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A novel prognostic indicator for in-hospital and 4-year outcomes in patients with pulmonary embolism: TIMI risk index
Journal of Critical Care 41 (2017) 183–190
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A novel prognostic indicator for in-hospital and 4-year outcomes in patients with pulmonary embolism: TIMI risk index Muhammed Keskin, MD a,⁎, Tolga Sinan Güvenç, MD b, Mert İlker Hayıroğlu, MD a, Adnan Kaya, MD c, Mustafa Adem Tatlısu, MD d, Şahin Avşar, MD e, Ahmet Öz, MD a, Taha Keskin, MD f, Ahmet Okan Uzun, MD g, Ömer Kozan, MD, Prof. a a
Sultan Abdulhamid Han Training and Research Hospital, Department of Cardiology, Istanbul, Turkey Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Center, Training and Research Hospital, Department of Cardiology, Istanbul, Turkey c Duzce University, Department of Cardiology, Duzce, Turkey d Texas A&M University, Department of Cardiology, TX, USA e Urla State Hospital, Urla, Izmir, Turkey f Yeshiva University, Albert Einstein College of Medicine, Montefiore Medical Center, Department of Allergy/Immunology, Bronx, New York, USA g Dortyol State Hospital, Department of Cardiology, Dortyol, Hatay, Turkey b
a r t i c l e
i n f o
Available online xxxx Keywords: TIMI risk index Pulmonary embolism Mortality Risk stratification
a b s t r a c t Background: Thrombolysis in Myocardial Infarction (TIMI) risk index (TRI) was recently evaluated in patients with acute myocardial infarction and found as an important prognostic index. In the current study, we evaluated the prognostic value of TRI in patients with moderate-high and high risk pulmonary embolism (PE) who were treated with thrombolytic agents. Methods: We retrospectively evaluated the in-hospital and long-term (4-year) prognostic impact of TRI in a total number of 456 patients with moderate-high and high risk PE. Patients were stratified by quartiles (Q) of admission TRI. Results: In-hospital analysis revealed significantly higher rates of in-hospital death for patients with TRI in Q4. After adjustment for confounding baseline variables, TRI in Q4 was associated with 2.8-fold hazard of in-hospital death. Upon multivariate analysis, admission TRI in Q4 vs. Q1–3 was associated with 3.1 fold hazard of 4-year mortality rate. Conclusion: TRI in Q4, as compared to Q1–3, was significantly predictive of short term and long-term outcomes in PE patients who treated with thrombolytic agents. Our data suggest TRI to be an independent, feasible, and costeffective tool for rapid risk stratification in moderate-high and high risk PE patients who treated with thrombolytic agents. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Pulmonary embolism (PE) and deep vein thrombosis (DVT) represent different manifestation of the same clinical entity referred to as venous thromboembolism (VTE) which is the third most common cardiovascular disorder that affects hospitalized and nonhospitalized patients [1]. Some patients may remain asymptomatic, although in some case, PE may be catastrophic. The sudden rise of pressure in pulmonary vascular bed leads to right ventricle (RV) dilatation and circulatory shock. As PE has a wide range of severity, risk stratification of an episode of acute PE is obligatory. In clinical guidelines, patients are initially categorized as high risk and non-high risk according to their ⁎ Corresponding author at: Sultan Abdulhamid Han Training and Research Hospital, Tibbiye Str. Uskudar, Istanbul, Turkey. E-mail address: [email protected] (M. Keskin).
http://dx.doi.org/10.1016/j.jcrc.2017.05.018 0883-9441/© 2017 Elsevier Inc. All rights reserved.
hemodynamic status at presentation [2]. Pulmonary Embolism Severity Index (PESI) and Geneva Score are other valuable risk indices however their awareness is low and implementation is difficult. There also have been some different simple novel biomarkers which were found significantly associated with mortality such as brain type natriuretic peptide (BNP), CK-MB, high sensitive troponin I etc. [3-5]. Although these techniques have many advantages, they require laboratory analysis to be able to perform scoring. Therefore, physicians need an easily accessible, cost-effective and laboratory independent method to carry out risk stratification to determine the severity and prognosis of PE. The Thrombolysis in Myocardial Infarction (TIMI) Risk Index (TRI) is a simple, generalizable, and well-validated instrument which is based on age and initial vital signs. Recently, the TRI has been proven to be useful in many studies due to its ability to predict mortality, and the ease of assessment and scoring with fewer parameters [age, systolic blood pressure (SBP), heart rate (HR), etc.] in patients with acute coronary
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syndrome (ACS) [6,7]. However many studies have examined the association between the ACS and TRI, there is not a study evaluating the prognostic value of TRI in patients with acute PE. Thus, the objective of the current study is to evaluate the predictive value of TRI in patients with acute PE. 2. Methods Between January 2004 and October 2011, 456 consecutive confirmed moderate-high and high risk PE patients who were admitted to a tertiary heart center and treated with t-PA were enrolled in this retrospective study. To create more homogenous groups, the patients who were not treated with thrombolytic therapy and the patients with low risk PE were not included in the study. Pulmonary multislice CT angiography (SOM-ATOM Sensation 64; Siemens, Erlangen, Germany) was used to diagnose PE. The only exclusion criterion was current renal replacement therapy. Emergency t-PA administered in coronary care unit for all patients. The TRI is calculated by using the following formula; TRI = (HR × [age/10]2)/systolic BP. 2.1. Analysis of patient data A clinical history of risk factors, such as age, sex, hypertension, diabetes mellitus, hyperlipidemia, chronic lung and kidney disease was determined from the hospital's medical database. Echocardiographic and pulmonary CT angiography findings were also obtained from the same database. Echocardiography was performed using a Vivid 7 System (GE Vingmed Ultrasound AS, Horten, Norway) in 96% patients at first 48 h in coronary care unit and left ventricular ejection fraction (LVEF) was calculated by using Simpson method [8]. The pulmonary arterial peak systolic pressure was calculated using the simplified Bernoulli equation. The occurrences of in-hospital and long-term events were evaluated by a trained study coordinator. The estimated glomerular filtration rate (eGFR) was calculated by using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Blood pressure and heart rate were measured at hospital admission. Blood values obtained from venous blood samples at hospital admission were recorded from the medical reports. White blood cell (WBC), hemoglobin level, and neutrophil counts were measured as part of the automated complete blood count using a Coulter LH 780 Hematology Analyzer (Beckman Coulter Ireland, Inc., Galway, Ireland). Biochemical measurements were performed using Siemens Healthcare Diagnostic Products kits and calibrators (Marburg, Germany). Creatinine kinase isoenzyme–MB levels were measured using an immune-inhibition method (Architect C 8000; Abbott Inc). 2.2. Administiration of t-PA All of the patients were administered 120-mg of the thrombolytic tPA agent by intravenous infusion over a period of 2 h. Intravenous unfractionated heparin infusion or subcutaneous low-molecular weight heparin were used after the thrombolytic therapy. In our institution, the patients with high risk and moderate-high risk pulmonary thromboembolism were routinely administered thrombolytic therapy if they had no absolute contraindications including any prior intracranial hemorrhage, known malignant intracranial neoplasm, ischemic stroke within 3 months, suspected aortic dissection, active bleeding or bleeding diathesis (excluding menses), significant closed-head or facial trauma within 3 months, intracranial or intraspinal surgery within 2 months and severe uncontrolled hypertension. 2.3. Risk stratification Risk stratification of PE was performed according to patients' clinical status at presentation, with “high-risk” being suspected of or confirmed in the presence of shock or persistent arterial hypotension and not high
