Troponin I as a risk stratification marker in acute pulmonary artery embolism*

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1 Original article 1 Troponin I as a risk stratification marker in acute pulmonary artery embolism K. Keller 1 ; J. Beule 2 ; A. Schulz 3 ; W. Dippold Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz und Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, ehemals Klinik für Innere Medizin des Katholischen Klinikums Mainz (KKM), St. Vincenz und Elisabeth Hospital Mainz; 2 Klinik für Innere Medizin des Katholischen Klinikums Mainz (KKM), St. Vincenz und Elisabeth Hospital Mainz; 3 2. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz; 4 Chefarzt der Klinik für Innere Medizin des Katholischen Klinikums Mainz (KKM), St. Vincenz und Elisabeth Hospital Mainz Keywords Troponin, risk stratification, pulmonary artery embolism, RV dysfunction Summary Introduction: An acute pulmonary artery embolism (PE) constitutes a cardiovascular emergency with high mortality. Studies have proved a relationship between positive troponin and right ventricular dysfunction (RVD) on one hand, and an increased mortality rate associated with acute PE on the other. The objective of our study was to investigate the connection between symptoms and examination findings, and particularly troponin levels and RVD. Methods: We retrospectively analysed the medical histories of 179 patients who were treated for acute PE in The patients were assigned to the PE group with or without RVD. Correspondence to: Dr. med. Karsten Keller 2. Medizinische Klinik und Poliklinik Universitätsmedizin Mainz Langenbeckstr. 1, Mainz/Germany Tel /17 Karsten.Keller@unimedizin-mainz.de This study has been realised in the Klinik für Innere Medizin, Katholisches Klinikums Mainz St. Vincenz und Elisabeth Hospitals Mainz (Chief physician Prof. Dr. med. W. Dippold). The patient data were focused on the troponin I levels and any RVD was assessed and statistically analysed. Results: The PE patients with RVD had a higher troponin level than patients without RVD (.8 ng/ml vs..1 ng/ml, p). The multivariable regression analysis showed a highly significant relationship between increased troponin levels and RVD (OR, 3.98; 95%CI: , p). The calculated optimum cutoff for troponin I for identifying RVD was.1 ng/ml (ROC curve analysis: AUC=.86). Conclusions: There is a close relationship between elevated troponin I levels and RVD in acute PE. Troponin I levels above.1 ng/ml indicate RVD associated with acute PE. Furthermore, D-dimer, systolic pulmonary artery pressure and increased heart rate, a lower systolic blood pressure, dyspnoea, syncope, collapse, hypotension, tachycardia, RBBB and S1-Q3-type are seen more often with RVD. Troponin I als Risikostratifikationsmarker bei akuter Lungenarterien embolie Phlebologie 213; 42: DOI: /phleb2138_5_213 Received: April 13, 213 Accepted: June 18, 213 An acute pulmonary artery embolism (PE) constitutes a cardiovascular emergency with high morbidity and mortality (1 4). Despite advances in medicine, the mortality rate in the acute phase is still 7 15 % (2 8). In pathophysiological terms a PE occurs when parts of the pulmonary arterial circulation are occluded by the thrombotic material (1, 4, 8). If the occlusion is haemodynamically relevant it results in increased pulmonary artery pressure (PAP) with right ventricular dysfunction (RVD) of the heart (1, 2, 4, 8 12). Depending on the extent of the RVD, the patient is threatened with a fall in cardiac output, reduced coronary perfusion, or even myocardial infarction and cardiogenic shock, right heart failure and, as a consequence of these changes, circulatory arrest and death (2, 4, 8, 1). The risk of death and complications of acute PE are closely linked to the initial haemodynamic stability and the cardiac changes (2 5, 8 11, 13, 14). Thus the ESC guidelines recommend a risk-adapted classification of acute PE (4, 8, 15). According to this classification, patients with haemodynamic instability are assigned to a high risk PE group; those with haemodynamic stability are assigned to a non-high risk PE group (3, 4, 8, 15). Those patients in the high risk PE group present as acute life-threatening emergencies with a high mortality rate of >15 % in the first 3 days after the event (1, 3 5, 8). Patients in the non-high risk PE group are assigned to the patient group with intermediate and low risks on the basis of RVD and the markers for direct cardiac in-

