Despite important advances in diagnosis and treatment,

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1 Importance of Cardiac Troponins I and T in Risk Stratification of Patients With Acute Pulmonary Embolism Stavros Konstantinides, MD; Annette Geibel, MD; Manfred Olschewski, PhD; Wolfgang Kasper, MD; Nadine Hruska, MD; Sebastian Jäckle, MD; Lutz Binder, MD Background Assessment of risk and appropriate management of patients with acute pulmonary embolism (PE) remains a challenge. Cardiac troponins I (ctni) and T (ctnt) are reliable indicators of myocardial injury and may be associated with right ventricular dysfunction in PE. Methods and Results The present prospective study included 106 consecutive patients with confirmed acute PE. ctni was elevated ( 0.07 ng/ml) in 43 patients (41%), and ctnt ( 0.04 ng/ml) was elevated in 39 (37%). Elevation of ctni or ctnt was significantly associated with echocardiographically detected right ventricular dysfunction (P and P 0.05, respectively). Moreover, a significant correlation was found between elevation of ctni or ctnt and the two major end points overall mortality and complicated in-hospital course. The negative predictive value of cardiac troponins for major clinical events was 92% to 93%. Importantly, there was obvious escalation of in-hospital mortality, the rate of complications, and the incidence of recurrent PE, when patients with high troponin concentrations (ctni 1.5; ctnt 0.1 ng/ml) were compared with those with only moderately elevated levels (ctni, 0.07 to 1.5; ctnt, 0.04 to 0.1 ng/ml). Logistic regression analysis confirmed that the mortality risk (OR) was significantly elevated only in patients with high ctni (P 0.019) or ctnt (P 0.038) levels. Furthermore, the risk of a complicated in-hospital course was almost 5 times higher (15.47 versus 3.16) in the high-ctni group compared with patients with moderate ctni elevation. Conclusions Our results indicate that ctni and ctnt may be a novel, particularly useful tool for optimizing the management strategy in patients with acute PE. (Circulation. 2002;106: ) Key Words: embolism pulmonary heart disease prognosis echocardiography Despite important advances in diagnosis and treatment, assessment of risk and appropriate management of patients with acute pulmonary embolism (PE) remains a difficult task in clinical practice. 1 Recently, two large prospective registries demonstrated that acute right ventricular dysfunction is, besides clinical and hemodynamic instability at presentation, a major determinant of outcome during the in-hospital phase of PE. 2,3 By detecting right ventricular enlargement and hypokinesis, bedside echocardiography can identify high-risk patients with overt or impending right ventricular failure 4 and possibly indicate those who may benefit from thrombolytic treatment. 5 However, the quality of ultrasound imaging may sometimes be poor in overweight or mechanically ventilated patients, as well as in those with chronic pulmonary disease. Besides, echocardiography cannot reliably diagnose acute PE in patients with certain diseases of the right ventricle or distinguish between precapillary and postcapillary causes of pulmonary hypertension. 4 Elevation of cardiac troponin I (ctni) and troponin T (ctnt) levels in serum is a reliable indicator of myocardial injury 6 and a significant predictor of subsequent cardiac events in patients with acute myocardial ischemia. 7,8 Based on this evidence, cardiac troponins are presently recommended for evaluation and management of patients presenting with unstable angina. 9,10 Recently, ctnt was reported to predict in-hospital death in patients with acute PE, 11 and elevated ctni levels were observed in patients with submassive PE. 12 In a preliminary report from one of our institutions, ctni correlated with the presence of right ventricular dilation on echocardiography. 13 We therefore conducted the prospective multicenter Management Strategies and Prognosis of Pulmonary Embolism-2 (MAPPET-2) study to define and compare the role of ctni and ctnt in the evaluation and risk stratification of patients with acute PE. Our results demonstrate that both cardiac troponins are significant predictors of mortality, a complicated in-hospital course, and recurrence of Received April 17, 2002; revision received June 17, 2002; accepted June 17, From Georg-August-Universität Göttingen, Abteilung Kardiologie und Pneumologie (S.K., N.H.); Albert-Ludwigs-Universität Freiburg, Abteilung Kardiologie und Angiologie (A.G., S.J.); Albert-Ludwigs-Universität Freiburg, Abteilung Medizinische Biometrie und Informatik (M.O.); St Josefs Hospital Wiesbaden, Innere Abteilung (W.K.); and Georg-August-Universität Göttingen, Abteilung Klinische Chemie (L.B.), Germany. Presented in part at the 74th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 11 14, 2001, and published in abstract form (Circulation. 2001;104[suppl II]:II-467). Correspondence to Stavros Konstantinides, MD, Department of Cardiology and Pulmonary Medicine, Georg August University of Goettingen, Robert Koch Strasse 40, D Goettingen, Germany. skonstan@med.uni-goettingen.de 2002 American Heart Association, Inc. Circulation is available at DOI: /01.CIR A2 1263

