Article Text
Abstract
Background Troponin I (TnI) is an important prognostic marker and risk-stratification tool in patients with pulmonary embolism (PE). However, the best timing for this biomarker measurement is still unclear.
Objective To analyse the kinetics of TnI in patients hospitalised for PE in order to better ascertain the evolution of the biomarker in this disease. In particular, we attempted to determine which measurement is the most appropriate to assess the PE risk according to this biomarker's status.
Design, setting, patients and main outcome measures This was a prospective, single center, cohort study. TnI (Beckman Access method) was measured on admission, then every 8 h for 72 h in 200 stable patients hospitalised for PE in our cardiology department. Patients were classified into two groups: TnI−(negative) or TnI +.
Results Mean TnI peak occurred at H8: 0.67±0.55 ng/ml. TnI values then decreased quickly, but remained positive (>0.06 ng/ml) beyond the 72-h surveillance period. The TnI biological profile varied widely after admission. Of the patients TnI− on the first assessment, 15% were positive at the second measurement. Among patients hospitalised less than 24 h after the onset of symptoms, 30% were misclassified on admission. In all cases, the second assessment, eight hours after admission, gave the biomarker's true status.
Conclusion Our study clarifies the kinetics of TnI in PE and highlights the situations in which an early TnI can be false negative. Many misclassifications could be avoided by taking into account the value of this biomarker obtained at H8.
- Biomarkers
- pulmonary embolism
- troponin I
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Introduction
Troponin (TnI) has been studied as a marker in pulmonary embolism (PE) risk stratification and has been incorporated in the diagnosis and care algorithm for identification of intermediate risk PE.1–14 However, its kinetics in this situation is poorly documented; in particular, the best time to assess its value is still unclear. This raises a real concern when TnI is used to classify PE related risk.
In this study, we sought to analyse the kinetics of TnI in 200 consecutive patients hospitalised for PE with stable haemodynamic condition. Our aim was to determine the best moment to obtain the correct value of this biomarker in PE. In particular, we wanted to know whether the first troponin measurement on admission was the most accurate one to classify patients' biological profile. We also wanted to compare baseline characteristics and clinical outcomes in our cohort of patients, based on their troponin status.
Methods
This was a monocentric prospective cohort study. From June 2008 to January 2010, the kinetics of TnI was studied in consecutive patients hospitalised in our cardiology department for a definite PE. CT scan confirmed PE in all cases, prior to the admission. Patients with haemodynamically unstable condition were excluded from our study. All patients gave their informed consent. Our local institution's committee on human research (University Hospital of Nice) approved the study protocol as a non-interventional study.
Blood samples for TnI assessment were obtained on admission, then every 8 h for 72 h. TnI measurements were performed with the Beckman Access method, with a lowest detection limit of 0.01 ng/ml and a positivity threshold of 0.06 ng/ml.
According to the TnI results, patients were classified into two groups:
TnI– when all TnI levels were <0.06 ng/ml
TnI+ when at least one TnI value was >0.06 ng/ml.
We analysed TnI kinetics in the whole population, then in patients hospitalised <24 h after the onset of symptoms.
Statistical analysis
Data were analysed with SAS software, version 9.1 (SAS Institue Inc). Continuous variables were presented as mean±SD or median with IQR. Fisher's exact test was used for comparison of percentages. Mann–Whitney and Kruskall–Wallis tests were used for other comparisons. Differences were considered statistically significant if p value was <0.05.
Results
Characteristics of the whole population
Two hundred consecutive stable patients were included out of 205 patients hospitalised for PE (five of them were excluded because of unstable PE). PE was diagnosed in all cases using 64 multidetector-row spiral CT. Mean age of patients was 67.6 years (16–92) with a sex ratio of 1.2. Table 1 shows the main features of our population.