2 2 K. Keller et al.: Troponin I as a risk stratification marker volvement, particularly the myocardial ischaemia marker troponin (1, 3, 4, 8). This is important because haemodynamically stable patients with RVD and/or positive troponin levels also show increased early mortality of 3 15 % in the first 3 days after the PE event (1, 4, 1). The haemodynamically stable PE patients without RVD and without positive troponin levels have the best prognosis with an early mortality rate of <2 % (1, 4, 8, 1). As already integrated in the ESC guidelines, cardiac ischaemia markers such as troponin are highly sensitive and specific markers for myocardial damage besides the morphological changes to the heart and are a useful addition for risk stratification in patients with acute PE (2, 4 6, 8 18). The correlation between increased troponin levels in patients with acute PE and a higher mortality rate has been proved in a number of studies (2, 4 6, 8 12, 14 16). The objective of our study was to investigate the connection between symptoms and examination findings, and particularly troponin levels and RVD. Further, troponin cutoff points for the presence of RVD on the one hand, and patient deaths in hospital after a PE were also to be determined. Patients and methods The study retrospectively analysed the characteristics of the medical histories of 179 patients who had been treated for acute PE at the Medical Department in the period May 26 to June 211. In order to identify patients with acute PE in the department s own IT system the patient data from the given period were searched for the DRG code I26. The patient data were analysed with regard to the history, comorbidities, complications, physical, laboratory chemical and technical examinations. We only included patients in the study who were > 18 years old when they were treated and who had confirmed PE. The diagnosis of a PE was seen as confirmed if a multidetector spiral computed tomography with CT angiography (MDS- CT-A) had demonstrated a filling defect in the pulmonary arterial system, or if the findings of a ventilation/perfusion scintigraphy of the lung indicated a high probability of a PE, or if there was evidence of a deep vein thrombosis (DVT) in a duplex ultrasonography or a phlebography with typical symptoms of acute PE (chest pain and/or dyspnoea) and a positive D-dimer level. All the radiological examinations were reported by experienced hospital radiologists. The patients were assigned to the group with RVD (PE group with RVD) or the group without RVD (PE group without RVD) on the basis of the echocardiography and computer-assisted tomography findings. In accordance with the ESC Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism (8) and the AHA scientific statement for management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension from 211 (19) RVD was defined as abnormal movement of the interventricular septum, right ventricular (RV) dilatation (quotient of the right ventricular end-diastolic diameter/left ventricular enddiastolic diameter >.9), right ventricular hypokinesia and right ventricular strain with tricuspid regurgitation (>I ) in the echocardiography or RV dilatation in the MDS-CT-A (quotient of the right ventricular end-diastolic diameter/left ventricular end-diastolic diameter >1.) (1, 4, 6, 8 1, 15, 19). Pulmonary hypertension was defined as a mean PAP of > 25 mmhg at rest on echocardiography (2, 21). Systolic PAP raised to >3 mmhg is determined by echocardiography. The comorbidities and complications recorded were infarction pneumonia, DVT, tumours and death during the inpatient period. Current tumours and a history of tumours were pooled as tumours. The patients laboratory parameters troponin I, CK, creatinine and D-dimer were analysed. Statistical analysis The data were analysed statistically using several statistical tests on the R Development Core Team (212) analytical software (R Foundation for Statistical Computing, Vienna, Austria). The two groups were compared using the Wilcoxon-Mann-Whitney test. A multivariable logistical regression analysis was run to assess the relationship between RVD and the parameters age, sex, troponin level, CK, creatinine, D-dimer and the heart rate. The effectiveness of troponin I as a marker was assessed by an ROC analysis to predict, first, RVD and, second, death in hospital after a PE event. The Youden index was applied to calculate the optimum cutoff for troponin levels for identifying RVD and an increased mortality risk. We also calculated the sensitivity, the specificity, the positive predictive value, and the negative predictive value. The significance threshold was set at p=.5. Results A total of 179 patients with confirmed PE were treated at the Medical Department and included in the study between May 26 and June 211. PE