2 1264 Circulation September 3, 2002 PE. Importantly, ctnt and, particularly, ctni levels can be used to distinguish between low-, intermediate-, and high-risk patients and are thus valuable parameters for emergency triage of patients with PE. Methods Patient Population and Study Design A total of 106 consecutive patients (64 women, 42 men; mean age, years) with acute pulmonary embolism were included in the 3 participating centers over a period of 32 months. Clinical suspicion of PE fulfilling the MAPPET criteria 5 had to be confirmed by ventilation-perfusion lung scan, spiral CT scan, or pulmonary angiography. Patients in whom PE was an accidental finding and not the primary clinical diagnosis on admission were not included. If the patient s condition was too unstable to permit transportation from the emergency room or intensive care unit, acute massive PE was diagnosed based on echocardiographic findings of pulmonary hypertension and acute right ventricular pressure overload in the absence of left ventricular or mitral valve disease. The echocardiographic criteria of acute major or massive PE as used in the MAPPET study have been described previously. 3 Right ventricular dysfunction was defined as end-diastolic diameter 30 mm from the parasternal view or the right ventricle appearing larger than the left ventricle from the subcostal or apical view, combined with absence of inspiratory collapse of the inferior vena cava. The study protocol was approved by the local ethics committee in each institution, and written informed consent was obtained from all patients. The study was prospectively designed to test the hypothesis that cardiac troponin elevation is associated with an adverse clinical outcome in pulmonary embolism. Based on studies examining the prognostic value of troponin I in acute myocardial ischemia, 7 as well as on our experience with other prognostic indicators in PE, 14 we estimated that a minimum of 100 patients would be required to show a significant difference between troponin-positive and troponinnegative patients with regard to the clinical outcome as judged by the incidence of predefined end points. Complete information on baseline parameters as well as the patients treatment and in-hospital course was obtained by means of a standardized protocol. Our observational study did not interfere with additional diagnostic workup, nor did it influence the therapeutic decisions. The clinicians were unaware of the patients troponin levels throughout the hospital stay. Troponin Testing Blood samples were obtained on admission (clinical suspicion of PE) as well as 4, 8, and 24 hours thereafter, and serum was stored at 20 C or colder at the enrolling site before being sent to the Department of Clinical Chemistry of the University of Goettingen, where samples were stored at 80 C. Samples were later analyzed in batches after a single thaw. The investigator (L.B.) responsible for the measurements was unaware of the patients baseline parameters or clinical course. Cardiac troponin I was determined on an ADVIA Centaur Analyzer (Bayer Vital GmbH, Fernwald, Germany) according to the manufacturer s instructions. Reported values in normal healthy adults were 0.07 ng/ml. ctnt was measured on an Elecsys 2010 immunoanalyzer (Roche Diagnostics). The manufacturer reported reference values 0.04 ng/ml. Furthermore, to semiquantitatively assess the prognostic value of cardiac troponin elevation in PE, we prospectively defined secondary or upper cut-off points for ctni and ctnt. For this purpose, we selected cut-off points used in the setting of ischemic myocardial injury. For troponin I, the secondary cut-off point was set at 1.5 ng/ml, corresponding to the diagnostic limit for myocardial infarction, as previously reported by the manufacturer. For troponin T, the secondary cut-off point distinguishing between moderate and marked elevation of serum levels was set at 0.1 ng/ml. 10 Definition of Clinical End Points Statistical analysis focused on the in-hospital period. The predefined clinical end points of the study were overall mortality and complicated course, defined as death or 1 of the following: need for thrombolytic treatment, catecholamine support of blood pressure (except for dopamine at the rate of 5 g/kg per min), endotracheal intubation, or cardiopulmonary resuscitation. Of the other in-hospital events, ischemic stroke was confirmed by CT scan or autopsy, and major bleeding was defined according to standardized criteria. 