Early diagnosis of acute myocardial infarction by bedside multimarker test at an emergency department in Hong Kong

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1 Hong Kong Journal of Emergency Medicine Early diagnosis of acute myocardial infarction by bedside multimarker test at an emergency department in Hong Kong CH Ho, W Cheng, G Chu, HF Ho Introduction: Cardiac biomarker measurement can aid diagnosis of acute myocardial infarction. The present study evaluates the efficacy and efficiency of point-of-care multimarkers measurement of myoglobin, creatine kinase (CK-MB) and troponin in identifying patients with acute myocardial infarction. Method: We prospectively enrolled consecutive patients (N=105) in the emergency department who were being evaluated for possible acute myocardial infarction. Point-of-care testing (POCT) of myoglobin, CK-MB and troponin I (TnI) was performed in all patients. Central laboratory measurement of troponin I was also performed simultaneously. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and receiver operating characteristic (ROC) curve were evaluated. Result: The specificity and positive likelihood ratio of TnI (POCT) and TnI (laboratory) were 98%, 13.0 and 98%, 21.8 respectively. The areas under curve of the ROC curve of TnI (POCT) and TnI (laboratory) were and respectively. Conclusion: A high positive likelihood ratio for acute myocardial infarction through point-of-care testing can help timely diagnosis and just-in-time appropriate management for patients presenting with chest pain. (Hong Kong j.emerg.med. 2010;17: ) MB N=105 MB I I I I 98% % 21.8 I I Keywords: Creatine kinase, myocardial infarction, myoglobin, point-of-care-systems, troponin Correspondence to: Ho Chung Hang, MBBS, MRCS(A&E) Queen Elizabeth Hospital, Accident and Emergency Department, 30, Gascoigne Road, Kowloon, Hong Kong chunghang1216@yahoo.com.hk Cheng Wendy, MBBS, FHKCEM, FHKAM (Emergency Medicine) Chu Gary, MBChB, FHKCEM, FHKAM (Emergency Medicine) Ho Hiu Fai, MBBS, FHKCEM, FHKAM (Emergency Medicine) Introduction Acute myocardial infarction (AMI) is a potential life threatening condition which can be difficult to diagnose in the emergency department. Diagnosis is mainly based on the clinical presentation, electrocardiogram (ECG) finding and elevated blood cardiac biomarkers. Two out of these three pillars are required for the diagnosis. 1

2 Ho et al./bedside multimarker test in myocardial infarction 143 For cardiac biomarker measurement, available point-ofcare testing (POCT) offers measurement of myoglobin, creatine kinase (CK-MB) and troponin I (TnI). As these biomarkers have different patterns of elevation after myocardial injury, the combination of these three cardiac markers has been reported to be associated with improved accuracy in AMI diagnosis. 2 Myoglobin, although not cardiac specific, gives high sensitivity for the detection of AMI within the first few hours after presentation. Myoglobin level starts to rise within 2-3 hours of AMI or other muscle injury, and generally falls back to normal within 24 hours after symptom onset. However, CK-MB and troponin will only be raised at 3-6 hours after symptom onset but will remain elevated for hours and 7-14 days respectively. The combination of these three biomarkers will thus enable us to identify AMI patients presenting at different time frames. Apart from aiding in the diagnosis of AMI, troponin level can also help to provide prognostic information. 3 There was a reported 50-70% reduction in death or recurrent AMI in troponin positive patients receiving low molecular weight heparin (LMWH) compared with those receiving aspirin alone. On the other hand, patients with negative troponin levels had no benefit from LMWH. 4 Point-of-care tests can provide rapid turn around times of about minutes. Previous studies in the western population showed that POCT can improve sensitivity and specificity in identifying patients suffering from AMI among those belonging to the high risk group. We aimed to speed up the time to diagnose AMI with a view to offer early intervention and to improve outcome. We also aimed at establishing a working guideline for applying point-of-care bedside cardiac biomarker tests to patients with a high risk of AMI who might benefit from immediate intervention. In this study, bedside POCT was employed to identify, in a timely manner, patients suffering from AMI among those belonging to the high risk group. Methods The study was approved by the Ethics Committee of Kowloon Central Cluster of the Hospital Authority. It was conducted from 1st November 2007 to 28th February 2009 in the Accident and Emergency Department of Queen Elizabeth Hospital. The inclusion and exclusion criteria are listed in Table 1. Informed written consent was obtained by the clinician. Blood specimens were obtained by clinicians, registered nurses or phlebotomists. The blood specimens were then sent to the biochemistry laboratory of the hospital for troponin I analysis and to the POCT station at bedside for the Triage Cardiac Panel tests (Biosite Diagnostics, San Diego, California, USA). Patients were then managed in the usual manner and would not be affected by the results of the pointof-care tests. All patients would then be admitted to the medical ward or coronary care unit. The results of the tests would be attached to the pro forma (Appendix 1) and collected. Clinicians caring for the subject patients were blinded to the results of the point-ofcare tests (Figure 1). The POCT was performed with 0.5 ml EDTA blood and a fluorescence immunoassay for simultaneous quantitative determination of myoglobin, CK-MB, and TnI. After the sample was added to the sample port, the cells were separated from the plasma via a filter. A predetermined quantity of plasma reacted with the fluorescent antibody conjugates within the reaction chamber. Complexes of the analytes and fluorescent antibody conjugates were then captured on discrete zones resulting in binding assays which were specific for each analyte. The concentration of the analyte was directly proportional to the fluorescence detected. Results were available in 15 minutes. The automatic Table 1. Inclusion and exclusion criteria Inclusion criteria Chinese patient Age 18 Chest pain likely acute coronary syndrome Exclusion criteria New onset ST elevation/left bundle branch block Recent acute myocardial infarction within two weeks Pregnancy Mentally unfit for consent

