organisation (WHO) as ‘a group of disorders of the heart and blood vessels’, which include coronary heart disease (acute coronary syndrome),cerebrovascular disease (stroke), peripheral arterial disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis and pulmonary embolism.1 Acute coronary syndrome (ACS) is caused by athero-thrombotic lesions of heart that are associated with a thrombus formation on a ruptured atherosclerotic plaque, leading to a reduction in the supply of oxygen and nutrients to the heart muscle and impairing cardiac functions, presenting acute myocardial infarction (AMI).2 ACS reflects the spectrum of coronary artery disease (CAD) resulting in acute myocardial ischemia and includes unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI).3 They can be distinguished as per their definitions defined by the Global Registry of Acute Coronary Events (GRACE) (Table 1).4Table 1: Definitions of the spectrum of acute coronary syndromeClinically these diagnoses encompass a wide variation in risk, requiring complex and timely risk stratification and representing a large social and economic burden. According to the World Health Organization, ACS claims 17 million lives every year.5 It has been and will continue to be the single leading cause of death. Typical symptoms of acute ACS/MI include, but are not limited to, sudden retrosternal chest pain (usually radiating to the left arm, left side of the neck, or abdomen) with shortness of breath,nausea, vomiting,palpitations, sweating, anxiety and sudden death, with no precursor signs.6 However, a sizeable proportion of myocardial infarctions (22-64%) are 'silent’, that is without chest pain or other symptoms.7 This has brought challenges to the diagnostic issues of AMI. Typically, the electrocardiogram (ECG) provides unique and important diagnostic information to distinguish STEMI and NSTEMI acute coronary syndromes. In the spectrum of ACS, UA/NSTEMI usually presents by chest pain, ECG with no ST-segment elevation but ST-segment depression or prominent T-wave inversion and/or positive biomarkers of necrosis (e.g. troponin).8 However, hyperacute T wave change on ECG may mislead diagnosis due to non-cardiac causes (e.g. hyperkalaemia, renal failure).9 If the patient has chest pain without ST-segment elevation on the ECG, the measurement of cardiac Troponin (cTn) becomes the cornerstone of ACS diagnosis.10 Introduction of point-of-care testing of Troponin Only two thirds of chest pain patients (66%) presented to hospitals, responsible for emergency hospital admissions, and the main reason for hospital attendance could be the possibility of acute myocardial infarction (AMI).12 Among the chest pain patients, half of presentations (46%) had chest pain with unlikely ischemic chest pain or ACS, but one third of them (33%) experienced MI, and one fifth (21%) of them had unstable angina or likely ischemic chest pain.12 To distinguish different spectrums of ACSs and non-cardiac cases and to do appropriate risk stratification and triage, current guidelines of ACS require a troponin sample taken on arrival or at least 6 hours after the onset of chest pain.13 Troponin is a complex of three regulatory proteins (Troponin C, Troponin I and Troponin T) that is integral tomuscle contraction inskeletal andcardiac muscles, but not in smooth muscles.14 Troponin C has identical form in skeletal muscles, therefore, it has not been used as a cardiac marker of myocardial ischaemia.9 Troponin I (cTn I) and Troponin T (cTn T) have been the focus of studies to determine diagnostic values in detecting cardiac injury or infarction since the late 1980s.15,16 They are very sensitive and specific indicators of damage to the myocardium. When heart damage has occurred, the proteins are released into the blood stream and can be measured in a blood sample, especially when having ‘heart attack’.17 Previously, Creatinine Kinase (CK) was preferred for diagnosis of ACS.18 In the past decade, cardiac Troponin (cTn) has emerged as a preferred choice over CK for the diagnostic need of ACS/AMI in chest pain patients. Cardio-specific enzyme Troponin I and Troponin T are not detectable in healthy people. Any elevation in cTn levels indicates some degree of myocardial necrosis. Therefore, cTn has become a gold standard cardiac marker (CM) of MI due to its high diagnostic specificity and prognostic value in the clinical setting.18,19 However, cTn is time dependent and needs to be detected within a few hours of chest pain onset. Point-of-Care testing of Troponin (PoCT-cTn) is a rapid test and practical in clinical settings. Point-of-Care Testing (PoCT) is defined as testing conducted at or near the site of patient care, allowing blood samples to be processed immediately.20 Point-of-Care testing of Troponin refers to PoCT for a rapid assay for cTn values, via doing finger pricks and testing on portable platforms. It can provide rapid results of cTn with turnaround times as short as 15-30 minutes in comparison with laboratory testing needing 60-90 minutes.21 PoCT-cTn can significantly reduce the turnaround time from testing to results, allowing more immediate patient triage and effective management.21 Evidence based management of ACS The American College of Cardiology (ACC) states that the cTn result should be available within 60 minutes of presentation and preferably within 30 minutes.22 PoCT-cTn has been highly recommended and subsequently included in ACS guidelines, specifically where the timely management of the condition is the focus. It is important for NSTEMI patients presenting with chest pain, who should be diagnosed and assigned to a risk group as rapidly as possible.23 Relevant guidelines include the guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA),24 the European Society of Cardiology's