14 Recurrent PE was confirmed by lung scan or spiral CT scan in all cases. Statistical Analysis The prognostic relevance of ctni, ctnt, and other important baseline parameters with respect to the two major end points and to recurrence of PE was analyzed univariately by Fisher s exact test. To additionally define the role of cardiac troponins as determinants of outcome, a multiple logistic regression model was applied to the two major end points. In this model, we distinguished between moderately elevated (ctni, 0.07 to 1.5; ctnt, 0.04 to 0.1 ng/ml) and high (ctni, 1.5; ctnt, 0.1 ng/ml) serum troponin levels. The results are presented as estimated ORs with the corresponding 95% CIs. All reported probability values are two-sided. Results Baseline Parameters: Correlation With ctni and ctnt Levels The patients clinical symptoms and major findings at presentation are shown in Table 1. Overall, 92 patients (87%) presented with dyspnea, and 87 patients (82%) had at least one predisposing factor for pulmonary embolism. ECG signs of acute right ventricular strain (at least one of the following: new-onset SI-QIII pattern, complete or incomplete right bundle-branch block, or inverted T waves in leads V 1 through V 3 ) were present in 56 patients (53%), and echocardiographic evidence of right ventricular dysfunction in 24 (23%). Significant elevation of creatine kinase levels in serum (defined as creatine kinase [CK] 80 unit/l and isoenzyme of CK with muscle and brain subunits [CK-MB] 10 unit/l) was noted in only 5 patients (4.7%). After clinical and echocardiographic examination, pulmonary embolism was confirmed by lung scan in 88 patients (83%), by spiral CT scan in 8 patients (7.5%), and by pulmonary angiography in 2 patients (1.9%). In 8 patients (7.5%), none of these procedures could be performed because of hemodynamic instability. In these latter cases, acute massive PE was diagnosed on the basis of clinical and echocardiographic findings. 3 Cardiac troponin I was elevated ( 0.07 ng/ml) in 43 of the 106 patients (41%), and troponin T ( 0.04 ng/ml) in 39 (37%). In all but 2 patients, the highest measured ctni or ctnt levels were those from either the first or the second serum probe, ie, those obtained within the first 4 hours after clinical suspicion of PE. As shown in Figure 1, elevation of ctni or ctnt was significantly associated with ECG signs of right ventricular strain and echocardiographically detected right ventricular dysfunction. On the other hand, troponin levels did not correlate significantly with arterial hypotension (Figure 1) or other clinical baseline parameters (not shown). Predictors of In-Hospital Clinical Events Table 2 shows the incidence of in-hospital clinical events in the study population. Overall, 7 patients (6.6%) died and 19

3 Konstantinides et al Troponins in Pulmonary Embolism 1265 TABLE 1. Clinical Symptoms and Relevant Findings at Presentation Parameter n (%) Acute symptom onset (within 24 h) 54 (51) Syncope 30 (28) Focal neurological deficits 1 (1.0) Peripheral arterial occlusion* 3 (2.8) Hemodynamic instability 5 (4.7) Recent major surgery (within 14 d) 22 (21) Recent major trauma (within 14 d) 3 (2.8) History of venous thrombosis 31 (29) History of pulmonary embolism 20 (19) Chronic pulmonary disease 10 (9.4) Cancer 27 (25) ECG SI-QIII pattern 28 (26) Complete/incomplete RBBB 19 (18) Inverted T waves in V 1 through V 3 31 (29) Cardiac ultrasound Enlargement of RV 47 (44) Paradoxical septal wall 23 (22) Congested IVC 36 (34) Laboratory findings CK 80 U/L 13 (12) CK-MB 10 U/L 16 (15) RBBB indicates right bundle-branch block; RV, right ventricle; and IVC, inferior vena cava. *Clinical and laboratory findings signifying renal, intestinal, or limb ischemia. Systolic blood pressure persistently 90 mm Hg with or without signs of cardiogenic shock. Right ventricular end-diastolic diameter 30 mm from the parasternal view, or right ventricle appearing larger than the left ventricle from the subcostal or apical view. patients (18%) had a complicated course, as defined in the