Is point-of-care triple cardiac marker testing reliable enough to exclude acute coronary syndromes?

Conditions & Diseases: Coronary Syndrome
By Ratna Merugumalla
Posted on October 10,2018

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The NHS Institute for Innovation and Improvement has ranked chest pain as the number one clinical scenario by volume of admissions with potential for outpatient management, estimating that 30-60% of patients admitted with chest pain could be treated outside the hospital.1

Each year 700,0002 people attend emergency departments (EDs) in England and Wales with chest pain. The majority of these patients are admitted to either acute medical or coronary care units for observation and a laboratory troponin assay 6-12 hours from time of symptom onset. 

Ultimately, 75-85% of patients evaluated for an acute coronary syndrome (ACS) do not have this as a final diagnosis5-7. Despite best efforts, 2-5% of patients evaluated for an ACS are erroneously sent home from the ED3 resulting in avoidable adverse cardiac events. 

ED physicians currently diagnose ACS and evaluate risk for adverse outcomes based on history, physical examination, 12-lead ECG, scoring systems such as The Global Registry of Acute Coronary Events9 (GRACE) and Thrombolysis in Myocardial Infarction10 (TIMI) and laboratory troponin estimation. 

Patients deemed high risk for an ACS are invariably admitted for further management but patients in the low risk category could be suitable for early discharge. 

Point-of-care (PoC) testing with triple cardiac markers (TCM) has the potential to assist clinicians in defining rapid care pathways to safely discharge low risk patients with minimal adverse event rate.

A perfect PoC cardiac marker test would reduce the number of adverse cardiac events in a defined time period to zero or have a high specificity and negative predictive value (NPV) index. 

PoC assays for cardiac markers – myoglobin, creatine kinase-MB (CK-MB), and cardiac troponins I (cTnI) and T (cTnT) are commercially available for clinical use.


Aim

The aim of this review is to ascertain whether point-of-care triple cardiac markers can be used to safely discharge low risk patients evaluated for suspected acute coronary syndromes.


Reason for Topic Choice:

A fifty-two year old man attended the ED with atypical chest pain which lasted for 25 minutes and had occurred 3 hours prior to presentation. He had never experienced similar complaints previously, had no past medical illnesses, and was pain free at the time of examination. He was a non-smoker and did not have a family history for ischaemic heart disease. Two ECGs (one pre-hospital and one in the department) were normal. When I told the patient that I planned to admit him for 12-hour troponin estimation, he asked me if there was a test that could be done earlier.  I wondered if PoC testing with TCM could be reliably used to safely discharge such patients. 


Three Part Question:

[In adult patients with low risk cardiac chest pain], [can point-of-care triple cardiac marker testing be used] to [safely discharge patients]?

Physiology of cardiac markers:

Myoglobin, CK-MB, and cTn are proteins released into the bloodstream after cardiac injury and are markers of myocardial necrosis with unique release characteristics and kinetics.4 cTnI is part of a three subunit complex comprised of troponin T and C. The release pattern of cTn is similar to CK-MB, but while CK-MB levels return to normal after 72 hours, cTn remains elevated for 6-10 days, thus providing a longer window of detection for cardiac injury. 


Appears Peaks Disappears

Myoglobin11,12 2 – 8 hours 9 – 12 hours 24 – 36 hours

CK-MB13 3 – 8 hours 9 – 30 hours 48 – 72 hours

Troponin14 4 – 6 hours 12 – 24 hours 6 – 10 days

Table 1: Triple cardiac marker release kinetics


Combined measurement of myoglobin, CK-MB, and cTn as a cardiac panel is a way of combining early and later markers. 

It is worth remembering that ischaemic process in an ACS can occur prior to actual necrosis and plaque instability or inflammation. In such a situation, markers of necrosis may not be elevated. 


Figure 1: Triple cardiac marker characteristics


Search summary:

Search Terms used: 

(acute coronary syndrome*).ti,ab; OR "unstable angina".ti,ab OR "myocardial infarction" .ti,ab

AND "point of care".ti,ab 

AND  "triple cardiac".ti,ab or troponin.ti,ab or "creatine kinase mb".ti,ab or myoglobin.ti,ab

AND (safe* and discharge*).ti,ab


A literature search was performed using the following databases: (Appendix 3)

Medline 1950 - present

Embase 1980 - present

CINAHL 1981 – present

Cochrane Library

ClinicalTrials.gov

Google Scholar

Additionally, a hand search of references from articles found and a grey literature search were also conducted.