was confirmed by MDS-CT-A in 153 patients, by ventilation/ perfusion scintigraphy in 17 patients, and diagnosed by confirming DVT with typical symptoms of PE and a positive D-dimer level in 9 patients. Four of the 179 patients were assigned to the high risk PE group (systolic blood pressure <9 mmhg). The remaining 175 patients belonged to the haemodynamically stable non-high risk PE group. The median age of the PE patients was 72. years (61./81.). The majority of the PE patients were female (61.5 %). A high percentage of the patients presented with the typical PE symptoms dyspnoea, tachycardia, chest pain and/or syncope. Dyspnoea was the most commonly reported symptom at >8 % ( Fig. 1). Furthermore, more than 2/3 of our PE patients had DVT. Almost 1/4 of the patients reported having had a DVT or PE sometime in the past ( Tab. 1). The comparison between the two PE groups with and without RVD showed that the median age of the patients with RVD was 5 years higher than those without RVD Phlebologie 5/213 Schattauer 213

3 K. Keller et al.: Troponin I as a risk stratification marker 3 (75. years vs. 7. years, p=.1). The groups did not differ with regard to sex, comorbidities, complications or previous disorders ( Tab. 1). The symptoms dyspnoea (87.6 % vs %, p=.39), syncope or collapse (16.9 % vs. 4.4 %, p=.14), hypotension (11.2 % vs. 1.1 %, p=.12) and tachycardia (53.9 % vs %, p) were reported significantly more frequently for the patients with RVD ( Tab. 1). Fig. 1 Symptoms of PE patients. Cardiogenic shock Haemoptysis Hypotension Syncope or collapse 1.65% 3.31% 7.14% 1.99% Chest pain Tachycardia 32.97% 36.81% Dyspnoea % 25% 5% 75% 81.32% 1% Tab. 1 Data of the PE groups with and without RV dysfunction. Continuous variables are given with the median, 25th and 75th percentiles. Variables with almost normal distribution are presented as mean values and standard deviation. Discrete variables are given with relative and absolute frequencies. The p value from the statistical comparison between the groups is shown in the right column. Number of patients Female Age (years) Death during inpatient hospitalisation Infarction pneumonia DVT Surgery or trauma in the last 3 months preceding pulmonary artery embolism History of DVT or PE Tumour now or previously Symptoms Chest pain Dyspnoea Haemoptysis Syncope or collapse All patients % (112) 72. (61./81.) 2.7% (5) 45.1% (82) 66.5% (121) 18.1% (33) 23.9% (43) 2.7% (37) 33.% (6) 81.3% (148) 3.3% (6) 11.% (2) No RV dysfunction % (56) 7. (61.9/77.1) 1.1% (1) 4.% (36) 66.7% (6) 18.9% (17) 23.9% (21) 15.6% (14) 35.6% (32) 74.4% (67) 2.2% (2) 4.4% (4) RV dysfunction % (54) 75. (6./81.) 4.5% (4) 49.4% (44) 66.3% (59) 18.% (16) 23.6% (21) 25.8% (23) 31.5% (28) 87.6% (78) 4.5% (4) 16.9% (15) p Hypotension 7.1% (13) 1.1% (1) 11.2% (1).12 Cardiogenic shock 1.6% (3) % () 3.4% (3).24 Tachycardia 36.8% (67) 18.9% (17) 53.9% (48) ECG changes Complete or incomplete RBBB 13.1% (23) 6.9% (6) 18.8% (16).35 S1-Q3 type 9.7% (17) 4.6% (4) 15.3% (13).36 Vital parameters Systolic blood pressure (mmhg) (126./166.) (13./167.8) 138. (124.67/162.33).36 Diastolic blood pressure (mmhg) ± ± ± Heart rate (/min) 91. (76./14.) 81. (71.8/97.) 1. (85./111.3) Laboratory parameters Troponin I (ng/ml).2 (/.13).1 (/.3).8 (.2/.28) CK (U/L) 63. (43.7/97.7) 62. (46./92.7) 65. (41./11.3).95 Creatinine (mg/dl) 1. (.9/1.2) 1. (.8/1.1) 1.1 (.97/1.4) D-dimer (ng/ml) 1.54 (.84/2.95) 1.19 (.67/2.15) 1.87 (1.7/3.38).47 Echocardiography PA pressure (mmhg) ± ± ± 15.61

4 4 K. Keller et al.: Troponin I as a risk stratification marker Heart rate (beats/min) Fig. 2 Heart rate in the two PE groups with and without RV dysfunction (boxplot graph). Pulmonary arterial pressure (mmhg) Fig. 3 Pulmonary arterial pressure (PAP) in the two PE groups with and without RV dysfunction (boxplot graph). RV dysfunction Sex Age log(troponin) CK Creatinine D-dimer Heart rate C-Index.852 R2.461 D-Dimer (ng/ml) Fig. 4 D-dimer in the two PE groups with and without RV dysfunction (boxplot graph). Troponin (ng/ml) OR (95% CI) per 1 SD.71 ( ).936 ( ) ( ) ( ) ( ) 1.5 ( ) ( ) Fig. 5 Troponin I in the two PE groups with and without RV dysfunction (boxplot graph). p Tab. 2 Multivariable logistic regression analysis to assess a correlation between RV dysfunction and various other variables. The table shows the odds ratio with a 95% confidence interval and the p value. The ECG changes showing complete or incomplete right bundle branch block (RBBB) (18.8 % vs. 6.9 %, p=.35) and an S1-Q3 type (15.3 % vs. 4.6 %, p=.36) occurred more frequently in the PE group with RVD ( Tab. 1). A lower systolic blood pressure (138 mmhg vs. 152 mmhg, p=.36) and a higher heart rate (1/min vs. 81/min, p) was recognisable in the PE group with RVD ( Fig. 2, Tab. 1). The systolic PAP in those patients with RVD was significantly higher than in those without RVD (42.3 mmhg vs mmhg, p) ( Fig. 3, Tab. 1). The laboratory values for creatinine (1.1 mg/dl vs. 1. mg/dl, p), D-dimer (1.87 ng/ml vs ng/ml, p=.47) and troponin (.8 ng/ml vs..1 ng/ml, p) were higher in the patients with RVD than in those without RVD ( Tab. 1, Fig. 4 and Fig. 5). The regression analysis showed a highly significant relationship between increased troponin levels and RVD (OR, 3.98; 95 %CI: , p). There were no significant relationships for the other laboratory parameters, heart rate, age or sex ( Tab. 2). The calculated optimum cutoff for troponin I for identifying RVD was.1 ng/ ml (ROC curve analysis: AUC=,86). The calculated optimum cutoff for troponin I as a marker for increased mortality in hospital was.48 ng/ml (ROC curve analysis: AUC =.719) ( Fig. 6). The cutoffs with sensitivity, specificity, positive and negative predictive value are listed in Tab. 3. Discussion Acute PE is a life-threatening emergency with a mortality rate of up to 3 % (1 4, 7, 8, 18). A haemodynamically relevant occlusion of parts of the pulmonary circulation by the thrombotic material is associated with a rise in PAP and RVD of the heart (1, 2, 4, 8, 9, 11, 15). There is a potential for reduced coronary perfusion, a fall in cardiac output, myocardial damage or even death as a result of the PE event (2, 4, 8). The prognosis, as well as the risks of mortality and complications of an acute PE Phlebologie 5/213 Schattauer 213

5 K. Keller et al.: Troponin I as a risk stratification marker 5 depend directly on the initial haemodynamic stability and RVD in PE patients (1 4, 6, 8, 9, 11, 12, 15). RVD is associated with increased rates of mortality and complications (1 4, 8, 1, 12, 15). Therefore it is important to identify patients with RVD early (1, 2, 1 12, 14). Besides the morphological changes to the heart, cardiac laboratory markers like troponin, a highly sensitive and specific marker, indicate myocardial damage (1, 2, 4, 6, 8, 9, 12, 14, 15, 18, 22, 23). Troponin is used to confirm myocardial ischaemia (6, 9, 12, 14, 16, 22 26). Besides acute coronary syndrome, increased troponin levels are also observed with heart defects, cardiomyopathy, myocarditis, tachycardia, exacerbated COPD and acute PE (2, 3, 6, 9 11, 14, 17, 23 25, 27). The troponin level is a prognostic marker in acute coronary syndrome, exacerbated COPD, dilatative cardiomyopathy, and acute PE. An elevated troponin level indicates a poorer prognosis and an increased risk of mortality (2, 5, 6, 1, 12, 14, 18, 23, 24, 27). A large number of studies have shown that there is a connection between elevated troponin levels and a higher mortality rate in patients with acute PE (2, 4 6, 8 12, 14 16, 18, 22, 24). The 3-month mortality rate in PE patients with elevated troponin levels is 3.5 times higher than in PE patients with normal troponin levels (5, 8, 1). 65 %. The positive predictive value was 7 %, the negative predictive value 78 %. Thus the troponin I level must be classified as a helpful marker for predicting RVD associated with PE events. Hence troponin has already been included in the ESC guidelines (8) and the AHA Statement (19) for risk stratification of acute PE. A positive troponin level indicates myocardial damage that occurs in a high percentage of cases as a result of the right ventricular strain associated with RVD following a pulmonary artery embolism. In view of its sensitivity of 5 %, specificity of 93 %, and a positive predictive value of 15 %, troponin I levels do not seem particularly promising in terms of these parameters for predicting death in hospital. Death in hospital occurred more often above the cutoff of.48 ng/ml. However, the very high negative predictive value of 99 % shows that PE patients whose troponin I level is not elevated can only very rarely be expected to die in hospital. Besides the troponin I levels, the D-dimer levels and the creatinine levels were also significantly elevated in RVD. D-dimer is a degradation product of crosslinked fibrin (8, 26, 28 3). An elevated D-dimer level results from a fibrin clot with simultaneous activation of coagulation and fibrinolysis (8, 29). A normal D-dimer level rules out an acute PE in hae- Sensititvity ROC plot for Troponin Specificity Fig. 6 ROC plot and AUC calculation for the connection between the troponin I level and RV dysfunction. AUC=.86 modynamically stable patients with a high degree of probability (8, 28). D-dimer has a high