Methods. Of the clinical baseline parameters, only hemodynamic instability at presentation (defined as systolic blood pressure persistently 90 mm Hg with or without signs of cardiogenic shock) was significantly associated with mortality or in-hospital complications (Figures 2A and 2B). Echocardiographic detection of right ventricular dysfunction was also significantly more frequent in patients who died during the acute phase (Figure 2A). Moreover, obvious differences existed between patients with and without either major end point with regard to elevation of ctni, ctnt, and CK/CK-MB levels (Figure 2). Because of the larger number of events, these differences were particularly significant when the combined end point complicated in-hospital course was analyzed (Figure 2B versus Figure 2A). In fact, the negative predictive value of elevated ctni for a complicated clinical course was as high as 92%, and that of ctnt was as high as 93%. As can be seen in Figure 2B, however, troponin elevation was also found in patients with uncomplicated PE (ctni, 24%; ctnt, 28%), and thus the positive predictive value of ctni and ctnt for a complicated course was relatively low (37% and 41%, respectively). CK/CK-MB elevation seemed to be more Figure 1. Correlation between cardiac troponin levels and relevant findings at presentation. Hatched bars represent patients without ctni ( 0.07 ng/ml; A) or ctnt ( 0.04 ng/ml; B) elevation; filled bars, patients with elevated ctni (A), or ctnt (B) levels. Hypotension denotes systolic blood pressure persistently 90 mm Hg; ECG, at least one of the following: SI-QIII pattern, complete/incomplete right bundle-branch block, or inverted T waves in V 1 through V 3 ; echo, right ventricular dysfunction on cardiac ultrasound as defined in the Methods; and CK, CK levels 80 U/L and CK-MB isoenzyme levels 10 U/L. *P 0.05; **P specific with regard to prognosis, because it was almost absent in patients who survived without major clinical events (Figure 2). However, as mentioned above, its overall incidence was very low, thus limiting its sensitivity. Finally, cardiac troponins were also significantly associated with recurrence of PE during the hospital stay (P for both ctni and ctnt). TABLE 2. In-Hospital Clinical Events Event n (%) Death (all causes) 7 (6.6) Thrombolytic treatment 8 (7.5) Catecholamine administration 13 (12) Endotracheal intubation 10 (9.4) Cardiopulmonary resuscitation 2 (1.9) Ischemic stroke 0 Peripheral arterial embolism 1 (1.0) Major bleeding 7 (6.6) Recurrent pulmonary embolism 7 (6.6)

4 1266 Circulation September 3, 2002 Figure 2. Correlation between baseline parameters and the clinical end points mortality (A) or complicated in-hospital course (B). In both panels, hatched bars represent patients who did not reach the end point and filled bars represent those who died (A) or had a complicated clinical course (B). Instability indicates systolic blood pressure persistently 90 mm Hg with or without signs of cardiogenic shock; ECG, echo; CK, see legend to Figure 1; TropI, troponin I serum levels 0.07 ng/ml; and TropT, troponin T levels 0.04 ng/ml. *P 0.02; **P Cardiac Troponins in Risk Stratification of Patients With Acute PE Studies in patients with unstable coronary artery disease have reported that the risk of cardiac events increases progressively with increasing levels of ctnt obtained in the first 24 hours. 15 We therefore examined whether such a relationship between ctni or ctnt levels and prognosis might also apply to patients with acute PE. There was indeed obvious escalation of in-hospital mortality, the rate of clinical complications, and the incidence of recurrent PE, not only when the patient groups with and without troponin elevation were compared with each other, but, importantly, also when patients with high levels of ctni ( 1.5 ng/ml) or ctnt ( 0.1 ng/ml) were compared with those with only moderate elevation of serum troponin concentrations (0.07 to 1.5 and 0.04 to 0.1 ng/ml, respectively; Figures 3A and 3B). In support of these findings, evidence of right ventricular dysfunction on echocardiography was present in 18% of patients without ctnt elevation as opposed to 20% of patients with moderate elevation and 48% of those with high ctnt levels. For ctni, the frequency of right ventricular dysfunction in the 3 groups was 9.6%, 43%, and 50%, respectively. Figure 3. Escalation of in-hospital mortality, complication, and pulmonary embolism recurrence rates depending on baseline levels of ctni (A) or ctnt (B). Open bars represent patients without ctni ( 0.07 ng/ml; A) or ctnt ( 0.04 