Inclusion Criteria

Patients aged =18y

English Language

Major adverse cardiac events

Negative Predictive Value, Specificity

Triple cardiac markers – myoglobin, 

CK-MB, Troponin I & T Exclusion Criteria

Animal Studies


Goodacre et al,15 Randomised Assessment of Treatment Using Panel Assay of Cardiac markers (RATPAC) trial – QUADAS 7

This pragmatic multicentre randomised controlled trial (RCT) was conducted in six acute hospitals in the United Kingdom (UK). Its aim was to determine if PoC testing with TCMs would increase the rate of successful discharge after assessment for suspected ACS and having no major adverse cardiac events (MACE) during the following 3 months.

Successful discharge was defined as having left hospital or awaiting transport home by 4h after ED attendance. MACE included death, non-fatal myocardial infarction (MI), emergency revascularisation, life-threatening arrhythmia or hospitalisation for myocardial ischaemia. 

Patients were randomly allocated to receiving either PoC TCM or standard assay using either cTnT measured at 6 hours or cTnI at 12 hours after worst symptom. PoC TCMs were measured at baseline and 90 min.

Patients were excluded if they had ECG changes >1 mm ST deviation or >3 mm T wave inversion, were to known to have coronary heart disease (CHD), prolonged (>1h) or recurrent episodes of cardiac-type pain, non-coronary pathology, co-morbidity or social problems that require hospital admission, significant pain duration >12h, previous participants, those unable to understand the trial information, and those unwilling to consent.

2263 patients were recruited to the trial. 1132 were allocated to PoC arm and 1131 to standard care arm of the study group. It was concluded that PoC testing was associated with an increased rate of successful discharge 358/1125 (32%) vs. 146/1118 (13%); (OR 3.81, 95% CI 3.01 to 4.82; p<0.001).

Of the 362 patients discharged from the PoC group, 4 re-attended with a MACE. Of the 147 patients discharged from the standard care group, 1 re-attended with a MACE. Overall MACE rate was reported as 36 (3%) vs. 26 (2%); (OR 1.31, 95% CI 0.78 to 2.20; p=0.313) suggesting that there was no significant difference in MACE rates within three months in the PoC group compared to patients managed conventionally. 

Study strengths include good randomisation (computer generated sequence and stratified) and concealed allocation with low rate of withdrawals before primary outcome. Being a multi-centre trial it included diverse hospital population making the results generalisable. 

Assay parameters were changed during the trial when a switch to a different cardiac panel was made thereby potentially altering data interpretation. The trial was initially powered for 3130 patients but terminated after recruiting 2263 patients due to funding issues. 3130 participant sample size was powered to detect a MACE reduction from 4-2%. 


Rathore et al,16 QUADAS 5 

This study aimed to determine if low to intermediate risk chest pain patients evaluated for an ACS can be safely discharged using TCM strategy. They conducted a single centre, retrospective analysis on patient test results and followed them prospectively for six months for future coronary events and hospital admissions.

325 patients aged >18 years who presented with low to intermediate risk cardiac sounding chest pain were included in the study. Patients were excluded if initial ECGs were abnormal. Paired cardiac markers (at 0 and 120 min) were negative in 100 patients and they were discharged home. 1 patient in this group re-attended with an ACS. No deaths were reported in six months. 36 (11%) patients had single cardiac marker tests and discharged home with a re-attendance rate with an ACS of 3%. Subgroup analysis showed a sensitivity and specificity of 85.7% and 96.5% respectively. The authors concluded that one-third of patients with low to intermediate risk for an ACS can be safely discharged from the ED following paired negative TCM testing.

Conducted in the UK, this study included a participant spectrum that is representative of a population that is similar to our patients. Although they described their selection criteria well, it was a retrospective analysis of data with prospective patient follow-up. A sample size of 325 patients is a small number and without a power calculation, is presumably underpowered to answer the clinical question. It is unclear from the analysis of results if all data had been studied and reported. The authors state that of the 325 patients, 110 had positive paired TCM and 100 had negative results. Of the 100 who were discharged home with a negative result, 30 had returned and were admitted for subsequent 12-hour laboratory cTn estimation. It would have been interesting to know how many patients were then tested positive by laboratory cTn analysis. 36 patients were discharged with a single negative triple cardiac marker and 49 patients were admitted after one negative triple cardiac marker test. 

Although the authors claim to have a high sensitivity and specificity index for TCM, it is difficult to share their enthusiasm given the fact that there is a large discrepancy in the manner in which results have been reported.

Than et al, 8 Asia-Pacific Evaluation of Chest Pain Trial (ASPECT) QUADAS 8

This trial evaluated the use of a predefined accelerated diagnostic pathway (ADP) incorporating TIMI score, serial 0-2h cardiac biomarker testing and 12-lead ECG evaluation to identify low risk chest pain patients for early discharge. This observational study was conducted in 14 EDs in nine countries in the Asia-Pacific region in patients aged = 18 years with at least 5 minutes of chest pain. Patients were excluded if they had an ST Elevation Myocardial Infarction (STEMI), chest pain not due to ACS, had terminal illness, refused to consent, were transferred from another hospital, were pregnant or were unable to be contacted after discharge.