risk in absence of them. Further risk stratification was considered after the diagnosis of PE was confirmed. Accordingly, normotensive patients in PESI Class ≥ III or a simplified PESI of ≥1 are considered to constitute the moderate risk group. Within this category; focusing on the status of the RV in response to the PE-induced acute pressure overload; patients who display evidence of both RV dysfunction (by echocardiography or CT angiography) and elevated cardiac biomarker levels in the circulation (particularly a positive cardiac troponin test) were considered in moderate-high-risk category. These risk stratifications were considered according to Europen Society of Cardiology guidelines on the diagnosis and management of acute pulmonary embolism [2]. 2.4. Definitions The primary end points were the incidence of in-hospital and longterm mortalies. In-hospital mortality was defined as death from any cause during hospitalization. Long-term mortality was defined as death from any cause after discharge. Evaluation of mortality was obtained from hospital's medical database, National Death Declaration system, or by follow-up interviews (directly or by telephone). As we do not have a national system of coding and classification of cause of death, we could not demonstrate the association between TRI and cardiovascular mortality. “Cardiogenic shock was defined as systolic pressure b90 mm Hg or systolic pressure drop greater than or equal to 40 mm Hg for N15 min without new-onset arrhythmia, hypovolemia, or sepsis. Major bleeding was defined as a decline in hemoglobin level of 20 g per liter or more or transfusion of 2 or more units of red cells. Altered mental status was defined as signs of disorientation, lethargy, stupor, or coma. Syncope was defined as a transient, self-limited loss of consciousness due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery [9]. 2.5. Follow-up The mean follow-up period was 42.7 ± 13.3 months. The primary end point was death. Recurrent PE, major and minor bleeding, use of fresh frozen plasma (FFP), and history of international normalized ratio N5 were noted. All patients without cancer were all prescribed warfarin treatment and followed up for three months following by their acute pulmonary embolism. Patients with cancer were prescribed enoxaparin treatment and followed up for three months. 2.6. Statistical analysis The study population was divided into four quartiles according to patients' admission TRI score starting with the lowest TRI as Q1 and categorized accordingly; Q1, Q2, Q3 and Q4. Kolmogorov-Smirnov test was used for testing of normality. Continuous variables with normal distributions were expressed as mean ± SD and were compared using oneway analysis of variance. The control of the homogeneity of variance was done with Levene test. One-way ANOVA was used for the homogeneity of variance ensured parameters; Welch robust test was used when the homogeneity of variance was not ensured. Continuous variables with skewed distributions were expressed as mean ± SD and were compared using the Kruskal-Wallis test. Categorical variables were expressed as numbers and percentages and Pearson's chi-square or Fisher's exact tests were used to evaluate the differences. Hierarchical logistic regression analysis was used for multivariable analysis to evaluate the prognostic confounders for in-hospital outcomes. The odds ratio (OR) indicate the relative risk of in-hospital outcomes of Q4 compared with Q1–3. After follow-up periods of 42.7 ± 13.3 months, the survivals of four groups were compared using the Kaplan-Meier survival method. Overall survival was calculated from the day of diagnosis to the day of death or last follow-up date. Differences between the groups were analyzed by the log-rank test. A Forward Cox proportional regression
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analysis was performed to assess the in-hospital outcomes of the Q4 compared with Q1–3. The hazard ratio (HR) indicates the relative risk of long-term outcomes of Q4 compared with Q1–3. To analyze the predictions of in-hospital and long-term outcomes, data from the admission parameters were employed as independent variables. In multivariable models, confounders in multivariate analysis as predictors of in-hospital and long-term outcomes were considered. Two models
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were generated to examine the impact of potential confounders on the association between TRI and outcomes. These 2 models include: [1] unadjusted; [2] adjusted for all confounders including demographics (age, sex); first measurement of SBP and HR at admission; first measurement of the following laboratory values during hospitalization; admission estimated glomerular filtration rate (eGFR) calculated by CKD-EPI, blood urea nitrogen, hemoglobin and white blood cell,
Table 1 Baseline characteristics stratified by admission TRI. Admission TRI level
Age, y Male gender TRI value In hospital stay, d Comorbidities Hypertension Diabetes mellitus Hyperlipidemia Current smoking status Previous MI Previous PCI Previous CABG Chronic kidney disease Heart failure Chronic lung disease Cerebrovascular disease DVT history Prior PE Cancer Use of OCS Use of warfarin Use of steroid At admission Systolic blood pressure, mm Hg Altered mental status Heart rate, beats per minute Respiratory rate, beats minute Temperature O2 saturation, % PESI score Wells score Geneva score Intensive care unit stay, d Admission blood gas analysis pH Lactate HCO3 Admission symptoms Syncope Chest pain Fatigue Dyspnea Lower limb pain Lower limb edema USG findings of DVT Electrocardiography Sinus tachycardia Right bundle branch block T- wave inversion (leads V1–3) Atrial dysrhythmia S1Q3T3 Localization of thrombosis in PCTA Common pulmonary artery Right pulmonary artery Left pulmonary artery Left and right pulmonary artery Segmental pulmonary artery Subsegmental pulmonary artery
P value
I (n = 114)
II (n = 114)
III (n = 114)
IV (n = 114)
65 ± 12 56 (49.1) 15 ± 4 9±4
72 ± 8 56 (49.1) 28 ± 3 9±5
74 ± 8 48 (42.1) 39 ± 4 10 ± 5
78 ± 6 50 (43.9) 66 ± 20 10 ± 8
b0.001 0.615 b0.001 0.064
40 (35.1) 40 (35.1) 29 (25.4) 51 (44.7) 6 (5.3) 6 (5.3) 8 (7.0) 8 (7.0) 6 (5.3) 21 (18.4) 4 (3.5) 51 (44.7) 8 (7.0) 8 (7.0) 7 (6.1) 6 (5.4) 6 (5.3)
45 (39.5) 40 (35.1) 27 (23.7) 43 (37.7) 6 (5.3) 6 (5.3) 8 (7.0) 9 (7.9) 9 (7.9) 19 (16.7) 6 (5.3) 37 (32.5) 10 (8.8) 10 (8.8) 6 (5.3) 5 (4.4) 4 (3.5)
39 (34.2) 43 (37.7) 26 (22.8) 36 (31.6) 7 (6.1) 7 (6.1) 7 (6.1) 10 (8.8) 8 (7.0) 21 (18.4) 6 (5.3) 35 (30.7) 9 (7.9) 9 (7.9) 4 (3.5) 6 (5.4) 7 (6.1)
36 (31.6) 39 (34.2) 24 (21.1) 39 (34.2) 7 (6.1) 8 (7.0) 9 (7.9) 20 (17.5) 16 (14.0) 25 (21.9) 8 (7.0) 36 (31.6) 11 (9.6) 12 (10.5) 3 (2.6) 9 (7.9) 6 (5.3)
0.655 0.951 0.887 0.190 0.983 0.933 0.966 0.032 0.095 0.780 0.704 0.086 0.902 0.806 0.554 0.700 0.833
132 ± 16 9 (7.9) 98 ± 15 19 ± 3 36.6 ± 0.2 93 ± 8 71 ± 23 5.2 ± 1.9 7±4 4±2
128 ± 19 10 (8.8) 96 ± 18 21 ± 4 36.5 ± 0.3 94 ± 3 90 ± 36 5.3 ± 1.8 6±3 4±3
129 ± 18 10 (8.8) 97 ± 18 20 ± 2 36.6 ± 0.3 91 ± 4 97 ± 29 4.9 ± 1.8 7±3 5±3
106 ± 23 14 (12.3) 111 ± 18 21 ± 3 36.6 ± 0.3 90 ± 8 123 ± 43 5.5 ± 2.0 7±4 5±4
b0.001 0.679 b0.001 0.128 0.389 b0.001 b0.001 0.325 0.463 0.205
7.4 ± 0.1 2.6 ± 1.3 22.1 ± 5.2
7.4 ± 0.2 2.8 ± 1.8 21.6 ± 4.8
7.3 ± 0.8 2.9 ± 1.4 21.1 ± 5.1
7.2 ± 1.4 4.5 ± 2.1 19.4 ± 4.2
0.016 0.027 0.012
27 (23.7) 27 (23.7)
28 (24.6) 26 (22.8)
32 (28.1) 24 (21.1)
33 (28.9) 24 (21.1)
0.759 0.952
98 (86.7) 69 (60.5) 63 (55.3) 60 (52.6)
93 (84.5) 59 (51.8) 53 (46.5) 52 (45.6)
96 (85.7) 53 (46.5) 49 (43.0) 43 (37.7)
94 (83.9) 51 (44.7) 46 (40.4) 42 (36.8)
0.937 0.076 0.121 0.053
79 (69.3) 32 (28.1) 38 (33.3) 9 (7.9) 39 (34.2)
78 (68.4) 29 (25.4) 42 (36.8) 12 (10.5) 42 (37.7)
76 (66.7) 33 (28.9) 33 (28.9) 17 (14.9) 42 (36.8)
73 (64.0) 38 (33.3) 25 (25.4) 27 (23.7) 45 (39.5)
0.841 0.617 0.265 0.004 0.872
25 (21.9) 46 (40.4) 24 (21.1) 5 (4.4) 9 (7.9) 5 (4.4)
29 (25.4) 52 (45.6) 19 (16.7) 5 (4.4) 6 (5.3) 3 (2.6)
27 (23.7) 45 (39.5) 25 (21.9) 6 (5.3) 9 (7.9) 2 (1.8)
29 (25.4) 47 (41.2) 26 (22.8) 8 (7.0) 4 (3.5) 0 (0.0)
0.913 0.790 0.670 0.788 0.434 0.150
Nominal variables presented as frequency (%). One-way ANOVA test was used for continuous variables with normal distribution. Kruskal-Wallis test was used for continuous variables with skewed distribution. TRI indicates Thrombolysis in myocardial infarction risk index; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; DVT, deep vein thrombosis; PE, pulmonary embolism; OCS, oral contraception; HCO3, Bicarbonate; USG, ultrasonography; PCTA, pulmonary CT angiography.
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neutrophil, lymphocyte and platelet count; creatine kinase-MB, troponin I, D-dimer and BNP comorbidities (diabetes, chronic kidney disease, hypertension, stroke, heart failure, cancer, chronic lung disease and atrial dysrhythmia) and medications (use of oral contraceptives, warfarin and steroid). A two-tailed P value of b0.05 was considered statistically significant, and 95% CIs were presented for all odds ratios and hazard ratios. Analyses were performed using Statistical Package for Social Sciences software, version 20.0 (SPSS; IBM, Armonk, New York, USA). 3. Results 3.1. Baseline characteristics The patients' baseline characteristics, categorized by admission TRI level, are listed in Table 1. A total of 456 patients (mean age 72 ± 11 years; men 46%) with PE were included. The history of patients were similar in terms of hypertension, diabetes mellitus, hyperlipidemia, current smoking status, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass graft surgery, heart failure, chronic lung disease, cerebrovascular disease, DVT, PE, cancer, and using oral contraceptives, warfarin and steroids. Whereas, Q4 had a higher incidence of chronic kidney disease. PESI score was higher and O2 saturation was lower in Q4. TRI was positively correlated with PESI score (r = 0.549, P b 0.001) (Fig. 1). ROC analysis showed that the best cut-off value of the TRI to predict in-hospital mortality was 38 with 68% sensitivity and 70% specificity (AUC: 0.77; 95% CI: 0.71–0.74; p b 0.001) and the best cut-off value of the PESI score to predict in-hospital mortality was 96 with 64% sensitivity and 76% specificity (AUC: 0.74; 95% CI: 0.67–0.81; p b 0.001) (Fig. 2). 3.2. Laboratory findings The patients' laboratory parameters are summarized in Table 2. and it significant differences among patients with respect to eGFR, creatinine, admission CK-MB, BNP, lymphocyte count and blood urea nitrogen; whereas the groups were similar with respect to troponin I, Ddimer, white blood cell count, neutrophil count and hemoglobin.
3.3. Echocardiographic findings The patients' echocardiographic parameters are summarized in Table 2. Left ventricular ejection fraction, pulmonary arterial peak systolic pressure, left ventricular and right ventricular end diastolic diameters, left atrial diameter, were similar between 2 groups. Right ventricular dilatation, more than + 2 tricuspid regurgitation and the presence of thrombus in pulmonary arteries of the 4 groups were similar. Tricuspid annular plane systolic excursion (TAPSE) and right ventricle S velocity showed significant differences between groups and the patients with higher TRI level had showed lower right ventricular systolic functions.