guidelines,23,25 the Guidelines for the management of ACS generated in 2006 by the National Heart Foundation of Australia (NHFA) and the Cardiac Society of Australia and New Zealand (CCANZ),18 and its Addendum enacted in 2011.13 According to the above evidence, chest pain patients who are suspected of ACS should have a comprehensive initial assessment to screen the risk of ACS, including collecting a medical history, performing a physical examination and recording risk factors. Initial management includes a 12 lead ECG and Troponin testing. If ECG presents ST segment elevation ≥1mm (STEMI) with or without Troponin changes, the patient is managed by the high risk pathway. However, if the patient's ECG is negative (NSTEMI), then Troponin values are significant to classify patients. If cTn is positive (above the 99th percentile or > 20% rise/fall of baseline by high sensitivity testing), MI is likely to be diagnosed and the patient will be managed with the moderate risk/high risk pathway, seeking cardiac consultation and further investigation. If a negative result is present, ACS is unlikely and treatment may proceed to early ‘rule-out’ CAD testing (e.g. stress ECG).13 Otherwise, the patient will be classified as low risk, and if there is no ongoing chest pain and hospitalization is not required, the patient can be discharged home.8, 26, 27 The national guidelines of ACS of Australia require that every chest pain patient suspected of ACS should perform cTn testing (high sensitivity) on arrival to the ED to ‘rule in’ ACS within the differential diagnosis in cTn level.13 In order to promptly rule in or rule out the risk of ACS, PoCT-cTn should be implemented if the high sensitivity cTn result is not available within 60 minutes. Although PoCT-cTn is not based on the new high sensitivity testing, it should be used to ensure timely risk assessment when likely substantial delay in cTn assays will occur.13 The thresholds of positive cTn values were reduced with technical development on the cTn assays. They were 1.5ng/ml defined in 1995, changed to1.0ng/ml in 2004 and further decreased to 0.04ng/ml since 2007.28 The positive value of acceptable accuracy for the diagnosis of AMI was defined as >99th percentile (equal to 0.04 mg/L), either doing serial specimens at least three hours apart or one specimen at least six hours from the onset of symptoms,29 which is sufficient to provide high accuracy for ruling out MI.13 If no high sensitivity testing is available, the diagnosis of MI requires both an elevation of troponin levels above the 99th percentile and a >20% change (rise and/or fall) when using older troponin assays, informed by recent consensus guidelines.30-32 The effects of PoCT-cTn Point-of-care testing of Troponin is usually performed at the bedside by ED staff. The best use of the result of Point-of-Care testing depends on clinicians who are prepared to act on the test results immediately.33 Optimal outcomes in chest pain patients rely on rapid diagnosis, accurate risk stratification and the effective implementation of evidence-based therapies, as advocated by clinical guidelines. This goal is reachable but the challenge is in effectively applying evidence in clinical practice and in understanding the evidence-practice gap that is objective and needs standardized quantification of clinical practice. It has been verified that PoCT-cTn rapidly provides a blood test of the Cardiac Enzyme of Troponin (cTn), being the gold standard of diagnosing ACS.18,19 It can be used to rule out and rule in ACS, thereby facilitating effective treatment of ACS patients.13 In a report from South Australia, PoCT-cTn benefited rural and remote areas where they did not have an on-site laboratory, and had to wait up to 36 hours to receive pathology results.34 PoCT-cTn was identified as a critical enabler for improving patient management in rural and remote areas.34 Conversely, the negative reports were found on the utilization of PoCT-cTn. Five studies opposed the utilization of PoCT-cTn in the ED and cardiac short-stay units.35-39 Two studies opposed the application of PoCT-cTn in the pre-hospital setting,40,41 and one opposed the utilization of PoCT-cTn in the outpatient clinic setting.42 In a large study performed by Takakuwa et al., on Point-of-care testing in ED patients suspected of ACS showed that of 568 hospitals and of 67,058 patients, differences existed in how hospitals utilized PoCT-cTn and the resultant intervention provided. High PoCT-cTn usage hospitals were less likely to give aspirin, β-blockers and heparin within the first 24 hours of admission. Patients with positive PoCT-cTn had fewer electrocardiograms within 10 minutes, but were more likely to be administered aspirin, β-blockers, glycoprotein IIb/IIIa inhibitors and heparin within 24 hours of arrival. They received fewer in-hospital and interventional procedures and had more adverse clinical events. This study showed negative outcomes of PoCT-cTn technology in triage and risk stratification of chest pain patients.43 In general, PoCT-cTn has been advocated by the guidelines for ACS and some studies have informed positive outcomes in clinical practice from its utilization. Within the literature, negative findings were also reported, yet there is no systematic review looking into whether PoCT-cTn improves the evidence-based practice (EBP) of chest pain patients suspected of ACS either in tertiary hospitals or country hospitals. Therefore, this review will be performed to pool evidence regarding the effect of PoCT-cTn on chest pain patients, determining the association of PoCT-cTn and the management of chest pain suspected ACS patients, focusing on timely diagnosis and triage, time to percutaneous coronary intervention (PCI) or fibrinolysis and length of stay in the ED.