Patients were followed up at 30 days from discharge for adverse events. MACE was defined as death, cardiac arrest, emergency revascularisation procedure, cardiogenic shock, ventricular arrhythmia needing intervention, atrio-ventricular block needing intervention, and MI. Reference standard used was cTn at 0 and 6 hours. Index test was PoC TCM with pre-defined cut-off values. Treating clinicians were blinded to index test results. 421 (11.8%) of the 3582 patients analysed, had a MACE within 30 days. The most common being an MI. The ADP identified 352/3582 (9.8%) as being low risk for a MACE within 30 days of whom 3 (0.9%) had an adverse outcome giving PoCT an NPV of 99.1% (97.3 – 99.8%) and specificity of 11% (10.0 – 12.2%).  It was concluded that the ADP identified patients with low risk of short term MACE for early discharge from the ED despite a specificity of only 11%. 

While the study itself was an ambitious multi-national project with a large group of diverse population, it was not a randomised controlled trial and could have benefitted from a more robust methodology using randomisation and concealed allocation. 

Newby et al,20 Chest pain evaluation by Creatine Kinase - MB, Myoglobin and Troponin I (CHECKMATE)  QUADAS 8

This study prospectively evaluated the ability of quantitative bedside measurement of combinations of cardiac markers to risk stratify patients with chest pain without ST-segment elevation. The objective was to examine the effect of PoC TCMs on time to detection of positive results and 30-day clinical outcome with single marker local laboratory (LL) results in 1005 patients in six chest pain units (CPUs) in the United States. 

LL used CK-MB when available or cTnI or cTnT as the reference standard. In 31 patients, the reference standard used was creatine kinase (CK).

Individuals =18 years old were eligible if they had chest pain or symptoms representing myocardial ischaemia. Patients were excluded if the initial ECG showed ST-segment elevation or left bundle-branch block (LBBB). 

PoC TCMs were measured at 0, 3, 6, 9 to 12, and 16 to 24 hours after admission. Two multi-marker strategies (MMS) were defined: MMS-1 (all 3 markers) and MMS-2 (CK-MB and cTnI only). The 30-day composite end point of death, MI, or revascularization for MMS-1 and MMS-2 was 5.8% and 6.3% respectively compared with LL of 5.9% in patients who had negative results.

Patient spectrum was wide and representative of the general population. Reviewers were blinded to patient identity, marker status, and other clinical data controlling observer bias. The accepted reference standard is cTn, so the choice of CK-MB and CK was unusual and could have introduced a diagnostic accuracy and differential verification bias. It is unclear how many results were compared to each of the reference standards used. This study also had a 5% loss to follow-up and incomplete data affecting risk prediction. 


McCord et al,17 QUADAS 8 

This study evaluated if PoC TCM could exclude an AMI in =3 hours. TCMs were measured in 817 patients with a PoC device at 0, 90 minutes, 3, and 9 hours after presentation to the ED. 4% of patients re-attended during the study period. Laboratory testing of CK-MB was done at the same time intervals. 

AMI was defined as =1 CK-MB value >9ng/mL measured in the laboratory over the 9 hour sampling period.

Sensitivity and NPV for PoC combination of myoglobin and TnI by 90 minutes was 96.9% and 99.6%, respectively. CK-MB measurements and blood sampling at 3 hours did not show any improvement in sensitivity or NPV. Combined TCM results were not reported.

The authors concluded that AMI can be excluded in the ED using PoC measurements of myoglobin and cTnI in 90 minutes after presentation. 206 patients were excluded from 1024 patients after enrolment when they were further screened for suitability resulting in possible selection bias. Study population was not randomised although treating physicians were blinded to PoCT results.   

This study used CK-MB as the reference standard although cTn is the preferred cardiac marker with better diagnostic and prognostic uses.  

Results were analysed using receiver-operating characteristic (ROC) curve for each of the three PoC markers measured. Since ROC values were generated from the study population, they cannot be extrapolated to other settings.   


Straface et al, 19 QUADAS 7

Straface et al compared PoC TCM protocol with single and serial cTnI only protocol in 5244 patients admitted with chest pain. Their study was conducted in three medical centres in Texas, United States of America (USA). PoC TCMs were measured at 0, 1-3h, and more at physician discretion.

3 patients had an MI after discharge from the ED based on PoC TCM assay. NPV of 99.9% (95% CI 99.9 – 100.0) and specificity of 99.8% (95% CI 99.6 – 99.9) with a diagnostic accuracy 99.7% was quoted. A statistical comparison of PoCT with single and serial specimen cTnI at a cut-off value of 0.05ng/mL was reported.  It revealed an NPV of 99.4% (95% CI 99.2 – 99.6) and specificity of 96.1% (95% CI 95.5 – 96.6) with single specimen cTnI cut-off value of 0.05ng/mL.  With serial specimen cTnI cut-off value of 0.05ng/mL, NPV of 99.1% (95% CI 99.8 -100) and specificity of 95.0% (95% CI 94.4 – 95.6) was quoted.