3.4. In-hospital and long-term outcomes Tables 3 presents the in-hospital and long-term clinical outcomes of the study population. In-hospital mortality was significantly higher in Q4 (57%, P b 0.001). Q4 also had a higher incidence of major bleeding, intracranial hemorrhage, use of fresh frozen plasma, red cell transfusion, hypotension, cardiogenic shock, use of inotropic drugs, asystole, inhospital hemodialysis treatment, and mechanical ventilation. However in-hospital minor bleeding rates were similar between groups. Hierarchical logistic regression analysis was performed to assess in-hospital outcomes of the Q4 compared with the Q1–3 and summarized in Table 4. The unadjusted risks for all-cause mortality, major bleeding, intracranial hemorrhagia, use of fresh frozen plasma, red cell transfusion, hemodialysis, asystolia, hypotension, cardiogenic shock, use of inotropic drug and mechanic ventilation were significantly higher in Q4 (OR: 10.3, 95% CI: 6.2 to 16.9, P b 0.001; OR: 3.1, 95% CI: 1.8 to 5.5, P b 0.001; OR: 5.6, 95% CI: 2.3 to 13.1, P b 0.001; OR: 2.9, 95% CI: 1.6 to 5.0, P b 0.001; OR: 3.2, 95% CI: 1.8 to 5.4, P b 0.001; OR: 3.1, 95% CI: 1.5 to 8.6, P = 0.025; OR: 4.5, 95% CI: 2.7 to 7.5, P b 0.001; OR: 5.3, 95% CI: 3.2 to 8.9, P b 0.001; OR: 3.7, 95% CI: 2.1 to 6.5, P b 0.001; OR: 4.3, 95% CI: 2.5 to 7.3, P b 0.001; OR: 4.4, 95% CI: 2.6 to 7.6, P b 0.001; respectively). Futhermore, the adjusted risks for all-cause mortality, asystole, hypotension, cardiogenic shock, use of inotropic drug and mechanic ventilation were significantly higher in Q4 (OR: 2.8, 95% CI: 1.8 to 4.4,
Fig. 1. Scatter plot shows the relationship between TRI and PESI. Spearman correlation analysis revealed a significant correlation between the TRI and PESI value (r = 0.549; P b 0.001).
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Fig. 2. ROC analysis showed that the best cut-off value of the TRI to predict the in-hospital mortality was 38 with 68% sensitivity and 70% specificity (AUC: 0.77; 95% CI: 0.71–0.74; p b 0.001) and the best cut-off value of the PESI score to predict the in-hospital mortality was 96 with 64% sensitivity and 76% specificity (AUC: 0.74; 95% CI: 0.67–0.81; p b 0.001).
P = 0.002; OR: 2.1, 95% CI: 1.5 to 3.9, P = 0.008; OR: 1.9, 95% CI: 1.3 to 3.7, P = 0.012; OR: 2.1, 95% CI: 1.8 to 3.3, P = 0.004; OR: 2.0, 95% CI: 1.6 to 3.6, P = 0.006; OR: 1.9, 95% CI: 1.4 to 3.8, P = 0.018; respectively). The patients were followed up for a mean period of 42.7 ± 13.3 months. During follow-up, recurrent PE, major and minor bleeding, use of FFP,
and history of international normalized ratio N 5 were similar between the 2 groups. The 4-year Kaplan-Meier overall survivals were 91%, 88%, 97% and 53% respectively (Fig. 3). A forward Cox regression analysis was performed to assess the long-term outcomes of the Q4 compared with the Q1–3 and summarized in Table 5. Crude and adjusted
Table 2 Laboratory and echocardiography findings. Admission TRI level
Laboratory variables Glomerular filtration rate (CKD-EPI) Troponin I, ng/mL Creatinine (mg/dL) D-dimer, ng/mL Creatine kinase-MB, U/L Brain type natriuretic peptide, pg/mL White blood cell, cells/μL Lymphocyte, cells/μL Neutrophil, cells/μL Hemoglobin, g/dL Blood urea nitrogen, mg/dL Echocardiography parameters LVEF, % RV TAPSE RV S′ velocity, cm/s PASP, mm Hg LV diameter, mm RV diameter, mm LA diameter, mm RV dilatation TR N +2 Presence of thrombus
P value
I (n = 114)
II (n = 114)
III (n = 114)
IV (n = 114)
90.4 ± 22.8 0.85 ± 1.18 0.98 ± 0.41 4750 ± 4520 25.8 ± 22.4 279 ± 159 11.9 ± 3.9 2.0 ± 1.0 9.0 ± 3.6 12.3 ± 2.0 17 ± 8
79.2 ± 19.9 0.92 ± 2.21 1.08 ± 0.36 5025 ± 5167 28.1 ± 22.9 414 ± 252 11.4 ± 4.0 1.8 ± 0.8 8.6 ± 3.6 12.7 ± 1.8 22 ± 9
73.1 ± 46.9 0.95 ± 1.84 1.14 ± 0.86 5308 ± 5443 35.9 ± 23.6 655 ± 899 11.5 ± 3.9 1.9 ± 0.8 8.6 ± 3.4 12.7 ± 2.1 27 ± 16
62.1 ± 21.1 0.98 ± 1.65 1.27 ± 0.69 5578 ± 5782 45.4 ± 28.7 829 ± 681 12.3 ± 3.7 1.5 ± 0.9 10.4 ± 6.3 12.1 ± 1.9 31 ± 16
b0.001 0.750 b0.001 0.143 0.001 0.011 0.073 b0.001 0.063 0.104 b0.001
60 ± 6 19 ± 4 11 ± 2 44 ± 11 4.9 ± 0.6 4.6 ± 0.8 3.8 ± 0.7 92 (80.7) 69 (60.5) 27 (23.7)
57 ± 8 16 ± 3 10 ± 2 44 ± 10 4.8 ± 0.5 4.7 ± 0.7 3.7 ± 0.5 98 (86.0) 76 (66.7) 21 (18.4)
59 ± 5 15 ± 3 10 ± 2 45 ± 10 4.8 ± 0.5 4.8 ± 0.8 3.9 ± 0.6 93 (81.6) 84 (73.7) 27 (23.7)
57 ± 9 14 ± 2 9±2 47 ± 8 4.9 ± 0.4 4.8 ± 0.5 3.9 ± 0.5 92 (80.7) 81 (71.1) 33 (28.9)
0.078 b0.001 0.002 0.109 0.096 0.092 0.073 0.685 0.158 0.322
Continuous variables are presented as mean ± SD. One-way ANOVA test was used for continuous variables with normal distribution. Kruskal-Wallis test was used for continuous variables with skewed distribution. TRI indicates Thrombolysis in myocardial infarction risk index; LVEF, left ventricular ejection fraction; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion; PASP, pulmonary artery systolic pressure; LV, left ventricle; LA, left atrium; TR, tricuspid regurgitation.
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Table 3 In-hospital and long-term outcomes. Admission TRI level
In-hospital course All-cause mortality Major bleeding Intracranial hemorrhagia Use of fresh frozen plasma Red cell transfusion Hemodialysis Minor bleeding Asystolia Hypotension, b90 mm Hg Cardiogenic Shock Use of inotropic drug Mechanic ventilation
P value
I (n = 114)
II (n = 114)
III (n = 114)
IV (n = 114)
11 (9.6) 12 (10.5) 2 (1.8) 12 (10.5) 11 (9.6) 2 (1.8) 41 (36.0) 9 (7.9) 9 (7.9) 9 (7.9) 9 (7.9) 9 (7.9)
13 (11.4) 14 (12.3) 2 (1.8) 11 (9.6) 14 (12.3) 0 (0.0) 53 (46.5) 13 (11.4) 12 (10.5) 10 (8.8) 12 (10.5) 12 (10.5)
15 (13.2) 6 (5.3) 5 (4.4) 13 (11.4) 12 (10.5) 6 (5.3) 41 (36.0) 18 (15.8) 16 (14.0) 13 (11.4) 13 (11.4) 12 (10.5)
65 (57.0) 28 (24.6) 15 (13.2) 29 (25.4) 32 (28.1) 8 (7.0) 56 (49.1) 43 (37.7) 45 (39.5) 32 (28.1) 37 (32.5) 37 (32.5)
Admission TRI level
Out-hospital course All cause mortality Recurrent pulmonary embolism Major bleeding Minor bleeding History of INR N5 Use of fresh frozen plasma
b0.001 b0.001 b0.001 0.001 b0.001 0.016 0.081 b0.001 b0.001 b0.001 b0.001 b0.001 P value
I (n = 103)
II (n = 101)
III (n = 99)
IV (n = 49)
9 (8.7) 6 (5.8) 5 (4.9) 8 (7.8) 18 (17.5) 8 (7.8)
12 (11.9) 2 (2.0) 8 (7.9) 12 (11.9) 25 (24.8) 13 (12.9)
12 (12.1) 9 (9.1) 10 (12.5) 9 (9.1) 22 (22.2) 13 (13.1)
25 (46.9) 2 (4.1) 6 (12.2) 7 (14.3) 11 (22.4) 5 (10.2)
b0.001 0.161 0.381 0.573 0.643 0.585
Nominal variables presented as frequency (%). TRI indicates Thrombolysis in myocardial infarction risk index.
