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Diagnostic and prognostic utility of troponin estimation in patients presenting with syncope: a prospective cohort study
  1. Matthew J Reed1,
  2. David E Newby2,
  3. Andrew J Coull3,
  4. Robin J Prescott4,
  5. Alasdair J Gray1
  1. 1Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK;
  2. 2Centre for Cardiovascular Sciences, Royal Infirmary of Edinburgh, Edinburgh, UK;
  3. 3Department of Medicine of the Elderly, Royal Infirmary of Edinburgh, Edinburgh, UK;
  4. 4Centre for Population Health Sciences, University of Edinburgh, Medical School, Edinburgh, UK
  1. Correspondence to Dr Matthew J Reed, Emergency Department, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK; mattreed1{at}hotmail.com

Abstract

Aims To primarily assess the value of troponin I to identify acute myocardial infarction (AMI), and second, to predict 1-month serious outcome or all-cause death in patients presenting with syncope to the Emergency Department (ED).

Design Prospective cohort study of all adult patients presenting to the ED after an episode of syncope.

Methods In admitted patients, plasma troponin I was measured 12 h after syncope, and in discharged patients, between 12 h and 7 days following discharge. Primary endpoints were the diagnosis of AMI, and the composite endpoint of serious outcome or all-cause death at 1 month.

Results Over an 8-month period, 289 patients were recruited. Troponin I was obtained in 186 admitted patients and was elevated in 13 (7%), and obtained in 103 discharged patients and was raised in only one (1%). Four patients had an AMI (1.4%) and all had ischaemic electrocardiographic (ECG) changes on their presenting ED ECG (ST segment deviation or pathological Q waves) that were 100% sensitive and 72% specific for AMI with a 100% negative predictive value. Seven of the 14 patients (50%) with a raised troponin I had a serious outcome that did not include AMI, or all-cause death compared with 16 of the 267 patients (6%) without a raised troponin (p<0.0001).

Conclusions AMI is infrequent (1.4%), and estimation of troponin I provides little additional benefit to the presenting ED ECG in identifying patients with syncope due to AMI. Troponin I should not be used to rule out AMI in adult patients presenting with isolated syncope. Troponin I may predict 1-month serious outcome or all-cause death in syncope.

  • Cardiovascular
  • emergency medicine
  • syncope
  • ischaemic heart disease
  • troponin
  • cardiac care
  • diagnosisn, cardiac care
  • acute myocardial infarct
  • acute coronary syndrome
  • clinical assessment
  • ECG
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Introduction and aims

In the 1960s, it was believed that cardiac causes, especially acute myocardial infarction (AMI), were responsible for most cases of syncope.1 More contemporary data suggest that cardiac causes account for approximately 10% of all cases of syncope. Most are attributable to arrhythmia or structural cardiopulmonary disease, and <2% are due to AMI.2 Cardiac arrhythmias can precipitate syncope if the heart rate is too fast or slow, and unable to maintain cardiac output and systemic blood pressure. Arrhythmias most commonly occur in patients with chronic cardiac, vascular and autonomic disease, and are a frequent complication of AMI. Arrhythmias occur in the majority of AMI patients treated in the coronary care unit, with ventricular tachycardia complicating 10–40% and ventricular fibrillation 4–18%.3 Myocardial ischaemia and infarction, and other structural cardiopulmonary diseases, such as pulmonary embolism and valvular heart disease, can cause syncope through non-arrhythmic mechanisms.

The 1971 WHO diagnosis of AMI was based on a typical history, characteristic electrocardiogram (ECG) changes and raised cardiac enzymes. In the last decade, troponin, a regulatory protein found in myofibrils, has become the recommended cardiac marker due to its increased specificity and sensitivity for myocyte necrosis. Patients with elevated serum troponin concentrations have an increased risk of death at 6 months.4 In 2007, a combined European Society of Cardiology (ESC), American College of Cardiology Foundation (ACCF), American Heart Association (AHA) and World Heart Federation (WHF) task force agreed a universal definition of AMI,5 which recognises even a small troponin rise in a clinical setting consistent with myocardial ischaemia as an AMI.