The study population was a convenience sample of patients with a potential to have introduced a recruitment bias. While index and reference tests were well described for replication, the fact that the second specimen in PoCT was obtained anytime between 1-3 hours could imply that there was a wide variation in the 2 hour time span for sample collection.  


Ng et al,18 QUADAS 3

Ng et al evaluated the performance of an accelerated critical pathway for patients with suspected coronary ischaemia using clinical history, ECG findings, and TCM in a single-centre, ED setting trial in USA. They determined sensitivity, specificity, positive predictive value (PPV), and NPV of TCM in diagnosing AMI in 90 minutes of presentation with chest pain. Study population included 1285 consecutive patients who were then sub-classified into 5 groups - AMI (~4%), unresolved chest pain / ST depression (6%), probable / possible angina with no ECG changes (38%), and non-cardiac chest pain (63%). 

90% of patients with negative TCM and a negative ECG at 90 minutes were discharged with 1 (0.2%) patient with an MI and 12 (2.4%) patients with unstable angina returning within 1 month. Ng et al quoted a specificity of 94% and NPV of 100% for PoCT. 

Of the 1285 patients enrolled in the study, it is unclear how many patients had multiple tests with TCM. The authors state that patients with chest pain duration of >6 hours and low suspicion of cardiac ischaemia had not received multiple testing with cardiac markers.

98% patients enrolled were male with onset of chest pain >6 hours prior to presentation in 50.2% resulting in recruitment bias and affecting generalisability. Data has not been cited comparing cardiac panel results with a reference test resulting in partial verification bias. 


Discussion:

Patients with ACS are a very heterogeneous population with varying early and long-term adverse events. Early risk stratification at admission is essential but there is no universally accepted definition of a low risk chest pain patient. According to Bayesian decision making, interpretation of post-test probability after a particular test result is dependent on knowledge of the pre-test probability21-25.

Goodacre et al, Than et al, and Ng et al quoted MACE, while Newby et al quoted a 30 day composite end point of Death / MI and Revascularisation.  

Goodacre et al showed no significant difference in MACE in 3 months but the trial was underpowered. Than et al claimed that MACE rate was 0.9% at one month in the low risk group with an NPV of 99.1% but had a low specificity of 11%. Ng et al concluded that MACE rate was 2.6% and PoCT had a specificity of 94% and NPV of 100% but their results are not generalisable. Newby et al stated that MMS-1 strategy had a MACE rate of 5.8% which is higher than in conventionally managed patients. 

Rathore et al, cited specificity of 96.5% for PoCT but did not quote any NPV.  McCord et al quoted an NPV of 99.6% using two markers (myoglobin and cTn) at 90 minutes but no results were reported for TCM. Straface et al demonstrated PoC tests had a specificity of 99.8% and NPV of 99.9%. 

Although NPV quoted in 4 papers ranged between 99.1 – 100%, specificity quoted showed a wide range varying from 11- 99.8%.

Current adverse outcome rate using laboratory cTn assay is between 2-5%3, 4 papers quoted varying results. While Goodacre et al found no difference in MACE, Newby et al had very high MACE rates. 

In comparing results of these papers, the fact that CK-MB was used in some studies as a reference standard should be considered. One study has not specified the reference they have used. cTn is currently deemed the gold standard marker for myocardial necrosis. 

All studies tested PoC TCM at varying times since baseline sampling. There is no universal consensus on timing of cardiac marker tests. 

A new generation of ultra/highly sensitive troponin (hsTn) assays being evaluated might improve diagnostic sensitivity and specificity for cardiac marker testing.

Keller et al26 and Reichlin et al27 have suggested that hsTn assays may facilitate rapid ED decision making. Body et al28, evaluated hsTnT in the exclusion of AMI, stating that undetectable hsTnT at presentation has a high NPV in patients at low risk of adverse events. 

Currently, hsTn assays are available on laboratory platforms only and not as PoCT. In future and  pending further validation, there may be a reduction in the need for serial testing with hsTn enabling earlier reassurance for patients and fewer unnecessary hospital admissions.


Conclusion:

PoC cardiac biomarker testing provides a convenient means to diagnosing ACS. But cardiac markers alone are insufficient to exclude ACS as a diagnosis in a patient being evaluated for chest pain. Combining TCMs with clinical risk scoring appears to identify patients at lower risk for an ACS and reduced MACE but this requires further prospective evaluation.

Given the available data, at the present time, PoC TCM testing cannot be used to safely discharge low risk patients evaluated for ACS. Further validation is required to investigate optimal biomarker combinations and cut-off levels to allow exclusion of ACS with a high degree of specificity. 


References:


1. NHS Institute for Innovation and Improvement. Directory of emergency ambulatory care for adults. Coventry: NHS Institute for Innovation and Improvement, 2007.


2. NHS: National Institute for Health Research Service Delivery and Organisation programme (NIHR SDO): The costs and benefits of managing patients attending NHS hospitals with acute chest pain in chest pain units. July 2008 [Accessed from sdo.nihr.ac.uk]


3. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischaemia in the emergency department. N Engl J Med 2000;342:1163-70


4. Califf RM, Ohman EM. The diagnosis of acute myocardial infarction. Chest. 1992;101(4 suppl): 106S-115S.


5. Pollack CV Jr, Sites FD, Shofer FS, Sease KL, Hollander JE. Application of the TIMI risk score for unstable angina and non-ST elevation acute coronary syndrome to an unselected emergency department chest pain population. Acad Emerg Med 2006; 13: 13–18.


6. Chase M, Robey JL, Zogby KE, Sease KL, Shofer FS, Hollander JE. Prospective validation of the Thrombolysis in Myocardial Infarction risk score in the emergency department chest pain population. Ann Emerg Med 2006; 48: 252–59.


7. Hollander JE. The continuing search to identify the very-low-risk chest pain patient. Acad Emerg Med 1999; 6: 979–81.


8. Than M, Cullen L, Reid CM, 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. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, Van De Werf F, Avezum A, Goodman SG, Flather MD, Fox KA. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 2003;163:2345-53.


10. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284:835–42.


11. Kagen LJ. Myoglobin methods and diagnostic uses. CRC Crit. Rev. Clin. Lab. Sci., 2:273, 1978


12. Chapelle JP, et al Serum myoglobin determinations in the assessment of acute myocardial infarction. Eur. Heart Journal, 3:122, 1982


13. Kallner A, Sylven C, Brodin U, et al. Early Diagnosis of acute myocardial infarction; a comparison between chemical predictors. Scand J Clin Lab Invest, 49:633-9, 1989


14. Adams, et al. Biochemical markers of myocardial injury, Immunoassay.Circulation,88:750-763, 1993


15. Goodacre SW, Bradburn M, Cross E, 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.


16. Rathore S, Knowles P, Mann APS, et al. Is it safe to discharge patients from accident and emergency using a rapid point of care triple cardiac marker test to rule out acute coronary syndrome in low to intermediate risk patients presenting with chest pain? Eur J Int Med 2008;19:537e40.


17. McCord J, Nowak RM, McCullough PA, et al. Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I. Circulation 2001;104:1483e8.


18. Ng SM, Krishnaswamy P, Morissey R, et al. Ninety-minute accelerated critical pathway for chest pain evaluation. Am J Cardiol 2001;88:611e17.


19. Straface AL, Myers JH, Kirchick HJ, et al. A rapid point-of-care cardiac marker testing strategy facilitates the rapid diagnosis and management of chest pain patients in the emergency department. Am J Clin Pathol 2008;129:788e95.


20. Newby LK, Storrow AB, Gibler WB, et al. Bedside multimarker testing for risk stratification in chest pain units: the CHECKMATE Study. Circulation 2001;103:1832e7.


21. Dolan JG, Bordley DR, Mushlin AI. An evaluation of clinicians’ subjective prior probability estimates. Med Decis Making 1986; 6: 216–23.


22. Kassirer JP, Kopelman RI. Cognitive errors in diagnosis: instantiation, classification, and consequences. Am J Med 1989; 86: 433–41.


23. Cahan A, Gilon D, Manor O, Paltiel O. Probabilistic reasoning and clinical decision-making: do doctors overestimate diagnostic probabilities? QJM 2003; 96: 763–69.


24. Attia JR, Nair BR, Sibbritt DW, et al. Generating pre-test probabilities: a neglected area in clinical decision making. Med J Aust 2004; 180: 449–54.


25. Phelps MA, Levitt MA. Pretest probability estimates: a pitfall to the clinical utility of evidence-based medicine? Acad Emerg Med 2004; 11: 692–94.


26. Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-77.


27. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361:858-67.


28. Body R, Carley S, McDowell G, et al. Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay. J Am Coll Cardiol 2011;58:1332–9.


29. Adapted from: Whiting P, Rutjes AW, Dinnes J et al. (2004) Development and validation of methods for assessing the quality of diagnostic accuracy studies. Health Technology Assessment 8: 1–234



Appendix 2: Methodology checklist - the QUADAS tool for studies of diagnostic test accuracy29

Circle one option for each question 

Was the spectrum of participants representative of the patients who will receive the test in practice? 

Yes No Unclear N/A 

Were selection criteria clearly described? 

Yes No Unclear N/A 

Was the reference standard likely to classify the target condition correctly? 

Yes No Unclear N/A 

Was the period between performance of the reference standard and the index test short enough to be reasonably sure that the target condition did not change between the two tests? 

Yes No Unclear N/A 

Did the whole sample or a random selection of the sample receive verification using the reference standard? 

Yes No Unclear N/A 

Did participants receive the same reference standard regardless of the index test result? 

Yes No Unclear N/A 

Was the reference standard independent of the index test? (i.e., the index test did not form part of the reference standard) Yes No Unclear N/A 

Was the execution of the index test described in sufficient detail to permit its replication? 

Yes No Unclear N/A 

Was the execution of the reference standard described in sufficient detail to permit its replication? 

Yes No Unclear N/A 

Were the index test results interpreted without knowledge of the results of the reference standard? 

Yes No Unclear N/A 

Were the reference standard results interpreted without knowledge of the results of the index test? 

Yes No Unclear N/A 

Were the same clinical data available when the test results were interpreted as would be available when the test is used in practice? Yes No Unclear N/A 

Were uninterpretable, indeterminate or intermediate test results reported? Yes No Unclear N/A 

Were withdrawals from the study explained? 

Yes No Unclear N/A 

The QUADAS tool is a methodological checklist used to assess the quality of diagnostic studies. When appraising a study, if the answer to a question from the above checklist is ‘yes’ then a 1+ is added. The final score for a study is the sum total of the ‘yes’ answers. A diagnostic study may score between 0+ and 14+.


Appendix 3: Search Details

EMBASE

1. EMBASE; (acute AND coronary AND syndrome*).ti,ab; 26869 results.

2. EMBASE; exp ACUTE CORONARY SYNDROME/; 21341 results.

3. EMBASE; "unstable angina".ti,ab; 13747 results.

4. EMBASE; exp UNSTABLE ANGINA PECTORIS/; 15696 results.

5. EMBASE; "myocardial infarction".ti,ab; 157425 results.

6. EMBASE; exp HEART INFARCTION/; 240260 results.

7. EMBASE; (heart AND infarction).ti,ab; 52236 results.

8. EMBASE; (acute AND myocardial AND infarction).ti,ab; 75967 results.

9. EMBASE; nstemi.ti,ab; 1972 results.

10. EMBASE; (non AND ST AND elevation AND MI).ti,ab; 1367 results.

11. EMBASE; (non AND st AND elevation AND myocardial AND infarction).ti,ab; 5369 results.

12. EMBASE; exp NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION/; 3237 results.

13. EMBASE; ischaemia*.ti,ab; 26422 results.

14. EMBASE; exp ISCHEMIA/; 487460 results.

15. EMBASE; ischemia*.ti,ab; 154307 results.

16. EMBASE; "point of care".ti,ab; 7256 results.

17. EMBASE; poct.ti,ab; 704 results.

18. EMBASE; ("patient near" AND test*).ti,ab; 10 results.

19. EMBASE; "near patient".ti,ab; 539 results.

20. EMBASE; (bedside OR "bed side").ti,ab; 20496 results.

21. EMBASE; exp POINT OF CARE TESTING/; 3283 results.

22. EMBASE; "cardiac marker*".ti,ab; 1464 results.

23. EMBASE; "cardiac multi-marker*".ti,ab; 4 results.

24. EMBASE; "triple marker*".ti,ab; 133 results.

25. EMBASE; ("triple cardiac" OR "cardiac triple").ti,ab; 15 results.

26. EMBASE; troponin.ti,ab; 18315 results.

27. EMBASE; "troponin t".ti,ab; 6024 results.

28. EMBASE; "troponin i".ti,ab; 7748 results.

29. EMBASE; ("ultra sensitive" AND troponin OR "high* sensitiv" AND troponin OR ultrasensitive AND

troponin).ti,ab; 63 results.

30. EMBASE; "creatine kinase mb".ti,ab; 2129 results.

31. EMBASE; "ck-mb".ti,ab; 4320 results.

32. EMBASE; exp TROPONIN/ OR exp TROPONIN I/ OR exp TROPONIN T/; 24071 results.

33. EMBASE; exp CREATINE KINASE MB/; 6618 results.

34. EMBASE; myoglobin.ti,ab; 10034 results.

35. EMBASE; exp MYOGLOBIN/; 12477 results.

36. EMBASE; (safe* AND discharge*).ti,ab; 15571 results.

37. EMBASE; exp HOSPITAL DISCHARGE/; 54305 results.

38. EMBASE; 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15; 582249

results.

39. EMBASE; 16 OR 17 OR 18 OR 19 OR 20 OR 21; 28825 results.

40. EMBASE; 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 OR 32 OR 33 OR 34 OR 35; 45132

results.

41. EMBASE; 36 OR 37; 66206 results.

42. EMBASE; 38 AND 39 AND 40 AND 41; 30 results.

MEDLINE

44. MEDLINE; (acute AND coronary AND syndrome*).ti,ab; 17496 results.

45. MEDLINE; "unstable angina".ti,ab; 10352 results.

46. MEDLINE; "myocardial infarction".ti,ab; 120465 results.

47. MEDLINE; (heart AND infarction).ti,ab; 37781 results.

48. MEDLINE; (acute AND myocardial AND infarction).ti,ab; 57869 results.

49. MEDLINE; nstemi.ti,ab; 794 results.

50. MEDLINE; (non AND ST AND elevation AND MI).ti,ab; 711 results.

51. MEDLINE; (non AND st AND elevation AND myocardial AND infarction).ti,ab; 3296 results.

52. MEDLINE; ischaemia*.ti,ab; 21578 results.

53. MEDLINE; ischemia*.ti,ab; 121169 results.

54. MEDLINE; "point of care".ti,ab; 5459 results.

55. MEDLINE; poct.ti,ab; 472 results.

56. MEDLINE; ("patient near" AND test*).ti,ab; 8 results.

57. MEDLINE; "near patient".ti,ab; 388 results.

58. MEDLINE; (bedside OR "bed side").ti,ab; 15823 results.

59. MEDLINE; "cardiac marker*".ti,ab; 1007 results.

60. MEDLINE; "cardiac multi-marker*".ti,ab; 2 results.

61. MEDLINE; "triple marker*".ti,ab; 115 results.

62. MEDLINE; ("triple cardiac" OR "cardiac triple").ti,ab; 13 results.

63. MEDLINE; troponin.ti,ab; 13524 results.

64. MEDLINE; "troponin t".ti,ab; 4475 results.

65. MEDLINE; "troponin i".ti,ab; 5720 results.

66. MEDLINE; ("ultra sensitive" AND troponin OR "high* sensitiv" AND troponin OR ultrasensitive AND

troponin).ti,ab; 36 results.

67. MEDLINE; "creatine kinase mb".ti,ab; 1836 results.

68. MEDLINE; "ck-mb".ti,ab; 3210 results.

69. MEDLINE; myoglobin.ti,ab; 9218 results.

70. MEDLINE; (safe* AND discharge*).ti,ab; 10216 results.

71. MEDLINE; exp ACUTE CORONARY SYNDROME/; 5686 results.

72. MEDLINE; exp ANGINA, UNSTABLE/; 9637 results.

73. MEDLINE; exp MYOCARDIAL INFARCTION/; 138161 results.

74. MEDLINE; exp ISCHEMIA/ OR exp MYOCARDIAL ISCHEMIA/; 380305 results.

75. MEDLINE; exp POINT-OF-CARE SYSTEMS/; 5995 results.

76. MEDLINE; exp TROPONIN/ OR exp TROPONIN I/ OR exp TROPONIN T/; 10822 results.

77. MEDLINE; exp CREATINE KINASE, MB FORM/; 1555 results.

78. MEDLINE; exp MYOGLOBIN/; 9287 results.

80. MEDLINE; exp PATIENT DISCHARGE/; 16987 results.

81. MEDLINE; 44 OR 45 OR 46 OR 47 OR 48 OR 49 OR 50 OR 51 OR 52 OR 53 OR 71 OR 72 OR 73 OR 74;

489217 results.

82. MEDLINE; 54 OR 55 OR 56 OR 57 OR 58 OR 75; 23407 results.

83. MEDLINE; 59 OR 60 OR 61 OR 62 OR 63 OR 64 OR 65 OR 66 OR 67 OR 68 OR 69 OR 76 OR 77 OR 78; 30812

results.