negative predictive value (8, 28). Even if D-dimer reacts highly specifically for fibrin, the specificity for a diagnosis of DVT or PE is low (8). A large number of different conditions such as cancer, inflammation, infection, necrosis and dissections of the aorta can also lead to elevated D-dimer levels (8, 29). Therefore, the positive predictive value is low (8) and a diagnosis of PE or DVT cannot be made on the strength of a positive D-dimer value alone (8). A troponin assay is a useful supplement for risk stratification in patients with acute PE (2, 4 6, 8 1, 12, 14 16, 18, 24, 26). This study was proposed to investigate whether measurements of the troponin I level in PE patients allows a conclusion to be drawn regarding increased right ventricular strain with RV dysfunction and whether it is possible to estimate the severity of the PE. Our study has confirmed that there is a close correlation between troponin I levels and RVD. The troponin I level in PE patients with RVD was significantly higher than that in PE patients without RVD. The calculated optimum cutoff for troponin I above which RVD is to be expected was.1 ng/ml. The sensitivity of the troponin I level for predicting RVD was reasonable at 82 %; the specificity was lower at Tab. 3 ROC analysis with calculation of the Youden index to assess the effectiveness of troponin I as a marker for predicting, first, RVD and, second, death in hospital after a PE event. The sensitivity, specificity, the positive predictive value and the negative predictive value were also calculated. Connection between troponin I and RV dysfunction Sensitivity Specificity Positive predictive value Negative predictive value Youden cutoff level for troponin I (ng/ml) Connection between troponin I and death Sensitivity Specificity Positive predictive value Negative predictive value Youden cutoff level for troponin I (ng/ml) Value Value L 95% CI L 95% CI U 95% CI U 95% CI

6 6 K. Keller et al.: Troponin I as a risk stratification marker Together with our own study results several studies have classified D-dimer as a helpful and useful risk stratification marker in acute PE for detecting RVD (29 34). The degree of D-dimer elevation in the studies correlated directly with the severity of the PE and the mortality rate after the PE event (29, 3, 32 34). The absolute value of the D-dimer levels was directly related to both RVD and the thrombus burden in the pulmonary artery vascular bed (29, 34). The elevated creatinine levels are probably due to the higher ages of the patients in the PE group with RVD. Creatinine levels increase with age while the glomerular filtration rate decreases with age. These changes start as early as the third decade of life, even in healthy adults (35 37). On the other hand, older patients commonly have more comorbidities such as chronic renal failure that are associated with an increased risk of PE (38) and can also increase the risk of RVD after a PE. The symptoms dyspnoea, syncope and collapse, hypotension and tachycardia are still indicative of RVD. This agrees with the study by Agterof et al. (31), that found an 8.1 times increase in the rate of serious complications in PE patients with tachycardia during the first 1 days after the acute PE event (31). In our study RVD led to a significantly lower systolic blood pressure and a heart rate that was almost 2 beats faster. ECG changes showing incomplete or complete RBBB or an S1-Q3 type were also more frequent in patients with RVD, as already described in the literature (8, 19). In the patients with RVD the systolic PAP was 2 mmhg higher on average than Conclusions There is a close relationship between elevated troponin I levels and RVD in acute PE. Troponin I levels above.1ng/ml indicate RVD associated with acute PE. Furthermore, D-dimer, PAP and an increased heart rate, a low systolic blood pressure, dyspnoea, syncope and collapse, hypotension and tachycardia, RBBB and an S1-Q3 type are encountered more often in acute PE with RVD. in those without RVD. This is not surprising since RVD is usually associated with increased PAP. Therefore, a number of studies have already added increased systolic PAP at the time of the acute PE to the criteria for RVD (8, 19, 39). A relevant occlusion of the pulmonary artery vascular bed by the thrombotic material is associated with increased PAP and the onset of RVD (1, 2, 4, 8, 9, 11, 15). RVD is found in more than 25 % of patients with acute PE (8). Increased PAP at the time of the acute PE event affects both the cardiovascular and the pulmonary systems. The study by Korkmaz et al. 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