risks for all-cause death was significantly higher in Q4 (HR: 7.2, 95% CI: 3.7 to 14.1, P b 0.001; HR: 3.1, 95% CI: 1.6 to 5.1, P = 0.004; respectively). 4. Discussion The main findings of the current study as follows: (a) patients in the higher TRI quartile (Q4) had a lower RV systolic function; (b) higher inhospital mortality, inotropic drug use and cardiogenic shock; (c) higher in-hospital bleeding complications and (d) higher long-term mortality. The association of TRI with in-hospital and long-term mortality was persisted even after multivariable analyses. Pulmonary embolism is a life-threatening disorder that comprises of a wide range of symptoms, signs and clinical outcomes. Rise in pulmonary artery pressure starts as N 30–50% of the total pulmonary arterial bed occluded by thromboemboli [10,11]. The rapid rise in pulmonary vascular resistance leads to RV dilation, which affects via the Frank-Starling mechanism. RV contraction time is prolonged, while neurohumoral
activation leads to inotropic and chronotropic stimulation. Together with systemic vasoconstriction, these compensatory mechanisms increase pulmonary artery pressure, to improve flow through the obstructed pulmonary vascular bed, and thus temporarily stabilize systemic blood pressure [12]. The extent of immediate adaptation is limited, since a non-preconditioned, thin-walled right ventricle (RV) is unable to generate a mean pulmonary artery pressure above 40 mm Hg. Failure in these excessive hemodynamic response can be result in circulatory shock. Because of its possible complications, risk stratification is vitally important for management of PE. Tachycardia may be explained by high levels of epinephrine released as a result of the PE-induced myocarditis [13]. This neurohumoral response may lead to further biventricular failure and hemodynamic deterioration. Because of these mechanisms tachycardia is a potent prognostic indicator in PE. RV contraction prolongs as a result of abrupt increment in preload and leads to leftward bowing of the interventricular septum and D-shaped left ventricle. Consequently, LV filling is blocked in diastole, and this
Table 4 In-hospital event rates and logistic regression models for outcomes by TRI level.
In-hospital course All-cause mortality Major bleeding Intracranial hemorrhagia Use of fresh frozen plasma Red cell transfusion Hemodialysis Minor bleeding Asystolia Hypotension, b90 mm Hg Cardiogenic Shock Use of inotropic drug Mechanic ventilation
Q1–3 (n = 342)
Q4 (n = 114)
Crude OR (95% CI)
P value
Adjusteda OR (95% CI)
P value
39 (11.4) 32 (9.4) 9 (2.6) 36 (10.5) 37 (10.8) 8 (2.3) 135 (39.5) 40 (11.7) 37 (10.8) 32 (9.4) 34 (9.9) 33 (9.6)
65 (57.0) 28 (24.6) 15 (13.2) 29 (25.4) 32 (28.1) 8 (7.0) 56 (49.1) 43 (37.7) 45 (39.5) 32 (28.1) 37 (32.5) 37 (32.5)
10.3 (6.2–16.9) 3.1 (1.8–5.5) 5.6 (2.3–13.1) 2.9 (1.6–5.0) 3.2 (1.8–5.4) 3.1 (1.5–8.6) 1.4 (0.9–2.2) 4.5 (2.7–7.5) 5.3 (3.2–8.9) 3.7 (2.1–6.5) 4.3 (2.5–7.3) 4.4 (2.6–7.6)
b0.001 b0.001 b0.001 b0.001 b0.001 0.025 0.071 b0.001 b0.001 b0.001 b0.001 b0.001
2.8 (1.8–4.4) 1.8 (0.7–4.8) 0.9 (0.2–3.9) 2.3 (0.9–5.9) 2.1 (0.8–5.4) 1.2 (0.4–5.8) 1.7 (0.8–3.4) 2.1 (1.5–3.9) 1.9 (1.3–3.7) 2.1 (1.8–3.3) 2.0 (1.6–3.6) 1.9 (1.4–3.8)
0.002 0.218 0.928 0.076 0.102 0.832 0.118 0.008 0.012 0.004 0.006 0.018
Abbreviations: TRI, Thrombolysis in myocardial infarction risk index; OR, Odds ratio. a Includes demographics (age, sex); first measurement of systolic blood pressure and heart rate; first measurement during hospitalization of the following laboratory values (admission glomerular filtration rate calculated by CKD-EPI, blood urea nitrogen, white blood cell count, hematocrit, platelet count); creatine kinase-MB, troponin I, D-dimer, brain type natriuretic peptide; comorbidities (diabetes, chronic kidney disease, hypertension, stroke, heart failure, cancer, chronic lung disease and atrial dysrhythmia) and medications (use of oral contraceptives, warfarin and steroid).
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Fig. 3. Kaplan Meier curve for overall survival in patients with pulmonary embolism (n = 352) stratified by TRI quartile.
may lead to reduction of cardiac output and contribute to systemic hypotension and haemodynamic instability. Tachycardia and hypotension are the consequences of similar mechanism and may be the harbingers of hemodynamic compromise. Age is another prognostic factor of mortality in patients with PE and is the mutual criterion of both Geneva score and PESI. In current study, TRI was strongly correlated with PESI. Also higher rates of major bleeding, intracranial hemorrhage and use of fresh frozen plasma in patients with higher TRI may attributable to higher age in these patients. TRI is a novel and cheap scoring system which was found significantly predictive for short-term and long-term mortality in some large cohorts and studies of patients with ACS [6,7,14]. ACS and PE commonly have similar precipitating and prognostic factors such as age, hypotension and tacyhcardia in admission [2,15]. PE requires a new risk index for immediate evaluation and referral of patients which is not based on laboratory analysis. Despite the predictive value of TRI in ACS, it has not been evaluated in patients with PE. 5. Conclusion This pilot investigation demonstrated that TRI, calculated based on age, SBP and HR, is an independent in-hospital and 4-year long-term prognostic factor for mortality in patients with moderate-high and
high risk PE who treated with t-PA. Albeit, TRI is recently developed and considered as an important predictive index in patients with ACS; its prognostic value in patients with PE has not been evaluated. This risk index could be used as a practical tool for risk stratification on patients with PE. We only included the patients with moderate-high and high risk PE, however, these subgroups constitute the majority of death. Therefore, the current study may provide a valuable risk prediction for in-hospital and long-term mortality in overall patients with PE. To put forward the interaction between the TRI and overall PE, some additional and large volume studies need to be established. 6. Study limitations Our study has several limitations. First, this is a single-center, retrospective and observational study based on relatively small number of patients. Second, TRI was designed to provide pre-hospital and initial risk estimation during the first patient contact. It does not associate the impact of therapy, comorbidity or baseline treatments with outcome. Third, SBP measurements were non invasive. Fourth, although we used multivariable analysis, we could not exclude the possibility of residual unmeasured covariables which might influence the outcomes. Fifth; although TRI level might be influenced by hormonal changes, we could not measure hormones such as serum catecholamine and
Table 5 Long-term (4-year) event rates and logistic regression models for outcomes by TRI level.
Out-hospital course All cause mortality Recurrent pulmonary embolism Major bleeding Minor bleeding History of INR N5 Use of fresh frozen plasma
Q1–3 (n = 303)
Q4 (n = 49)
Crude HR (95% CI)
P value
Adjusteda HR (95% CI)
P value
33 (10.9) 17 (5.6) 23 (7.6) 29 (9.6) 65 (21.5) 34 (11.2)
23 (46.9) 2 (4.1) 6 (12.2) 7 (14.3) 11 (22.4) 5 (10.2)
7.2 (3.7–14.1) 0.7 (0.2–3.2) 1.7 (0.6–4.4) 1.5 (0.6–3.8) 1.1 (0.5–2.1) 0.9 (0.3–2.4)
b0.001 0.662 0.276 0.316 0.875 0.833
3.1 (1.6–5.1) 0.5 (0.1–2.1) 1.6 (0.5–5.4) 1.3 (0.4–4.9) 1.1 (0.4–3.1) 0.9 (0.2–3.7)
0.004 0.275 0.289 0.699 0.766 0.885
Abbreviations: TRI, Thrombolysis in myocardial infarction risk index; HR, Hazard ratio. a Includes demographics (age, sex); first measurement of systolic blood pressure and heart rate; first measurement during hospitalization of the following laboratory values (admission glomerular filtration rate calculated by CKD-EPI, blood urea nitrogen, white blood cell count, hematocrit, platelet count); creatine kinase-MB, troponin I, D-dimer, brain type natriuretic peptide; comorbidities (diabetes, chronic kidney disease, hypertension, stroke, heart failure, cancer, chronic lung disease and atrial dysrhythmia) and medications (use of oral contraceptives, warfarin and steroid).
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cortisol. Sixth; despite the fact that warfarin sodium is the most commonly used oral anticoagulation; guidelines recommend new generation oral anticoagulation treatment as an alternative, at the moment. Finally; because of methodological limitations of retrospective analysis, it is not possible to define the exact causal relationship between TRI level and mortality. These limitations require further examinations to validate our present findings; a prospective study in a larger patient population is needed. Conflict of interest The authors have no conflict of interest and all authors have made substantive contributions to the study and all authors endorse the data and conclusions. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with human participants performed by any of the authors. References [1] Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008;28(3):370–2. [2] Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, et al. ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35(43) (3033-69, 69a-69k). [3] Bozbay M, Uyarel H, Avsar S, Oz A, Keskin M, Tanik VO, et al. Creatinine kinase isoenzyme-MB: a simple prognostic biomarker in patients with pulmonary embolism treated with thrombolytic therapy. J Crit Care 2015;30(6):1179–83.
[4] Daquarti G, March Vecchio N, Mitrione CS, Furmento J, Ametrano MC, Dominguez Pace MP, et al. High-sensitivity troponin and right ventricular function in acute pulmonary embolism. Am J Emerg Med 2016;34(8):1579–82. [5] Verschuren F, Bonnet M, Benoit MO, Gruson D, Zech F, Couturaud F, et al. The prognostic value of pro-B-type natriuretic peptide in acute pulmonary embolism. Thromb Res 2013;131(6):e235–9. [6] Ilkhanoff L, O'Donnell CJ, Camargo CA, O'Halloran TD, Giugliano RP, Lloyd-Jones DM. Usefulness of the TIMI risk index in predicting short- and long-term mortality in patients with acute coronary syndromes. Am J Cardiol 2005;96(6):773–7. [7] Wiviott SD, Morrow DA, Frederick PD, Giugliano RP, Gibson CM, McCabe CH, et al. Performance of the thrombolysis in myocardial infarction risk index in the National Registry of myocardial infarction-3 and -4: a simple index that predicts mortality in ST-segment elevation myocardial infarction. J Am Coll Cardiol 2004;44(4):783–9. [8] Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989;2(5):358–67. [9] Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30(21): 2631–71. [10] McIntyre KM, Sasahara AA. The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am J Cardiol 1971;28(3):288–94. [11] Smulders YM. Pathophysiology and treatment of haemodynamic instability in acute pulmonary embolism: the pivotal role of pulmonary vasoconstriction. Cardiovasc Res 2000;48(1):23–33. [12] Molloy WD, Lee KY, Girling L, Schick U, Prewitt RM. Treatment of shock in a canine model of pulmonary embolism. Am Rev Respir Dis 1984;130(5):870–4. [13] Begieneman MP, van de Goot FR, van der Bilt IA, Vonk Noordegraaf A, Spreeuwenberg MD, Paulus WJ, et al. Pulmonary embolism causes endomyocarditis in the human heart. Heart 2008;94(4):450–6. [14] Acet H, Ertas F, Bilik MZ, Aydin M, Yuksel M, Polat N, et al. The relationship of TIMI risk index with SYNTAX and Gensini risk scores in predicting the extent and severity of coronary artery disease in patients with STEMI undergoing primary percutaneous coronary intervention. Ther Adv Cardiovasc Dis 2015;9(5):257–66. [15] Yan AT, Yan RT, Tan M, Eagle KA, Granger CB, Dabbous OH, et al. In-hospital revascularization and one-year outcome of acute coronary syndrome patients stratified by the GRACE risk score. Am J Cardiol 2005;96(7):913–6.
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A novel prognostic indicator for in-hospital and 4-year outcomes in patients with pulmonary embolism: TIMI risk index Muhammed Keskin, MD a,⁎, Tolga Sinan Güvenç, MD b, Mert İlker Hayıroğlu, MD a, Adnan Kaya, MD c, Mustafa Adem Tatlısu, MD d, Şahin Avşar, MD e, Ahmet Öz, MD a, Taha Keskin, MD f, Ahmet Okan Uzun, MD g, Ömer Kozan, MD, Prof. a a
Sultan Abdulhamid Han Training and Research Hospital, Department of Cardiology, Istanbul, Turkey Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Center, Training and Research Hospital, Department of Cardiology, Istanbul, Turkey c Duzce University, Department of Cardiology, Duzce, Turkey d Texas A&M University, Department of Cardiology, TX, USA e Urla State Hospital, Urla, Izmir, Turkey f Yeshiva University, Albert Einstein College of Medicine, Montefiore Medical Center, Department of Allergy/Immunology, Bronx, New York, USA g Dortyol State Hospital, Department of Cardiology, Dortyol, Hatay, Turkey b
a r t i c l e
i n f o
Available online xxxx Keywords: TIMI risk index Pulmonary embolism Mortality Risk stratification
a b s t r a c t Background: Thrombolysis in Myocardial Infarction (TIMI) risk index (TRI) was recently evaluated in patients with acute myocardial infarction and found as an important prognostic index. In the current study, we evaluated the prognostic value of TRI in patients with moderate-high and high risk pulmonary embolism (PE) who were treated with thrombolytic agents. Methods: We retrospectively evaluated the in-hospital and long-term (4-year) prognostic impact of TRI in a total number of 456 patients with moderate-high and high risk PE. Patients were stratified by quartiles (Q) of admission TRI. Results: In-hospital analysis revealed significantly higher rates of in-hospital death for patients with TRI in Q4. After adjustment for confounding baseline variables, TRI in Q4 was associated with 2.8-fold hazard of in-hospital death. Upon multivariate analysis, admission TRI in Q4 vs. Q1–3 was associated with 3.1 fold hazard of 4-year mortality rate. Conclusion: TRI in Q4, as compared to Q1–3, was significantly predictive of short term and long-term outcomes in PE patients who treated with thrombolytic agents. Our data suggest TRI to be an independent, feasible, and costeffective tool for rapid risk stratification in moderate-high and high risk PE patients who treated with thrombolytic agents. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Pulmonary embolism (PE) and deep vein thrombosis (DVT) represent different manifestation of the same clinical entity referred to as venous thromboembolism (VTE) which is the third most common cardiovascular disorder that affects hospitalized and nonhospitalized patients [1]. Some patients may remain asymptomatic, although in some case, PE may be catastrophic. The sudden rise of pressure in pulmonary vascular bed leads to right ventricle (RV) dilatation and circulatory shock. As PE has a wide range of severity, risk stratification of an episode of acute PE is obligatory. In clinical guidelines, patients are initially categorized as high risk and non-high risk according to their ⁎ Corresponding author at: Sultan Abdulhamid Han Training and Research Hospital, Tibbiye Str. Uskudar, Istanbul, Turkey. E-mail address: [email protected] (M. Keskin).
http://dx.doi.org/10.1016/j.jcrc.2017.05.018 0883-9441/© 2017 Elsevier Inc. All rights reserved.
hemodynamic status at presentation [2]. Pulmonary Embolism Severity Index (PESI) and Geneva Score are other valuable risk indices however their awareness is low and implementation is difficult. There also have been some different simple novel biomarkers which were found significantly associated with mortality such as brain type natriuretic peptide (BNP), CK-MB, high sensitive troponin I etc. [3-5]. Although these techniques have many advantages, they require laboratory analysis to be able to perform scoring. Therefore, physicians need an easily accessible, cost-effective and laboratory independent method to carry out risk stratification to determine the severity and prognosis of PE. The Thrombolysis in Myocardial Infarction (TIMI) Risk Index (TRI) is a simple, generalizable, and well-validated instrument which is based on age and initial vital signs. Recently, the TRI has been proven to be useful in many studies due to its ability to predict mortality, and the ease of assessment and scoring with fewer parameters [age, systolic blood pressure (SBP), heart rate (HR), etc.] in patients with acute coronary
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syndrome (ACS) [6,7]. However many studies have examined the association between the ACS and TRI, there is not a study evaluating the prognostic value of TRI in patients with acute PE. Thus, the objective of the current study is to evaluate the predictive value of TRI in patients with acute PE. 2. Methods Between January 2004 and October 2011, 456 consecutive confirmed moderate-high and high risk PE patients who were admitted to a tertiary heart center and treated with t-PA were enrolled in this retrospective study. To create more homogenous groups, the patients who were not treated with thrombolytic therapy and the patients with low risk PE were not included in the study. Pulmonary multislice CT angiography (SOM-ATOM Sensation 64; Siemens, Erlangen, Germany) was used to diagnose PE. The only exclusion criterion was current renal replacement therapy. Emergency t-PA administered in coronary care unit for all patients. The TRI is calculated by using the following formula; TRI = (HR × [age/10]2)/systolic BP. 2.1. Analysis of patient data A clinical history of risk factors, such as age, sex, hypertension, diabetes mellitus, hyperlipidemia, chronic lung and kidney disease was determined from the hospital's medical database. Echocardiographic and pulmonary CT angiography findings were also obtained from the same database. Echocardiography was performed using a Vivid 7 System (GE Vingmed Ultrasound AS, Horten, Norway) in 96% patients at first 48 h in coronary care unit and left ventricular ejection fraction (LVEF) was calculated by using Simpson method [8]. The pulmonary arterial peak systolic pressure was calculated using the simplified Bernoulli equation. The occurrences of in-hospital and long-term events were evaluated by a trained study coordinator. The estimated glomerular filtration rate (eGFR) was calculated by using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Blood pressure and heart rate were measured at hospital admission. Blood values obtained from venous blood samples at hospital admission were recorded from the medical reports. White blood cell (WBC), hemoglobin level, and neutrophil counts were measured as part of the automated complete blood count using a Coulter LH 780 Hematology Analyzer (Beckman Coulter Ireland, Inc., Galway, Ireland). Biochemical measurements were performed using Siemens Healthcare Diagnostic Products kits and calibrators (Marburg, Germany). Creatinine kinase isoenzyme–MB levels were measured using an immune-inhibition method (Architect C 8000; Abbott Inc). 2.2. Administiration of t-PA All of the patients were administered 120-mg of the thrombolytic tPA agent by intravenous infusion over a period of 2 h. Intravenous unfractionated heparin infusion or subcutaneous low-molecular weight heparin were used after the thrombolytic therapy. In our institution, the patients with high risk and moderate-high risk pulmonary thromboembolism were routinely administered thrombolytic therapy if they had no absolute contraindications including any prior intracranial hemorrhage, known malignant intracranial neoplasm, ischemic stroke within 3 months, suspected aortic dissection, active bleeding or bleeding diathesis (excluding menses), significant closed-head or facial trauma within 3 months, intracranial or intraspinal surgery within 2 months and severe uncontrolled hypertension. 2.3. Risk stratification Risk stratification of PE was performed according to patients' clinical status at presentation, with “high-risk” being suspected of or confirmed in the presence of shock or persistent arterial hypotension and not high