Little evidence exists of the incidence of raised troponin in syncope. Because of anxiety about discharging syncope patients without an AMI ‘rule-out,’ it is the practice in many Emergency Departments (EDs) to measure troponin in patients who present with syncope. This widespread practice occurs despite the absence of evidence that measurement of troponin in patients with syncope in the absence of chest pain has clinical utility in identifying AMI.

Troponin may have a role in the risk stratification of patients with syncope. An elevated serum troponin concentration can occur outwith AMI6 and, when present, is associated with an adverse prognosis in many conditions.7–11

Patients with cardiac syncope have a 1-year mortality between 10 and 30%.12 If a relationship between troponin and serious outcome or all-cause death after syncope is found, it might aid the identification of those people at greatest risk, and/or enable the early discharge of those who are at lowest risk.

The primary aim of this study was to assess the value of a troponin I measurement to identify AMI in patients presenting with syncope to the ED. The secondary aim was to assess the value of troponin I to predict 1-month serious outcome or all-cause death.

Methodology

This is a study on patients prospectively recruited into the derivation cohort of the ROSE (Risk Stratification of Syncope in the Emergency Department) study being conducted in the ED of the Royal Infirmary of Edinburgh. The study was granted ethical approval by the MREC for Scotland A Ethics committee (06/MRE00/107) and the Lothian Regional Ethical Committee (06/S11ADMIN/151).

Study population

Patients presenting with syncope aged 16 years or over were prospectively enrolled. Syncope was defined as a transient loss of consciousness with an inability to maintain postural tone followed by spontaneous recovery without any intervention. Patients were excluded if they were under 16 years, were unable to give consent, had near-syncope, that is, no loss of consciousness, had previously been recruited into the study, had collapsed due to excessive alcohol consumption, or had a good history of seizure or a prolonged (>15 min) postictal phase. Written consent or relative assent was obtained from all patients.

Potentially eligible patients were flagged in the ED triage area and assessed for study inclusion by the attending ED physician. A decision to enrol a patient was not later overturned by the study team, and enrolled patients were analysed on an intention-to-treat basis. Data were collected using a standardised proforma and patients were admitted, referred for outpatient investigation, or discharged according to our current ED protocol (appendix 1). Patients who remained in the ED for >12 h were defined as admitted.

Troponin measurement

Patients admitted to hospital had plasma troponin I concentration measured 12 h after admission with syncope. Discharged patients were invited to return and blood samples obtained as soon as possible after the incident syncopal episode but no earlier than 12 h and no later than 7 days (Troponin I has a half life of about 24 h13 and has been shown to remain elevated for 7–10 days after an episode of myocardial necrosis14). Plasma troponin I concentrations were measured using an automated immunoassay (Abbott Architect STAT Troponin-I assay), which is similar to other assays used in clinical practice. This assay has a 99th percentile upper reference limit in an apparent healthy population of 0.012 ng/ml and coefficients of variation <10% for all troponin I values ≥0.20 ng/ml.15 The normal cut-off threshold was therefore taken as a troponin <0.20 ng/ml.

Endpoint measures

The primary endpoints for this study were admission AMI as defined by the universal definition,5 and the combination of serious outcome (excluding admission AMI) and all-cause death both at 1 month after ED presentation. Because we used troponin I as both a predictor of risk and an endpoint, while we included admission AMI as an endpoint for AMI diagnosis prediction, in order to avoid incorporation bias we excluded admission AMI as a serious outcome prior to statistical analysis for risk prediction. Patients who had an admission AMI but who died were included.

Serious outcome measures were chosen by an expert panel consisting of six representatives from emergency, cardiovascular, general and geriatric medicine, and medical statistics who met in January 2007. They were defined as: (1) AMI as defined by the ESC/ACC/AHA/WHF Universal Definition of Myocardial Infarction 20075; (2) life-threatening arrhythmia (recorded episode of VF, sustained VT>120 beats per minute for more than three beats, ventricular pause greater than 3 s, ventricular standstill or asystole documented on monitor or ECG during ED or inpatient stay or on outpatient Holter monitoring and requiring treatment); (3) insertion of a pacemaker, or insertion of an internal cardiac defibrillator device, or a decision that the patient requires such a device within 1 month of the ED attendance, or subsequent insertion related to index collapse; (4) pulmonary embolus (confirmed on ventilation/quantification scan, CT pulmonary angiography scan or angiography); (5) cerebrovascular accident, intracranial haemorrhage or subarachnoid haemorrhage (CT, MRI or LP diagnosis); (6) haemorrhage requiring a blood transfusion of two units or more during inpatient stay; or (7) acute surgical procedure or endoscopic intervention secondary to a suspected cause of syncope.

Patient follow-up

Patients were followed up 1 month after presentation through the hospital Electronic Patient Record system, hospital pacemaker records, radiological reports and direct contact with the patient or general practitioner. Two investigators (MR and AC) independently reviewed all clinical data and assigned endpoints with any disagreement agreed by consensus.

Statistical analysis

Based on an earlier pilot study of 100 patients,16 17 we assumed that the study population would have a raised troponin I rate of 10% and that serious outcome or all-cause death would occur in 50% of troponin I-positive patients and 15% of troponin I-negative patients. We calculated that, to detect a difference in outcome with troponin I measurement, we would need 185 patients with 17 serious outcomes or all-cause deaths to have 80% power at p<0.05.

Statistical analysis (SPSS V.15 for Windows; SPSS, Chicago) was performed using Fisher exact tests and receiver operating characteristic (ROC) curves. Statistical significance was taken as a two-sided p<0.05.

Results

Between 1 March 2007 and 27 October 2007, 1241 consecutive patients were screened for enrolment into the study (figure 1, 890 were eligible, 289 of which were enrolled and had a plasma troponin I performed (table 1).

Figure 1

Bar chart showing cuff inflation pressures.

Table 1

Characteristics of analysed patients (n=281)

Plasma troponin I concentrations were measured in 186 (74%) of the 254 enrolled patients admitted to hospital; 173 of these were normal (<0.2 ng/ml), and 13 were raised (appendix 2). Of the 294 enrolled patients who were discharged from the ED, 103 (35%) patients had plasma troponin I concentrations measured at a mean of 42±53 h after discharge, and only one patient had a troponin I ≥0.2 ng/ml (patient 53).

Four troponin I-positive patients had an AMI according to the 2007 universal definition.5 None had chest pain, but all had ECG abnormalities on their presenting ED ECG. The presence of ST segment deviation or pathological Q waves had 100% (95% CI 40 to 100) sensitivity, 72% (95% CI 66 to 77) specificity and 100% (95% CI 98 to 100) negative predictive value for the diagnosis of AMI after presentation with syncope.

Of the 289 patients in whom a plasma troponin I concentration had been measured, eight were lost to follow-up. None of these eight patients had died or re-presented to a hospital in the Lothian area. Seven of the 14 patients (50%) with a raised troponin I had a serious outcome (that did not include AMI) or all-cause death (table 2) compared with 16 of the 267 patients (6%) without a raised troponin (p<0.0001). The area under the receiver operator characteristic curve of troponin I versus serious outcome (excluding AMI) or all-cause death was 0.64 (95% CI 0.50 to 0.78).

Table 2

Contingency table of serious outcome (excluding acute myocardial infarction) and all-cause death and troponin I value (n=281)

Discussion

We have demonstrated that AMI is an infrequent (1.4%) cause of isolated syncope presenting to the ED, and measurement of plasma troponin I concentrations provides little additional benefit in identifying patients with syncope as a consequence of AMI. Troponin I concentrations do though predict 1-month serious outcome or all-cause death, and a negative troponin may assist the identification of those patients who can be safely discharged early after admission.

Three previous studies18–20 have looked at the diagnostic yield of a troponin to diagnose AMI in patients presenting to the ED with syncope. These studies were predominantly retrospective and, in comparison with the present study, had smaller sample sizes (n=80–141) and lower recruitment rates (22–44%). These studies also reported a low incidence of AMI (1.4–3.5%) although they may have potentially overestimated the incidence of AMI due to the low rate of troponin estimations in the study populations. Our study was prospective and is the largest to date. These data confirm the earlier findings and extend them by demonstrating that, in the absence of ST deviation or pathological Q waves on the ECG, the diagnostic yield of a troponin I to diagnose AMI in patients presenting with syncope is extremely low. This is consistent with the concept that syncope induced by AMI is predominantly driven by life-threatening arrhythmia or major haemodynamic compromise due to profound or widespread ischaemia. These conditions are likely to be associated with marked and readily identifiable ECG abnormalities that will be apparent at presentation.

To meet the new universal criteria for AMI,5 patients presenting with syncope must have a troponin rise and one of the following: symptoms of ischaemia, ECG changes, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Syncope in itself is not a specific symptom of ischaemia. Therefore, in the absence of a history consistent with myocardial ischaemia or ECG changes, it is extremely unlikely that patients with syncope will be diagnosed as having AMI in the ED. We suggest that there is no role for measuring troponin in the ED in order to exclude AMI in patients with isolated syncope (ie, absence of chest pain of other symptoms of ischaemia or ECG changes on presenting ED ECG). It must be noted that only four patients were diagnosed as having AMI in our study. Further corroborating studies will be required to ensure that this observation is robust.

Troponin has been associated with an adverse prognosis in many conditions,7–11 some of which are known to cause syncope. In acute pulmonary embolism, troponin release occurs secondary to acute systemic haemodynamic compromise and right heart pressure overload. The haemodynamic compromise and intense sympathetic nervous system discharge may also underlie the elevation in plasma troponin concentrations associated with conditions such as subarachnoid haemorrhage and type A aortic dissection.21 It would therefore seem likely that troponin release following syncope is a marker of adverse haemodynamic compromise and a possible serious underlying cause. While a delayed (12 h) troponin would not be available to contribute to any ED syncope risk score, with a specificity of 97%, a negative troponin in an admitted patient would be useful in ruling out serious underlying pathology.

In our study, only 74% of patients admitted to hospital had a troponin I measured. This may reflect case selection bias by the attending clinician. Although there was no sex bias (p=0.394), the mean age was higher in those who had troponin measured (74±14 vs 68±18 years, p=0.018). This suggests that the attending physician was more likely to measure plasma troponin in older patients, perhaps reflecting concern of excluding silent AMI as a cause of syncope. However, there were 23 serious outcomes or all-cause deaths in the 185 patients who had a troponin I estimation (12%), and 12 serious outcomes or all-cause deaths in the 67 who did not have a level estimated (18%; p=0.303). Assuming troponin was more likely to be measured in those perceived to be at high risk, this would suggest that the clinician was unable to identify high-risk patients reliably.

Study limitations

This was a prospective cohort observational study that assessed the apparent clinical utility of troponin measurement in patients presenting with syncope. A more robust approach would have been to measure plasma troponin I concentrations in all patients in order to get full case ascertainment and a more robust prediction of risk. These data would suggest that this is particularly applicable to those patients hospitalised following syncope.

We used troponin I as both a predictor of risk and an endpoint (AMI) which could lead to incorporation bias. We adjusted for this problem by excluding admission AMI as a serious outcome prior to statistical analysis for risk prediction.

Conclusions

AMI is infrequent (1.4%), and estimation of troponin I provides little additional benefit to the presenting ECG in identifying patients with syncope due to AMI. Troponin I should not be used to rule out AMI in adult patients presenting with isolated syncope. Troponin I may predict 1-month serious outcome or all-cause death in patients presenting with syncope to the ED.

Acknowledgments

Thanks to all the staff in the ED of the Royal Infirmary of Edinburgh for their help with patient recruitment for this study. Thanks to the Research Nurses at the Wellcome Trust Clinical Research Facility and to all the staff in the Emergency Department of the Royal Infirmary of Edinburgh for their help with this study. Thank you to J Languish for ECG reporting. Thank you to all the General Practitioners in Lothian for their help with patient follow-up.

References

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Footnotes

  • Funding This work was supported by a Chief Scientist Office research fellowship (CSO/CAF/06/01) for MJR.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by the MREC for Scotland A Ethics committee (06/MRE00/107) and the Lothian Regional Ethical Committee (06/S11ADMIN/151).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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