The time between onset of symptoms and hospital admission was less than 24 h in 39% of patients and more than one week in 19% of them. Sixty-one per cent of PE (n=122) were unprovoked or idiopathic. Patients were treated according to the ACCP/ESC recommendations14 15: Heparin, mainly low molecular weight heparin, was prescribed as a first step. Warfarin was used in 94% of cases (some patients were treated with long-term low molecular weight heparin). None of these patients received thrombolytics. In-hospital mortality rate was 2% and all deaths occurred within 48 h.
All unprovoked cases were treated with anticoagulants for at least 6 months. Two per cent (n=4) were prescribed anticoagulants indefinitely for a recurrent event. Patients with provoked venous thromboembolism were treated with anticoagulants during 3 months. Four patients died during the 6-month follow-up, one from intracranial haemorrhage and three from cancer. In all, 96% were still alive at 6-month follow-up. Three out of 200 had a proven recurrence of PE and two patients developed chronic thromboembolic pulmonary hypertension.
Comparison between TnI− and TnI+
Seventy-eight patients were TnI− while 122 were TnI+. A comparison of patients' characteristics is given in table 2.
Patients in the TnI+ group suffered from more severe forms of PE. In particular, they were older (p=0.008), more tachycardic (p=0.04); atrial fibrillation (p=0.04) and right heart failure were more frequent. Electrocardiographic and echocardiographic data suggest evidence of right ventricular dysfunction more frequently in TnI+ patients, whereas TnI− patients report more symptoms of distal PE. Lastly, TnI+ patients had prolonged hospital stay (p=0.02) but we failed to find any significant difference in the in-hospital and 6-month mortality rates between those two groups.
Troponin I kinetics
The kinetics obtained is shown in figure 1. On average, the first TnI value was already positive on admission. TnI peak occurred on average at H8. Mean peak value was 0.67±0.55 ng/ml. TnI levels decreased rapidly but remained positive (>0.06 ng/ml) beyond the 72-h surveillance period.
The TnI kinetics of patients hospitalised within 24 h after onset of symptoms (n=78) follows the same kinetics pattern with an increasing phase, a peak reached at H8 and a gradual decrease after H8. Maximum TnI level was 2.52 ng/ml.
Of 92 patients TnI− on admission, 14 (15%) subsequently had at least one positive TnI value. This delayed positive value was always confirmed by a second and third positive measurement. Regarding patients hospitalised early, misclassification would have been even greater since nine out of 31 (30%) patients admitted within 24 h after onset of symptoms and negative TnI on admission had a positive TnI on further assessment (figure 2).
In all, in our study, the second measurement performed 8 h after admission allowed us to classify all patients in their accurate biological profile. When the first two TnI measurements were negative at an 8-h interval, the biomarker status remained negative throughout hospitalisation. When an initially negative marker became positive, the finding was always made at the 2nd evaluation, 8 h after admission. Finally, when TnI was positive on admission, this initial biological profile was accurate and further assessments did not change the status of the patient.
Comparison between TnI+ patients misclassified on the first assessment and TnI− patients
As shown in table 3, patients initially misclassified with negative TnI on the first measurement (which became positive on the 2nd assessment) are significantly different from patients with negative TnI: they are older and more tachycardic. Their clinical presentation as well as the electrocardiographic and echocardiographic data is more severe. They also had longer hospital stay compared to ‘well’ classified TnI negative patients.
Discussion
Although most patients with acute PE have an uncomplicated clinical course, this condition remains severe with high hospital mortality reported in some large registries.16 Thrombolytic treatment, usually indicated in severe PE with haemodynamic impairment, may offer an alternative in those patients with normal haemodynamic status but right heart failure.17–19 TnI increase is one of the markers indicating myocardial injury and right heart failure despite normal blood pressure.20 It is crucial therefore to be aware of all the data likely to optimise TnI value interpretation in PE, particularly when early discharge or outpatient care is considered in low-risk patients, based on the TnI measurement. Currently, the most appropriate moment for accurate assessment of this biomarker value is unknown. Usually, only the first assessment on admission is considered. The example of acute coronary syndrome has taught us that in order to detect late elevations of TnI, we need to consider not only the admission value, but also the value obtained several hours after the initial chest pain.
In a previous study, Müller-Bardorff et al21 analysed troponin kinetics in patients surviving severe PE. They observed that in 4 out of 9 cases, troponin was negative at initial assessment and became positive within 8 h. However, the troponin assessed was troponin T and their kinetics was based on a small group of patients. Based on a large group of 200 patients, our data help to establish the kinetics of TnI in haemodynamic stable patients with proven PE. In all situations, when TnI was positive, the highest rate was always reached at H8. However, the intensity of the TnI peak is not useful in the setting of PE. In TnI+ patients, normalisation of TnI level occurs slowly and negative measurements can only be found more than 72 h after the first assessment. Patients with initial negative TnI that became positive on the 2nd assessment are significantly different from persistent TnI− patients, with an obvious higher risk profile, even if we failed to demonstrate any prognostic difference in this study, given our short follow-up and relatively small number of events.
The kinetics of this biomarker demonstrates that if only the first TnI assessment on admission had been considered, 15% of patients would have been misclassified as TnI negative. Based on their biological profile, these patients would have appeared to have a low risk profile and could have benefit from outpatient care in the absence of other risk factor, whereas they are indeed at intermediate risk. This misclassification rate can reach up to 30% of patients, if we consider those hospitalised early after onset of symptoms. We believe these misclassifications with the first troponin measurement occur because of delay between the right heart injury related to PE and the release of troponins.
These data may be clinically relevant. Indeed, the management of patients presenting PE may differ depending on the initial prognostic evaluation. In an ongoing multicenter randomised trial to assess the impact of thrombolytics in submassive PE without haemodynamic instability (PEITHO trial),22 TnI positivity is one of the main criteria for patient selection. On the other hand, patients without any severity criteria may be treated as outpatients after an early hospital discharge.11–13 Among the necessary conditions governing possible home care, troponin must be negative.14 Consequently, misclassification could have major repercussions. Our results highlight the situation in which, too early, a TnI measurement can be ‘false negative’.
The choice of the TnI cut-off is still debated. Actually, an AHA statement on the management of PE considers that the optimal cut-off for TnI should be 0.4 ng/ml.23 However, risk stratification according to the ESC guidelines only states the increased troponin, without any limitation regarding the cut-off value.14 Previous studies used cut-off values for TnI from 0.04–0.5 ng/ml.4 24 Given those discrepancies, we decided to use the positivity threshold given by the manufacturer for our method (0.06 ng/ml).
This study was not designed to evaluate differences in mortality. However, it tends to confirm the prognostic value of TnI. Our patients' condition was obviously more severe when this biomarker was positive. Our in-hospital mortality rate was too low to allow us to detect any difference according to the biomarker results. Among the four patients who died, three were TnI+ and died soon after admission from cardiac arrest; the fourth was TnI−. This last patient, whose initial PE was not severe, died at discharge following a documented recurrence of severe PE from a femoral deep vein thrombosis. In the next future, the ultra-sensitive troponin, not yet studied in PE, deserves specific investigations in this field of research, given that it could improve the detection of intermediate-risk PE patients.
Conclusion
Our study describes the kinetics of TnI in a series of 200 patients hospitalised for normotensive PE. A single TnI level measured on admission is associated with a 15% risk of misclassification. This risk can reach up to 30% in patients hospitalised early. According to our data, two consecutive assessments of TnI at an 8-h interval allow the correct risk stratification of patients suffering from PE and in patients with increased TnI on admission, no further blood sample for TnI assessment should be necessary.
References
Footnotes
Competing interests None.
Ethics approval Nice University Hospital ethics committee.
Provenance and peer review Not commissioned; internally peer reviewed.