risk in absence of them. Further risk stratification was considered after the diagnosis of PE was confirmed. Accordingly, normotensive patients in PESI Class ≥ III or a simplified PESI of ≥1 are considered to constitute the moderate risk group. Within this category; focusing on the status of the RV in response to the PE-induced acute pressure overload; patients who display evidence of both RV dysfunction (by echocardiography or CT angiography) and elevated cardiac biomarker levels in the circulation (particularly a positive cardiac troponin test) were considered in moderate-high-risk category. These risk stratifications were considered according to Europen Society of Cardiology guidelines on the diagnosis and management of acute pulmonary embolism [2]. 2.4. Definitions The primary end points were the incidence of in-hospital and longterm mortalies. In-hospital mortality was defined as death from any cause during hospitalization. Long-term mortality was defined as death from any cause after discharge. Evaluation of mortality was obtained from hospital's medical database, National Death Declaration system, or by follow-up interviews (directly or by telephone). As we do not have a national system of coding and classification of cause of death, we could not demonstrate the association between TRI and cardiovascular mortality. “Cardiogenic shock was defined as systolic pressure b90 mm Hg or systolic pressure drop greater than or equal to 40 mm Hg for N15 min without new-onset arrhythmia, hypovolemia, or sepsis. Major bleeding was defined as a decline in hemoglobin level of 20 g per liter or more or transfusion of 2 or more units of red cells. Altered mental status was defined as signs of disorientation, lethargy, stupor, or coma. Syncope was defined as a transient, self-limited loss of consciousness due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery [9]. 2.5. Follow-up The mean follow-up period was 42.7 ± 13.3 months. The primary end point was death. Recurrent PE, major and minor bleeding, use of fresh frozen plasma (FFP), and history of international normalized ratio N5 were noted. All patients without cancer were all prescribed warfarin treatment and followed up for three months following by their acute pulmonary embolism. Patients with cancer were prescribed enoxaparin treatment and followed up for three months. 2.6. Statistical analysis The study population was divided into four quartiles according to patients' admission TRI score starting with the lowest TRI as Q1 and categorized accordingly; Q1, Q2, Q3 and Q4. Kolmogorov-Smirnov test was used for testing of normality. Continuous variables with normal distributions were expressed as mean ± SD and were compared using oneway analysis of variance. The control of the homogeneity of variance was done with Levene test. One-way ANOVA was used for the homogeneity of variance ensured parameters; Welch robust test was used when the homogeneity of variance was not ensured. Continuous variables with skewed distributions were expressed as mean ± SD and were compared using the Kruskal-Wallis test. Categorical variables were expressed as numbers and percentages and Pearson's chi-square or Fisher's exact tests were used to evaluate the differences. Hierarchical logistic regression analysis was used for multivariable analysis to evaluate the prognostic confounders for in-hospital outcomes. The odds ratio (OR) indicate the relative risk of in-hospital outcomes of Q4 compared with Q1–3. After follow-up periods of 42.7 ± 13.3 months, the survivals of four groups were compared using the Kaplan-Meier survival method. Overall survival was calculated from the day of diagnosis to the day of death or last follow-up date. Differences between the groups were analyzed by the log-rank test. A Forward Cox proportional regression
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analysis was performed to assess the in-hospital outcomes of the Q4 compared with Q1–3. The hazard ratio (HR) indicates the relative risk of long-term outcomes of Q4 compared with Q1–3. To analyze the predictions of in-hospital and long-term outcomes, data from the admission parameters were employed as independent variables. In multivariable models, confounders in multivariate analysis as predictors of in-hospital and long-term outcomes were considered. Two models
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were generated to examine the impact of potential confounders on the association between TRI and outcomes. These 2 models include: [1] unadjusted; [2] adjusted for all confounders including demographics (age, sex); first measurement of SBP and HR at admission; first measurement of the following laboratory values during hospitalization; admission estimated glomerular filtration rate (eGFR) calculated by CKD-EPI, blood urea nitrogen, hemoglobin and white blood cell,
Table 1 Baseline characteristics stratified by admission TRI. Admission TRI level
Age, y Male gender TRI value In hospital stay, d Comorbidities Hypertension Diabetes mellitus Hyperlipidemia Current smoking status Previous MI Previous PCI Previous CABG Chronic kidney disease Heart failure Chronic lung disease Cerebrovascular disease DVT history Prior PE Cancer Use of OCS Use of warfarin Use of steroid At admission Systolic blood pressure, mm Hg Altered mental status Heart rate, beats per minute Respiratory rate, beats minute Temperature O2 saturation, % PESI score Wells score Geneva score Intensive care unit stay, d Admission blood gas analysis pH Lactate HCO3 Admission symptoms Syncope Chest pain Fatigue Dyspnea Lower limb pain Lower limb edema USG findings of DVT Electrocardiography Sinus tachycardia Right bundle branch block T- wave inversion (leads V1–3) Atrial dysrhythmia S1Q3T3 Localization of thrombosis in PCTA Common pulmonary artery Right pulmonary artery Left pulmonary artery Left and right pulmonary artery Segmental pulmonary artery Subsegmental pulmonary artery
P value
I (n = 114)
II (n = 114)
III (n = 114)
IV (n = 114)
65 ± 12 56 (49.1) 15 ± 4 9±4
72 ± 8 56 (49.1) 28 ± 3 9±5
74 ± 8 48 (42.1) 39 ± 4 10 ± 5
78 ± 6 50 (43.9) 66 ± 20 10 ± 8
b0.001 0.615 b0.001 0.064
40 (35.1) 40 (35.1) 29 (25.4) 51 (44.7) 6 (5.3) 6 (5.3) 8 (7.0) 8 (7.0) 6 (5.3) 21 (18.4) 4 (3.5) 51 (44.7) 8 (7.0) 8 (7.0) 7 (6.1) 6 (5.4) 6 (5.3)
45 (39.5) 40 (35.1) 27 (23.7) 43 (37.7) 6 (5.3) 6 (5.3) 8 (7.0) 9 (7.9) 9 (7.9) 19 (16.7) 6 (5.3) 37 (32.5) 10 (8.8) 10 (8.8) 6 (5.3) 5 (4.4) 4 (3.5)
39 (34.2) 43 (37.7) 26 (22.8) 36 (31.6) 7 (6.1) 7 (6.1) 7 (6.1) 10 (8.8) 8 (7.0) 21 (18.4) 6 (5.3) 35 (30.7) 9 (7.9) 9 (7.9) 4 (3.5) 6 (5.4) 7 (6.1)
36 (31.6) 39 (34.2) 24 (21.1) 39 (34.2) 7 (6.1) 8 (7.0) 9 (7.9) 20 (17.5) 16 (14.0) 25 (21.9) 8 (7.0) 36 (31.6) 11 (9.6) 12 (10.5) 3 (2.6) 9 (7.9) 6 (5.3)
0.655 0.951 0.887 0.190 0.983 0.933 0.966 0.032 0.095 0.780 0.704 0.086 0.902 0.806 0.554 0.700 0.833
132 ± 16 9 (7.9) 98 ± 15 19 ± 3 36.6 ± 0.2 93 ± 8 71 ± 23 5.2 ± 1.9 7±4 4±2
128 ± 19 10 (8.8) 96 ± 18 21 ± 4 36.5 ± 0.3 94 ± 3 90 ± 36 5.3 ± 1.8 6±3 4±3
129 ± 18 10 (8.8) 97 ± 18 20 ± 2 36.6 ± 0.3 91 ± 4 97 ± 29 4.9 ± 1.8 7±3 5±3
106 ± 23 14 (12.3) 111 ± 18 21 ± 3 36.6 ± 0.3 90 ± 8 123 ± 43 5.5 ± 2.0 7±4 5±4
b0.001 0.679 b0.001 0.128 0.389 b0.001 b0.001 0.325 0.463 0.205
7.4 ± 0.1 2.6 ± 1.3 22.1 ± 5.2
7.4 ± 0.2 2.8 ± 1.8 21.6 ± 4.8
7.3 ± 0.8 2.9 ± 1.4 21.1 ± 5.1
7.2 ± 1.4 4.5 ± 2.1 19.4 ± 4.2
0.016 0.027 0.012
27 (23.7) 27 (23.7)
28 (24.6) 26 (22.8)
32 (28.1) 24 (21.1)
33 (28.9) 24 (21.1)
0.759 0.952
98 (86.7) 69 (60.5) 63 (55.3) 60 (52.6)
93 (84.5) 59 (51.8) 53 (46.5) 52 (45.6)
96 (85.7) 53 (46.5) 49 (43.0) 43 (37.7)
94 (83.9) 51 (44.7) 46 (40.4) 42 (36.8)
0.937 0.076 0.121 0.053
79 (69.3) 32 (28.1) 38 (33.3) 9 (7.9) 39 (34.2)
78 (68.4) 29 (25.4) 42 (36.8) 12 (10.5) 42 (37.7)
76 (66.7) 33 (28.9) 33 (28.9) 17 (14.9) 42 (36.8)
73 (64.0) 38 (33.3) 25 (25.4) 27 (23.7) 45 (39.5)
0.841 0.617 0.265 0.004 0.872
25 (21.9) 46 (40.4) 24 (21.1) 5 (4.4) 9 (7.9) 5 (4.4)
29 (25.4) 52 (45.6) 19 (16.7) 5 (4.4) 6 (5.3) 3 (2.6)
27 (23.7) 45 (39.5) 25 (21.9) 6 (5.3) 9 (7.9) 2 (1.8)
29 (25.4) 47 (41.2) 26 (22.8) 8 (7.0) 4 (3.5) 0 (0.0)
0.913 0.790 0.670 0.788 0.434 0.150
Nominal variables presented as frequency (%). One-way ANOVA test was used for continuous variables with normal distribution. Kruskal-Wallis test was used for continuous variables with skewed distribution. TRI indicates Thrombolysis in myocardial infarction risk index; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; DVT, deep vein thrombosis; PE, pulmonary embolism; OCS, oral contraception; HCO3, Bicarbonate; USG, ultrasonography; PCTA, pulmonary CT angiography.
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neutrophil, lymphocyte and platelet count; creatine kinase-MB, troponin I, D-dimer and BNP comorbidities (diabetes, chronic kidney disease, hypertension, stroke, heart failure, cancer, chronic lung disease and atrial dysrhythmia) and medications (use of oral contraceptives, warfarin and steroid). A two-tailed P value of b0.05 was considered statistically significant, and 95% CIs were presented for all odds ratios and hazard ratios. Analyses were performed using Statistical Package for Social Sciences software, version 20.0 (SPSS; IBM, Armonk, New York, USA). 3. Results 3.1. Baseline characteristics The patients' baseline characteristics, categorized by admission TRI level, are listed in Table 1. A total of 456 patients (mean age 72 ± 11 years; men 46%) with PE were included. The history of patients were similar in terms of hypertension, diabetes mellitus, hyperlipidemia, current smoking status, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass graft surgery, heart failure, chronic lung disease, cerebrovascular disease, DVT, PE, cancer, and using oral contraceptives, warfarin and steroids. Whereas, Q4 had a higher incidence of chronic kidney disease. PESI score was higher and O2 saturation was lower in Q4. TRI was positively correlated with PESI score (r = 0.549, P b 0.001) (Fig. 1). ROC analysis showed that the best cut-off value of the TRI to predict in-hospital mortality was 38 with 68% sensitivity and 70% specificity (AUC: 0.77; 95% CI: 0.71–0.74; p b 0.001) and the best cut-off value of the PESI score to predict in-hospital mortality was 96 with 64% sensitivity and 76% specificity (AUC: 0.74; 95% CI: 0.67–0.81; p b 0.001) (Fig. 2). 3.2. Laboratory findings The patients' laboratory parameters are summarized in Table 2. and it significant differences among patients with respect to eGFR, creatinine, admission CK-MB, BNP, lymphocyte count and blood urea nitrogen; whereas the groups were similar with respect to troponin I, Ddimer, white blood cell count, neutrophil count and hemoglobin.
3.3. Echocardiographic findings The patients' echocardiographic parameters are summarized in Table 2. Left ventricular ejection fraction, pulmonary arterial peak systolic pressure, left ventricular and right ventricular end diastolic diameters, left atrial diameter, were similar between 2 groups. Right ventricular dilatation, more than + 2 tricuspid regurgitation and the presence of thrombus in pulmonary arteries of the 4 groups were similar. Tricuspid annular plane systolic excursion (TAPSE) and right ventricle S velocity showed significant differences between groups and the patients with higher TRI level had showed lower right ventricular systolic functions.
3.4. In-hospital and long-term outcomes Tables 3 presents the in-hospital and long-term clinical outcomes of the study population. In-hospital mortality was significantly higher in Q4 (57%, P b 0.001). Q4 also had a higher incidence of major bleeding, intracranial hemorrhage, use of fresh frozen plasma, red cell transfusion, hypotension, cardiogenic shock, use of inotropic drugs, asystole, inhospital hemodialysis treatment, and mechanical ventilation. However in-hospital minor bleeding rates were similar between groups. Hierarchical logistic regression analysis was performed to assess in-hospital outcomes of the Q4 compared with the Q1–3 and summarized in Table 4. The unadjusted risks for all-cause mortality, major bleeding, intracranial hemorrhagia, use of fresh frozen plasma, red cell transfusion, hemodialysis, asystolia, hypotension, cardiogenic shock, use of inotropic drug and mechanic ventilation were significantly higher in Q4 (OR: 10.3, 95% CI: 6.2 to 16.9, P b 0.001; OR: 3.1, 95% CI: 1.8 to 5.5, P b 0.001; OR: 5.6, 95% CI: 2.3 to 13.1, P b 0.001; OR: 2.9, 95% CI: 1.6 to 5.0, P b 0.001; OR: 3.2, 95% CI: 1.8 to 5.4, P b 0.001; OR: 3.1, 95% CI: 1.5 to 8.6, P = 0.025; OR: 4.5, 95% CI: 2.7 to 7.5, P b 0.001; OR: 5.3, 95% CI: 3.2 to 8.9, P b 0.001; OR: 3.7, 95% CI: 2.1 to 6.5, P b 0.001; OR: 4.3, 95% CI: 2.5 to 7.3, P b 0.001; OR: 4.4, 95% CI: 2.6 to 7.6, P b 0.001; respectively). Futhermore, the adjusted risks for all-cause mortality, asystole, hypotension, cardiogenic shock, use of inotropic drug and mechanic ventilation were significantly higher in Q4 (OR: 2.8, 95% CI: 1.8 to 4.4,
Fig. 1. Scatter plot shows the relationship between TRI and PESI. Spearman correlation analysis revealed a significant correlation between the TRI and PESI value (r = 0.549; P b 0.001).
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Fig. 2. ROC analysis showed that the best cut-off value of the TRI to predict the in-hospital mortality was 38 with 68% sensitivity and 70% specificity (AUC: 0.77; 95% CI: 0.71–0.74; p b 0.001) and the best cut-off value of the PESI score to predict the in-hospital mortality was 96 with 64% sensitivity and 76% specificity (AUC: 0.74; 95% CI: 0.67–0.81; p b 0.001).
P = 0.002; OR: 2.1, 95% CI: 1.5 to 3.9, P = 0.008; OR: 1.9, 95% CI: 1.3 to 3.7, P = 0.012; OR: 2.1, 95% CI: 1.8 to 3.3, P = 0.004; OR: 2.0, 95% CI: 1.6 to 3.6, P = 0.006; OR: 1.9, 95% CI: 1.4 to 3.8, P = 0.018; respectively). The patients were followed up for a mean period of 42.7 ± 13.3 months. During follow-up, recurrent PE, major and minor bleeding, use of FFP,
and history of international normalized ratio N 5 were similar between the 2 groups. The 4-year Kaplan-Meier overall survivals were 91%, 88%, 97% and 53% respectively (Fig. 3). A forward Cox regression analysis was performed to assess the long-term outcomes of the Q4 compared with the Q1–3 and summarized in Table 5. Crude and adjusted
Table 2 Laboratory and echocardiography findings. Admission TRI level
Laboratory variables Glomerular filtration rate (CKD-EPI) Troponin I, ng/mL Creatinine (mg/dL) D-dimer, ng/mL Creatine kinase-MB, U/L Brain type natriuretic peptide, pg/mL White blood cell, cells/μL Lymphocyte, cells/μL Neutrophil, cells/μL Hemoglobin, g/dL Blood urea nitrogen, mg/dL Echocardiography parameters LVEF, % RV TAPSE RV S′ velocity, cm/s PASP, mm Hg LV diameter, mm RV diameter, mm LA diameter, mm RV dilatation TR N +2 Presence of thrombus
P value
I (n = 114)
II (n = 114)
III (n = 114)
IV (n = 114)
90.4 ± 22.8 0.85 ± 1.18 0.98 ± 0.41 4750 ± 4520 25.8 ± 22.4 279 ± 159 11.9 ± 3.9 2.0 ± 1.0 9.0 ± 3.6 12.3 ± 2.0 17 ± 8
79.2 ± 19.9 0.92 ± 2.21 1.08 ± 0.36 5025 ± 5167 28.1 ± 22.9 414 ± 252 11.4 ± 4.0 1.8 ± 0.8 8.6 ± 3.6 12.7 ± 1.8 22 ± 9
73.1 ± 46.9 0.95 ± 1.84 1.14 ± 0.86 5308 ± 5443 35.9 ± 23.6 655 ± 899 11.5 ± 3.9 1.9 ± 0.8 8.6 ± 3.4 12.7 ± 2.1 27 ± 16
62.1 ± 21.1 0.98 ± 1.65 1.27 ± 0.69 5578 ± 5782 45.4 ± 28.7 829 ± 681 12.3 ± 3.7 1.5 ± 0.9 10.4 ± 6.3 12.1 ± 1.9 31 ± 16
b0.001 0.750 b0.001 0.143 0.001 0.011 0.073 b0.001 0.063 0.104 b0.001
60 ± 6 19 ± 4 11 ± 2 44 ± 11 4.9 ± 0.6 4.6 ± 0.8 3.8 ± 0.7 92 (80.7) 69 (60.5) 27 (23.7)
57 ± 8 16 ± 3 10 ± 2 44 ± 10 4.8 ± 0.5 4.7 ± 0.7 3.7 ± 0.5 98 (86.0) 76 (66.7) 21 (18.4)
59 ± 5 15 ± 3 10 ± 2 45 ± 10 4.8 ± 0.5 4.8 ± 0.8 3.9 ± 0.6 93 (81.6) 84 (73.7) 27 (23.7)
57 ± 9 14 ± 2 9±2 47 ± 8 4.9 ± 0.4 4.8 ± 0.5 3.9 ± 0.5 92 (80.7) 81 (71.1) 33 (28.9)
0.078 b0.001 0.002 0.109 0.096 0.092 0.073 0.685 0.158 0.322
Continuous variables are presented as mean ± SD. One-way ANOVA test was used for continuous variables with normal distribution. Kruskal-Wallis test was used for continuous variables with skewed distribution. TRI indicates Thrombolysis in myocardial infarction risk index; LVEF, left ventricular ejection fraction; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion; PASP, pulmonary artery systolic pressure; LV, left ventricle; LA, left atrium; TR, tricuspid regurgitation.
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Table 3 In-hospital and long-term outcomes. Admission TRI level
In-hospital course All-cause mortality Major bleeding Intracranial hemorrhagia Use of fresh frozen plasma Red cell transfusion Hemodialysis Minor bleeding Asystolia Hypotension, b90 mm Hg Cardiogenic Shock Use of inotropic drug Mechanic ventilation
P value
I (n = 114)
II (n = 114)
III (n = 114)
IV (n = 114)
11 (9.6) 12 (10.5) 2 (1.8) 12 (10.5) 11 (9.6) 2 (1.8) 41 (36.0) 9 (7.9) 9 (7.9) 9 (7.9) 9 (7.9) 9 (7.9)
13 (11.4) 14 (12.3) 2 (1.8) 11 (9.6) 14 (12.3) 0 (0.0) 53 (46.5) 13 (11.4) 12 (10.5) 10 (8.8) 12 (10.5) 12 (10.5)
15 (13.2) 6 (5.3) 5 (4.4) 13 (11.4) 12 (10.5) 6 (5.3) 41 (36.0) 18 (15.8) 16 (14.0) 13 (11.4) 13 (11.4) 12 (10.5)
65 (57.0) 28 (24.6) 15 (13.2) 29 (25.4) 32 (28.1) 8 (7.0) 56 (49.1) 43 (37.7) 45 (39.5) 32 (28.1) 37 (32.5) 37 (32.5)
Admission TRI level
Out-hospital course All cause mortality Recurrent pulmonary embolism Major bleeding Minor bleeding History of INR N5 Use of fresh frozen plasma
b0.001 b0.001 b0.001 0.001 b0.001 0.016 0.081 b0.001 b0.001 b0.001 b0.001 b0.001 P value
I (n = 103)
II (n = 101)
III (n = 99)
IV (n = 49)
9 (8.7) 6 (5.8) 5 (4.9) 8 (7.8) 18 (17.5) 8 (7.8)
12 (11.9) 2 (2.0) 8 (7.9) 12 (11.9) 25 (24.8) 13 (12.9)
12 (12.1) 9 (9.1) 10 (12.5) 9 (9.1) 22 (22.2) 13 (13.1)
25 (46.9) 2 (4.1) 6 (12.2) 7 (14.3) 11 (22.4) 5 (10.2)
b0.001 0.161 0.381 0.573 0.643 0.585
Nominal variables presented as frequency (%). TRI indicates Thrombolysis in myocardial infarction risk index.
risks for all-cause death was significantly higher in Q4 (HR: 7.2, 95% CI: 3.7 to 14.1, P b 0.001; HR: 3.1, 95% CI: 1.6 to 5.1, P = 0.004; respectively). 4. Discussion The main findings of the current study as follows: (a) patients in the higher TRI quartile (Q4) had a lower RV systolic function; (b) higher inhospital mortality, inotropic drug use and cardiogenic shock; (c) higher in-hospital bleeding complications and (d) higher long-term mortality. The association of TRI with in-hospital and long-term mortality was persisted even after multivariable analyses. Pulmonary embolism is a life-threatening disorder that comprises of a wide range of symptoms, signs and clinical outcomes. Rise in pulmonary artery pressure starts as N 30–50% of the total pulmonary arterial bed occluded by thromboemboli [10,11]. The rapid rise in pulmonary vascular resistance leads to RV dilation, which affects via the Frank-Starling mechanism. RV contraction time is prolonged, while neurohumoral
activation leads to inotropic and chronotropic stimulation. Together with systemic vasoconstriction, these compensatory mechanisms increase pulmonary artery pressure, to improve flow through the obstructed pulmonary vascular bed, and thus temporarily stabilize systemic blood pressure [12]. The extent of immediate adaptation is limited, since a non-preconditioned, thin-walled right ventricle (RV) is unable to generate a mean pulmonary artery pressure above 40 mm Hg. Failure in these excessive hemodynamic response can be result in circulatory shock. Because of its possible complications, risk stratification is vitally important for management of PE. Tachycardia may be explained by high levels of epinephrine released as a result of the PE-induced myocarditis [13]. This neurohumoral response may lead to further biventricular failure and hemodynamic deterioration. Because of these mechanisms tachycardia is a potent prognostic indicator in PE. RV contraction prolongs as a result of abrupt increment in preload and leads to leftward bowing of the interventricular septum and D-shaped left ventricle. Consequently, LV filling is blocked in diastole, and this
Table 4 In-hospital event rates and logistic regression models for outcomes by TRI level.
In-hospital course All-cause mortality Major bleeding Intracranial hemorrhagia Use of fresh frozen plasma Red cell transfusion Hemodialysis Minor bleeding Asystolia Hypotension, b90 mm Hg Cardiogenic Shock Use of inotropic drug Mechanic ventilation
Q1–3 (n = 342)
Q4 (n = 114)
Crude OR (95% CI)
P value
Adjusteda OR (95% CI)
P value
39 (11.4) 32 (9.4) 9 (2.6) 36 (10.5) 37 (10.8) 8 (2.3) 135 (39.5) 40 (11.7) 37 (10.8) 32 (9.4) 34 (9.9) 33 (9.6)
65 (57.0) 28 (24.6) 15 (13.2) 29 (25.4) 32 (28.1) 8 (7.0) 56 (49.1) 43 (37.7) 45 (39.5) 32 (28.1) 37 (32.5) 37 (32.5)
10.3 (6.2–16.9) 3.1 (1.8–5.5) 5.6 (2.3–13.1) 2.9 (1.6–5.0) 3.2 (1.8–5.4) 3.1 (1.5–8.6) 1.4 (0.9–2.2) 4.5 (2.7–7.5) 5.3 (3.2–8.9) 3.7 (2.1–6.5) 4.3 (2.5–7.3) 4.4 (2.6–7.6)
b0.001 b0.001 b0.001 b0.001 b0.001 0.025 0.071 b0.001 b0.001 b0.001 b0.001 b0.001
2.8 (1.8–4.4) 1.8 (0.7–4.8) 0.9 (0.2–3.9) 2.3 (0.9–5.9) 2.1 (0.8–5.4) 1.2 (0.4–5.8) 1.7 (0.8–3.4) 2.1 (1.5–3.9) 1.9 (1.3–3.7) 2.1 (1.8–3.3) 2.0 (1.6–3.6) 1.9 (1.4–3.8)
0.002 0.218 0.928 0.076 0.102 0.832 0.118 0.008 0.012 0.004 0.006 0.018
Abbreviations: TRI, Thrombolysis in myocardial infarction risk index; OR, Odds ratio. a Includes demographics (age, sex); first measurement of systolic blood pressure and heart rate; first measurement during hospitalization of the following laboratory values (admission glomerular filtration rate calculated by CKD-EPI, blood urea nitrogen, white blood cell count, hematocrit, platelet count); creatine kinase-MB, troponin I, D-dimer, brain type natriuretic peptide; comorbidities (diabetes, chronic kidney disease, hypertension, stroke, heart failure, cancer, chronic lung disease and atrial dysrhythmia) and medications (use of oral contraceptives, warfarin and steroid).
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Fig. 3. Kaplan Meier curve for overall survival in patients with pulmonary embolism (n = 352) stratified by TRI quartile.
may lead to reduction of cardiac output and contribute to systemic hypotension and haemodynamic instability. Tachycardia and hypotension are the consequences of similar mechanism and may be the harbingers of hemodynamic compromise. Age is another prognostic factor of mortality in patients with PE and is the mutual criterion of both Geneva score and PESI. In current study, TRI was strongly correlated with PESI. Also higher rates of major bleeding, intracranial hemorrhage and use of fresh frozen plasma in patients with higher TRI may attributable to higher age in these patients. TRI is a novel and cheap scoring system which was found significantly predictive for short-term and long-term mortality in some large cohorts and studies of patients with ACS [6,7,14]. ACS and PE commonly have similar precipitating and prognostic factors such as age, hypotension and tacyhcardia in admission [2,15]. PE requires a new risk index for immediate evaluation and referral of patients which is not based on laboratory analysis. Despite the predictive value of TRI in ACS, it has not been evaluated in patients with PE. 5. Conclusion This pilot investigation demonstrated that TRI, calculated based on age, SBP and HR, is an independent in-hospital and 4-year long-term prognostic factor for mortality in patients with moderate-high and
high risk PE who treated with t-PA. Albeit, TRI is recently developed and considered as an important predictive index in patients with ACS; its prognostic value in patients with PE has not been evaluated. This risk index could be used as a practical tool for risk stratification on patients with PE. We only included the patients with moderate-high and high risk PE, however, these subgroups constitute the majority of death. Therefore, the current study may provide a valuable risk prediction for in-hospital and long-term mortality in overall patients with PE. To put forward the interaction between the TRI and overall PE, some additional and large volume studies need to be established. 6. Study limitations Our study has several limitations. First, this is a single-center, retrospective and observational study based on relatively small number of patients. Second, TRI was designed to provide pre-hospital and initial risk estimation during the first patient contact. It does not associate the impact of therapy, comorbidity or baseline treatments with outcome. Third, SBP measurements were non invasive. Fourth, although we used multivariable analysis, we could not exclude the possibility of residual unmeasured covariables which might influence the outcomes. Fifth; although TRI level might be influenced by hormonal changes, we could not measure hormones such as serum catecholamine and
Table 5 Long-term (4-year) event rates and logistic regression models for outcomes by TRI level.
Out-hospital course All cause mortality Recurrent pulmonary embolism Major bleeding Minor bleeding History of INR N5 Use of fresh frozen plasma
Q1–3 (n = 303)
Q4 (n = 49)
Crude HR (95% CI)
P value
Adjusteda HR (95% CI)
P value
33 (10.9) 17 (5.6) 23 (7.6) 29 (9.6) 65 (21.5) 34 (11.2)
23 (46.9) 2 (4.1) 6 (12.2) 7 (14.3) 11 (22.4) 5 (10.2)
7.2 (3.7–14.1) 0.7 (0.2–3.2) 1.7 (0.6–4.4) 1.5 (0.6–3.8) 1.1 (0.5–2.1) 0.9 (0.3–2.4)
b0.001 0.662 0.276 0.316 0.875 0.833
3.1 (1.6–5.1) 0.5 (0.1–2.1) 1.6 (0.5–5.4) 1.3 (0.4–4.9) 1.1 (0.4–3.1) 0.9 (0.2–3.7)
0.004 0.275 0.289 0.699 0.766 0.885
Abbreviations: TRI, Thrombolysis in myocardial infarction risk index; HR, Hazard ratio. a Includes demographics (age, sex); first measurement of systolic blood pressure and heart rate; first measurement during hospitalization of the following laboratory values (admission glomerular filtration rate calculated by CKD-EPI, blood urea nitrogen, white blood cell count, hematocrit, platelet count); creatine kinase-MB, troponin I, D-dimer, brain type natriuretic peptide; comorbidities (diabetes, chronic kidney disease, hypertension, stroke, heart failure, cancer, chronic lung disease and atrial dysrhythmia) and medications (use of oral contraceptives, warfarin and steroid).
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