84. MEDLINE; 81 AND 82 AND 83; 253 results.

85. MEDLINE; 70 OR 80; 26324 results.

86. MEDLINE; 84 AND 85; 10 results.



CINAHL


87. CINAHL; (acute AND coronary AND syndrome*).ti,ab; 3197 results.

88. CINAHL; "unstable angina".ti,ab; 957 results.

89. CINAHL; "myocardial infarction".ti,ab; 13744 results.

90. CINAHL; (heart AND infarction).ti,ab; 3523 results.

91. CINAHL; (acute AND myocardial AND infarction).ti,ab; 6639 results.

92. CINAHL; nstemi.ti,ab; 115 results.

93. CINAHL; (non AND ST AND elevation AND MI).ti,ab; 0 results.

94. CINAHL; (non AND st AND elevation AND myocardial AND infarction).ti,ab; 545 results.

95. CINAHL; ischaemia*.ti,ab; 799 results.

96. CINAHL; ischemia*.ti,ab; 6502 results.

97. CINAHL; "point of care".ti,ab; 1638 results.

98. CINAHL; poct.ti,ab; 137 results.

99. CINAHL; ("patient near" AND test*).ti,ab; 3 results.

100. CINAHL; "near patient".ti,ab; 91 results.

101. CINAHL; (bedside OR "bed side").ti,ab; 4773 results.

102. CINAHL; "cardiac marker*".ti,ab; 172 results.

104. CINAHL; "triple marker*".ti,ab; 19 results.

106. CINAHL; troponin.ti,ab; 1304 results.

107. CINAHL; "troponin t".ti,ab; 416 results.

108. CINAHL; "troponin i".ti,ab; 501 results.

110. CINAHL; "creatine kinase mb".ti,ab; 162 results.

111. CINAHL; "ck-mb".ti,ab; 177 results.

112. CINAHL; myoglobin.ti,ab; 235 results.

113. CINAHL; (safe* AND discharge*).ti,ab; 1672 results.

114. CINAHL; exp ACUTE CORONARY SYNDROME/; 1384 results.

115. CINAHL; exp ANGINA, UNSTABLE/; 1390 results.

116. CINAHL; exp MYOCARDIAL INFARCTION/; 20639 results.

117. CINAHL; exp ISCHEMIA/ OR exp MYOCARDIAL ISCHEMIA/; 50960 results.

119. CINAHL; exp TROPONIN/ OR exp TROPONIN I/ OR exp TROPONIN T/; 1607 results.

121. CINAHL; exp MYOGLOBIN/; 237 results.

122. CINAHL; exp PATIENT DISCHARGE/; 13857 results.

125. CINAHL; 102 OR 103 OR 104 OR 105 OR 106 OR 107 OR 108 OR 109 OR 110 OR 111 OR 112 OR 119 OR

120 OR 121; 2412 results.

127. CINAHL; 113 OR 122; 15148 results.

129. CINAHL; exp POINT-OF-CARE TESTING/; 1328 results.

130. CINAHL; 97 OR 98 OR 99 OR 100 OR 101 OR 129; 7028 results.

131. CINAHL; 87 OR 88 OR 89 OR 90 OR 91 OR 92 OR 94 OR 95 OR 96 OR 114 OR 115 OR 116 OR 117; 57073

results.

132. CINAHL; 102 OR 104 OR 106 OR 107 OR 108 OR 110 OR 111 OR 112 OR 119 OR 121; 2412 results.

133. CINAHL; 113 OR 122; 15148 results.

134. CINAHL; 130 AND 131 AND 132 AND 133; 3 results Cochrane Library


#1 "point of care" 497

#2 MeSH descriptor: [Point-of-Care Systems] explode all trees 301

#3 acute coronary syndrome*:ti,ab,kw 1685

#4 myocardial infarction:ti,ab,kw 13489

#5 unstable angina:ti,ab,kw 1791

#6 st elevation:ti,ab,kw 1836

#7 ischaemia:ti,ab,kw 1334

#8 ischemia:ti,ab,kw 6936

#9 non st elevation:ti,ab,kw 1129

#10 MeSH descriptor: [Myocardial Infarction] explode all trees 7936

#11 MeSH descriptor: [Angina, Unstable] explode all trees 935

#12 MeSH descriptor: [Acute Coronary Syndrome] explode all trees 518

#13 MeSH descriptor: [Ischemia] explode all trees 779

#14 cardiac multi-marker:ti,ab,kw 0

#15 triple marker*:ti,ab,kw 112

#16 troponin:ti,ab,kw 994

#17 creatine kinase mb 800

#18 myoglobin 252

#19 MeSH descriptor: [Troponin] explode all trees 593

#20 MeSH descriptor: [Creatine Kinase, MB Form] explode all trees 234

#21 MeSH descriptor: [Myoglobin] explode all trees 133

#22 safe discharge:ti,ab,kw 783

#23 #1 or #2 497

#24 #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 21006

#25 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 1743

#26 #22 and #23 and #24 and #25 0 results 


Point of care testing, triple markers and safe discharge on Clinicaltrials.gov


Trim term to: markers AND safe AND discharge "point of care" AND markers AND safe AND discharge 


Trim term to: triple AND markers AND safe "point of care" AND triple AND markers AND safe 


Trim term to: markers AND discharge "point of care" AND markers AND discharge 


Trim term to: triple AND discharge "point of care" AND triple AND discharge 


Trim term to: triple AND markers "point of care" AND triple AND markers 


Trim term to: safe AND discharge "point of care" AND safe AND discharge 


Trim term to: markers AND safe "point of care" AND markers AND safe 


Trim term to: triple AND safe "point of care" AND triple AND safe 


Trim term to: discharge "point of care" AND discharge 


Trim term to: markers "point of care" AND markers 


8 studies found for:    "point of care" cardiac markers