ng/ml; B) elevation; hatched bars, patients with moderately elevated ctni (0.07 to 1.5 ng/ml; A) or ctnt (0.04 to 0.1 ng/ml; B) concentrations in serum; and filled bars, those with high ctni ( 1.5 ng/ml; A) or ctnt ( 0.1 ng/ml; B) levels. Logistic regression analysis applied to the two major end points confirmed these observations (Table 3). Thus, the mortality risk (OR) was significantly elevated (P 0.019) in patients with high but not in those with moderately elevated ctni levels. Similarly, the risk (OR) of a complicated in-hospital course was almost 5 times higher (15.47 versus TABLE 3. Cardiac Troponins as Determinants of Outcome in Acute Pulmonary Embolism Event ctni, ng/ml Overall In-Hospital Mortality OR (95% CI) Complicated In-Hospital Course OR (95% CI) ( ) 3.16 ( ) P P ( ) ( ) P P ctnt, ng/ml ( ) 4.43 ( ) P P ( ) 8.71 ( ) P P Complicated in-hospital course was defined as explained in Methods.

5 Konstantinides et al Troponins in Pulmonary Embolism ) when patients with high ctni levels were compared with those with only moderate elevations. Directionally similar but slightly less pronounced differences were observed for high versus moderately elevated ctnt levels (Table 3). Of note, no adjustments for other baseline parameters were made when multiple comparisons of troponin levels were performed. Finally, multivariate logistic regression analysis also revealed that elevation of creatine kinase concentrations was not an independent predictor of a complicated in-hospital course (OR 1.80; 95% CI, 0.41 to 7.92, when adjusted for ctni, and OR 1.36; 95% CI, 0.26 to 7.27, when adjusted for ctnt). Discussion The importance of risk stratification of patients with acute pulmonary embolism is highlighted by the results of major clinical studies that reported in-hospital mortality rates ranging from 1% to 30%, depending on the clinical and hemodynamic profile of the patients included Considering such apparently contradicting data, it is not surprising that the appropriate treatment of patients with acute PE, with the exception of those presenting with overt right ventricular failure and cardiogenic shock, remains the subject of controversial discussions. 19 Right ventricular dysfunction has been recognized as a key determinant of prognosis in PE, 20 and the validity of bedside echocardiography for its detection has repeatedly been emphasized. 3,4,21 This thesis is also supported by the results of the present study. However, echocardiography has some technical limitations, and it cannot be used for quantitative assessment of the severity of right ventricular damage and dysfunction. The results of the present prospective study in 106 consecutive, unselected patients with confirmed PE extend previous observations 11 and indicate that ctni and ctnt may be novel, particularly useful tools for optimizing the management strategy in patients with acute PE. The findings of our study can be summarized in the following points. First, ctni and ctnt correlate significantly with electrocardiographic and echocardiographic parameters of right ventricular pressure overload and myocardial dysfunction. Second, the maximum levels of cardiac troponins in serum can be obtained within 4 hours of the clinical suspicion of PE. Third, ctni and ctnt are significantly associated with overall mortality, major clinical events, and recurrence of PE during the hospital stay. Fourth, the negative predictive value of both cardiac troponins with regard to a complicated in-hospital course is high (92% to 93%), suggesting that patients with PE but no troponin elevation at presentation have a good prognosis, at least in the acute phase. Fifth, distinguishing between moderate and pronounced elevation of ctnt and ctni levels correlates with the incidence of echocardiographically detected right ventricular dysfunction and can classify troponin-positive patients with acute PE into an intermediate- and a high-risk group with regard to mortality and major clinical events. Although the results obtained with both cardiac troponins were directionally similar, the slight superiority of ctni compared with ctnt in risk assessment of PE seems to be supported by existing evidence in favor of ctni. 8,22 However, some investigators observed no appreciable differences in the prognostic value of ctni and ctnt, 9 and our own data cannot be interpreted as favoring one cardiac troponin over the other for risk stratification of acute PE in clinical practice. In the present study, all measurements were performed in one central core laboratory (Department of Clinical Chemistry, University