3 144 Hong Kong j. emerg. med. Vol. 17(2) Apr 2010 printout of the test results would be filed together with the pro forma. The pro forma were collected and evaluated. Demographic data including age, sex, length of stay, hospital discharge diagnosis as well as creatinine and troponin I levels from the central laboratory were sought through the Clinical Management System of the hospital computer. Together with the results generated from the POCT, all data were tabulated in Excel file and evaluated through SPSS version Diagnostic usefulness (sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio) and receiver operating characteristic (ROC) curves were evaluated. Results Between November 2007 and February 2009, there were totally 107 subjects recruited. Two of them were excluded. One was a non-chinese and the other died in the resuscitation room before written consent could be obtained. The mean age of the subjects was 71.2 (SD12.7) years old and 59% were males. The mean length of hospital stay was 6 days (range 1-36 days). The primary discharge diagnoses are listed in Table 2. Chest pain (including atypical chest pain) was the most frequent discharge diagnosis, and constituted 36.2% (38 out of 105 patients) of our subject cohort. The exact cause of chest pain in this group of patients was not determined. Positive cardiac events including acute coronary syndrome (ACS), acute myocardial infarction, Figure 1. The research protocol. Table 2. Distribution of diagnosis Diagnosis n % Chest pain Acute coronary syndrome Acute myocardial infarction Unstable angina Acute non-q-wave myocardial infarction Congestive heart failure Hypertension Pneumonia Non-ST elevation myocardial infarction Fluid overload Dizziness Ischaemic heart disease Atypical chest pain Acute pulmonary oedema, chest pain Atrial fibrillation, chest pain Atrial fibrillation Dissecting thoracic aortic aneurysm Syncope Common bile duct stone Menorrhagia Total

4 Ho et al./bedside multimarker test in myocardial infarction 145 acute non-q wave myocardial infarction, non-st elevation myocardial infarction (NSTEMI) and unstable angina constituted 43.8% (46 out of 105 patients). Using cut-off values of 107 ng/ml (myoglobin), 4.3 ng/ml (CK-MB), 0.4 ng/ml (TnI [POCT]) and 0.3 ng/ml (TnI [laboratory]) respectively, the diagnostic usefulness of the biomarkers was calculated (Table 3). Myoglobin had the highest sensitivity for acute myocardial infarction (57%), while those of CK-MB, TnI (POCT) and TnI (laboratory) were 48%, 26% and 37% respectively. There was no statistically significant difference between the sensitivity of TnI (POCT) and TnI (laboratory) by using proportional difference test. Both TnI (POCT) and TnI (laboratory) had high specificity (98%), and the positive likelihood ratios of TnI (POCT) and TnI (laboratory) were 13.0 and 21.8 respectively. Receiver operating characteristic (ROC) curves of all the biomarkers are listed in Figure 2. The area under curve (AUC) of myoglobin was (p=0.000), AUC of CK-MB was (p=0.033), AUC of TnI (POCT) was (p=0.001) and that of TnI (laboratory) was (p=0.000). Discussion It is always a challenge for the emergency physician to make a rapid and accurate diagnosis of AMI. Frequently, the history and physical examination are nonspecific and the ECG is only diagnostic in around 50% of cases. Thus an elevation of cardiac biomarker can be useful for diagnostic purpose. 2 However, the turn around time for results from the central laborary can take as long as 1-2 hours. Since early diagnosis and management can significantly improve the outcome of patients with AMI, the importance of a fast and accurate cardiac biomarker test is therefore crucial. 2 As already demonstrated in many recent studies, cardiac biomarkers are one cornerstone in the evaluation and selection of target therapy for AMI patients. Multiple studies have shown that patients with an elevated troponin level are at increased risk of AMI. There is a direct relationship between the raised troponin level and subsequent mortality. 3 Troponin is now recognised as the preferred cardiac biomarker for the diagnosis of AMI, among consensus documents on the management of unstable angina and non-st segment elevation myocardial infarction. 5 Point-of-care testing offers a quicker turn around time than the conventional laboratory. The turn around time of our point-of-care machine is about 15 minutes whereas the turn around time for troponin I in our central biochemistry laboratory is about 1-2 hours. A quicker turn around time will definitely speed up the diagnosis. A specificity of 98% and a positive likelihood ratio of 13 in TnI (POCT) make it especially useful in ruling in the disease and aid in timely management of acute myocardial infarction. Patients attending the emergency department complaining of chest pain were heterogeneous. In our study, we had selected those chest pain patients with high clinical suspicion of cardiac origin. Of this cohort, 43.8% had 'cardiac event' (i.e. AMI, ACS, unstable angina, NSTEMI). This diagnostic tool facilitates clinicians to gain confidence in making the diagnosis of AMI, especially when the ECG is not diagnostic (such as in cases of unstable angina, NSTEMI) or nonspecific (T-wave inversion) or in circumstances when history is difficult to obtain such as in elderly patients. Clinicians could provide treatment (e.g. MONA - Table 3. Diagnostic usefulness of biomarkers (N=105) Sensitivity Specificity PPV NPV Positive LR Negative LR Myoglobin CK-MB TnI (POCT) TnI (Lab) CK-MB=creatine kinase-mb, Lab=laboratory, LR=likelihood ratio, NPV=negative predictive value, POCT=point-of-care testing, PPV=positive predictive value

5 146 Hong Kong j. emerg. med. Vol. 17(2) Apr 2010 morphine, oxygen, nitrate and aspirin) while waiting for the result of the POCT. Specific treatment such as early clopidogrel or low molecular weight heparin can follow when POCT results are available. Reperfusion strategy can be sped up with potential benefit in myocardial salvage. One potential improvement in this study is to correlate the level of cardiac markers with the time of onset of symptoms. In this study, the onset of symptoms was not included. Further studies will be required. There was one potential false-positive case of the TnI (POCT). (Figure 3) Myocarditis induced by herbs was suspected. However, the patient died with no autopsy confirmation. In conclusion, point of care testing yields high positive likelihood ratio in the selected group of patients with high probability of cardiac chest pain and provides results in a timely manner for the initiation of specific treatment. a. Under nonparametric assumption b. Null hypothesis: true area=0.5 CK-MB=creatine kinase-mb, POCT=point-of-care testing Figure 2. Receiver operating characteristic (ROC) curve of different cardiac enzymes.

6 Ho et al./bedside multimarker test in myocardial infarction 147 Figure 3. Flow chart of patients undergoing point-of-care testing. Acknowledgement The test cartridges were supplied by Biosite Diagnostics, San Diego, California, USA. References 1. Karlson BW, Herlitz J, Wiklund O, Richter A. Hjalmarson A. Early prediction of acute myocardial infarction from clinical history, examination and electrocardiogram in the emergency room. Am J Cardiol 1991;68(2): Newby LK, Storrow AB, Gibler WB, Garvey JL, Tucker JF, Kaplan AL, et al. Bedside multimarker testing for risk stratification in chest pain units: the Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I (CHECKMATE) Study. Circulation 2001; 103(14): Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335(18): Morrow DA, AntmanEM, Tanasijevic M, Rifai N, de Lemos JA, McCabe CH, et al. Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI-IIB substudy. J Am Coll Cardiol 2000;36(6): Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-st segment elevation myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2000;102(10): Erratum in: Circulation 2000;102(14):1739.

7 148 Hong Kong j. emerg. med. Vol. 17(2) Apr 2010 Appendix 1. Pro forma for point-of-care cardiac enzymes study

Most patients ( 85%) who present to an emergency department

Most patients ( 85%) who present to an emergency department Ninety-Minute Exclusion of Acute Myocardial Infarction By Use of Quantitative Point-of-Care Testing of Myoglobin and Troponin I James McCord, MD; Richard M. Nowak, MD, MBA; Peter A. McCullough, MD, MPH;