of Goettingen), and the same assays for ctni and ctnt were used in all patients. However, the possibility of some imprecision remains, particularly at low ctni or ctnt concentrations, and present problems with standardization of troponin measurements between different laboratories 23 may limit the generalization of our cut-off points. In addition, it cannot be excluded that significant coronary artery stenosis or even an acute coronary syndrome may have been present in some of the study patients, thus limiting the specificity of troponin measurements. However, all patients had clinical suspicion of PE based on standardized criteria, and the study protocol required confirmation of PE in all cases. Therefore, additional diagnostic workup, and particularly invasive coronary angiography to exclude concomitant coronary artery disease, was not deemed appropriate. Finally, the results of D-dimer assays, an established, particularly sensitive laboratory tool in the diagnosis of PE, were not analyzed in our study, because we focused on risk stratification of patients with confirmed PE. In conclusion, the results of the present prospective study demonstrate the prognostic value of cardiac troponin elevation in acute pulmonary embolism. Thus, our data combined with the results of previous studies strongly support the integration of troponin testing into the risk stratification and management of patients with established PE. Additional therapeutic trials are now needed to determine whether cardiac troponins, alone or in combination with clinical or echocardiographic parameters of right ventricular dysfunction, can be used to guide treatment of patients with pulmonary embolism and, particularly, improve the prognosis of high-risk patient groups. Acknowledgments We are grateful to Sigrid Keusemann for her skillful technical assistance in handling of the serum probes and performance of the troponin measurements. References 1. Konstantinides S, Kasper W. Pulmonary embolism. In: Massie BM, Drexler H, eds. Cardiology. London: Mosby International; 2001: Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353: Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol. 1997;30: Kasper W, Konstantinides S, Geibel A, et al. Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart. 1997;77: Konstantinides S, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation. 1997;96: Katus HA, Remppis A, Neumann FJ, et al. Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation. 1991;83:

6 1268 Circulation September 3, Galvani M, Ottani F, Ferrini D, et al. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina. Circulation. 1997;95: Hamm CW, Goldmann BU, Heeschen C, et al. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med. 1997;337: Morrow DA, Cannon CP, Rifai N, et al. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-st elevation myocardial infarction: results from a randomized trial. JAMA. 2001;286: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on the management of patients with unstable angina). Circulation. 2000;102: Giannitsis E, Muller-Bardorff M, Kurowski V, et al. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. Circulation. 2000;102: Douketis JD, Crowther MA, Stanton EB, et al. Elevated cardiac troponin levels in patients with submassive pulmonary embolism. Arch Intern Med. 2002;162: Meyer T, Binder L, Hruska N, et al. Cardiac troponin I elevation in acute pulmonary embolism is associated with right ventricular dysfunction. J Am Coll Cardiol. 2000;36: Konstantinides S, Geibel A, Kasper W, et al. Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism. Circulation. 1998;97: Lindahl B, Venge P, Wallentin L. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease: the FRISC study group. Circulation. 1996;93: Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med. 1992;326: Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet. 1992;340: Alpert JS, Smith R, Carlson J, et al. Mortality in patients treated for pulmonary embolism. JAMA. 1976;236: Konstantinides S, Geibel A, Kasper W. Submassive and massive pulmonary embolism: a target for thrombolytic therapy? Thromb Haemost. 1999;82(suppl 1): Cannon CP, Goldhaber SZ. Cardiovascular risk stratification of pulmonary embolism. Am J Cardiol. 1996;78: Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation. 2000;101: Adams JE III, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I: a marker with high specificity for cardiac injury. Circulation. 1993;88: Quinn MJ, Moliterno DJ. Troponins in acute coronary syndromes: more TACTICS for an early invasive strategy. JAMA. 2001;286: