Journal of Thrombosis and Haemostasis, 12: 1020–1027
DOI: 10.1111/jth.12589
ORIGINAL ARTICLE
Prognostic significance of tricuspid annular displacement in normotensive patients with acute symptomatic pulmonary embolism ,** R. OTERO,†† J . L . L O B O , * A . H O L L E Y , † V . T A P S O N , ‡ L . M O O R E S , § M . O R I B E , ¶ M . B A R R ON D . N A U F F A L , ‡ ‡ R . V A L L E , § § M . M O N R E A L , ¶ ¶ R . D . Y U S E N * * * a n d D . J I M EN E Z , † † † F O R T H E PROTECT AND THE RIETE INVESTIGATORS *Respiratory Department, Txagorritxu Hospital, Vitoria, Spain; †Department of Pulmonary, Critical Care, and Sleep Medicine, Walter Reed National Military Medical Center, Bethesda, MD; ‡Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC; §F. Edward Hebert School of Medicine, Uniformed Services University, Bethesda, MD, USA; ¶Respiratory Department, Galdakao ~o; ††Respiratory Department, Virgen del Rocıo Hospital, Sevilla; Hospital, Galdakao; **Respiratory Department, San Pedro Hospital, Logron ‡‡Respiratory Department, La Fe Hospital, Valencia; §§Medicine Department, Hospital Sierrallana, Cantabria; ¶¶Medicine Department, Germans Trias I Pujol Hospital, Badalona, Spain; ***Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, n y Cajal Hospital, IRYCIS, Madrid, Washington University School of Medicine, St Louis, MO, USA; and †††Respiratory Department, Ramo Spain
n M, Otero R, Nauffal D, Valle R, Monreal M, Yusen RD, Jimenez D, To cite this article: Lobo JL, Holley A, Tapson V, Moores L, Oribe M, Barro for the PROTECT and the RIETE investigators. Prognostic significance of tricuspid annular displacement in normotensive patients with acute symptomatic pulmonary embolism. J Thromb Haemost 2014; 12: 1020–7.
Summary. Background: Tricuspid annular plane systolic excursion (TAPSE) is an emerging prognostic indicator in patients with acute symptomatic pulmonary embolism (PE). Methods and Results: We prospectively examined 782 normotensive patients with PE who underwent echocardiography in a multicenter study. As compared with patients with a TAPSE of > 1.6 cm, those with a TAPSE of ≤ 1.6 cm had increased systolic pulmonary artery pressure (53.7 16.7 mmHg vs. 40.0 15.5 mmHg, P < 0.001), right ventricle (RV) end-diastolic diameter (3.5 0.8 cm vs. 3.0 0.6 cm, P < 0.001), and RV to left ventricle end-diastolic diameter ratio (1.0 0.3 vs. 0.8 0.2, P < 0.001), and a higher prevalence of RV free wall hypokinesis (68% vs. 11%, P < 0.001). Patients with a TAPSE of ≤ 1.6 cm at the time of PE diagnosis were significantly more likely to die from any cause (hazard ratio [HR] 2.3; 95% confidence interval [CI] 1.2–4.7; P = 0.02) and from PE (HR 4.4; 95% CI 1.3–15.3; P = 0.02) during follow-up. In an external validation cohort of 1326 patients with acute PE enrolled in the international multicenter Registro Informatizado de la Correspondence: David Jimenez, Respiratory Department, Ram on y Cajal Hospital, IRYCIS, 28034 Madrid, Spain. Tel.: +34 913368314; fax: +34 913369016. E-mail: [email protected] Received 4 February 2014 Manuscript handled by: P. de Moerloose Final decision: F. R. Rosendaal, 21 April 2014
Enfermedad TromboEmb olica, a TAPSE of ≤ 1.6 cm remained a significant predictor of all-cause mortality (HR 2.1; 95% CI 1.3–3.2; P = 0.001) and PE-specific mortality (HR 2.5; 95% CI 1.2–5.2; P = 0.01). Conclusions: In normotensive patients with PE, TAPSE reflects right ventricular function. For these patients, TAPSE is independently predictive of survival. Keywords: echocardiography; prognosis; pulmonary embolism; right ventricular dysfunction; survival.
Introduction Early mortality rates for pulmonary embolism (PE) range from 5% in patients who are clinically stable to 58% in patients with cardiogenic shock [1–3]. Some patients with PE may safely undergo treatment at home and avoid admission to a hospital [4,5], whereas others require hospital admission and even immediate recanalization of the occluded pulmonary arteries. Risk stratification tools may help to distinguish between these different categories of patient [6,7]. In the setting of acute PE, complex hemodynamic changes affect right ventricular function [8]. Mechanical obstruction of the pulmonary arteries and the release of vasoconstrictive mediators may cause abrupt increases in pulmonary vascular resistance and right ventricle (RV) afterload. Increased RV afterload may cause RV dilatation and a subsequent increase in RV regional wall stress. © 2014 International Society on Thrombosis and Haemostasis
Prognostic significance of TAPSE 1021
Localized ischemic effects may also affect the RV free wall. Interventricular septal shifting towards the left ventricle (LV) may affect LV preload and cardiac output. Arrhythmias may also affect cardiac function. Subsequent systemic hypotension may compromise coronary perfusion and cause ischemia. The severity and combination of these events may lead to varying degrees of cardiovascular compromise. Several risk stratification algorithms using different combinations of clinical and laboratory variables have been developed for use in the work-up of PE. Evaluation of right heart function has also proven to be an integral part of the initial evaluation, with transthoracic echocardiography (TTE) being particularly valuable for predicting morbidity and mortality [9]. Despite the documented value of right heart assessment via TTE, the complex geometry of the RV and the subjective nature of the standard measurements routinely obtained often limit its utility [10,11]. Tricuspid annular plane systolic excursion (TAPSE) is a quantitative echocardiographic parameter obtained in M-mode that has been correlated with standard TTE measures and laboratory values in PE [12,13], and with clinical outcomes in pulmonary arterial hypertension [14] and congestive heart failure [15]. Because visualization of the RV free wall is not required and a numerical value is obtained, TAPSE has the potential to provide objective and valuable information that does not require specialized training for measurement and interpretation. Existing data obtained with TAPSE for prognostic purposes in PE are limited by small sample sizes and the absence of correlation with morbidity and mortality [12,13,16]. The purpose of this study was to establish the relationship between TAPSE and clinical outcomes in normotensive patients with acute symptomatic PE. Furthermore, we aimed to determine the optimal combination of echocardiographic findings for risk stratification of acute PE. To achieve these aims, we conducted a prospective cohort study, and we externally and retrospectively validated our findings in a large, independent cohort of patients. Methods PROTECT is a prospective, multicenter observational cohort study designed by the authors and sponsored by the Institute of Health Carlos III, Spain (NCT00880737) [17]. This PROTECT substudy was a priori designed to test the predictive characteristics of TAPSE in normotensive patients (i.e. without hemodynamic instability) with acute symptomatic PE. Local ethics committees approved the study. All patients provided written informed consent. Patients
Only patients diagnosed with acute PE (first symptoms occurring within 14 days) by multidetector computed © 2014 International Society on Thrombosis and Haemostasis
tomography (CT) were eligible [18]. Exclusion criteria consisted of treatment with thrombolytics at the time of PE diagnosis, life-expectancy of < 3 months, pregnancy, geographic inaccessibility precluding follow-up, age of < 18 years, renal insufficiency (creatinine clearance of < 30 mL min 1), inability to complete CT testing (e.g. allergy to intravenous contrast agents, unavailability of CT, or patient too ill), or hemodynamic instability at presentation (defined as cardiogenic shock, systolic blood pressure of < 90 mmHg, or the use of inotropic support). We also excluded patients who did not successfully complete the protocol-required TTE. Baseline examinations
The study protocol required that patients undergo echocardiography (i.e. TTE) within 24 h after diagnosis of PE. Patients underwent testing in the left lateral position. Trained and certified local cardiologists, blinded to the patient’s clinical data and laboratory test results, interpreted each echocardiogram. Echocardiographic right ventricular dysfunction (RVD) was defined as the presence of at least two of the following: dilatation of the RV (end-diastolic diameter of > 30 mm from the parasternal view or the RV appearing larger than the LV from the subcostal or apical view), hypokinesis of the RV free wall (any view), or tricuspid regurgitant jet velocity of > 2.6 m s 1 [19]. To obtain TAPSE, the apical fourchamber view was used, and an M-mode cursor was placed through the lateral tricuspid annulus in real time. TAPSE was measured as the total displacement of the tricuspid annulus (centimeters) from end-diastole to endsystole, with values representing the average TAPSE of three to five beats [20]. Study outcome measures
The study used all-cause mortality 30 days after the diagnosis of PE as the primary outcome. For this substudy, PE-specific mortality was the secondary outcome [17]. An independent Adjudication Committee, whose members were blinded to initial prognostic test results, adjudicated all serious adverse events. Validation cohort
To externally validate the prognostic significance of TAPSE, patient data from the Registro Informatizado de la Enfermedad TromboEmb olica (RIETE) were used. The RIETE is an ongoing, international multicenter, observational registry of consecutively enrolled patients, designed to collect and analyze data on treatment patterns and clinical outcomes in patients with acute symptomatic venous thromboembolism. Study design and patient eligibility criteria of the RIETE have been described elsewhere [21]. The validation cohort for this
1022 J. L. Lobo et al
study consisted of the subgroup of 1326 patients enrolled in the RIETE who had acute symptomatic PE, had undergone TTE, had TAPSE measurement and follow-up data, and had not been included in this study. Statistical analyses
Descriptive statistics were used for baseline data, chi-square or Fisher’s exact tests were used to compare categorical data between groups, and unpaired two-tailed t-tests or the Mann–Whitney U-test were used to compare continuous data between groups. A receiver operating characteristic (ROC) curve was used to assess the accuracy of TAPSE for detecting the primary outcome of all-cause mortality. The optimum cut-off point was established by selecting the point of test values that provided the greatest sum of sensitivity and specificity – i.e. the point closest to the top left-hand corner on the ROC curve. To estimate mortality over time, we used Kaplan– Meier curves [22], with differences between groups being assessed with the log-rank test. Cox proportional hazards regression models were used to test for an independent association between TAPSE at presentation and outcome measures [23]. A manual backward stepwise approach was used to develop the multivariate model. In the full model, variables with an imbalance between groups at baseline were considered for inclusion. When two or more variables were closely related, only one was included in a given multivariate model. Variables that showed evidence of confounding (that is, the coefficient of the variable group changed by > 10% when that variable was removed from the full model) for the effect of TAPSE on the outcome undergoing analysis were not removed from the model. In addition, we performed multivariate analysis, with 30-day PE-related mortality as the outcome, to determine the optimal combination of echocardiographic findings for risk stratification of PE. No adjustments for other baseline parameters were made in this latter model. We assessed the performance of TAPSE and the new combination of echocardiographic criteria with traditional echocardiographic measures for RVD (see Baseline examinations) by evaluating discrimination with the overall c-statistic [24]. Statistical significance was defined as a two-tailed Pvalue of < 0.05 for all analyses. Analyses were performed with SPSS version 14.0 for the PC (SPSS, Chicago, IL, USA).
normotensive patients diagnosed with acute PE for eligibility. The study excluded 66 patients because they did not have the complete baseline echocardiographic data required for analyses (7.8%; 95% confidence interval [CI] 6.0–9.6%). No statistically significant difference was observed between included and excluded patients regarding demographics, medical history, and clinical presentation. A total of 782 patients (382 men and 400 women; 92% of the screened population) were included in the present study. Table 1 shows the patients’ clinical symptoms, predisposing conditions, and relevant findings at presentation. At enrollment, all patients (100%) were receiving anticoagulant treatment. The overall number of patients treated with inferior vena cava filters was small (0.9%; 7/782). TAPSE and right ventricular function
On admission, TAPSE measurements ranged from 0.9 to 4.0 cm, with a median value of 2.0 cm (25–75th percentile, 1.8–2.3 cm). ROC curve analysis revealed that TAPSE was a sensitive and specific indicator of overall mortality (area under the ROC curve [AUC] 0.64, P = 0.005). To identify low-risk patients with PE, ROC curve analysis for TAPSE determined that 1.6 cm was the optimal cut-off. When only PE-related mortality was considered, the AUC was 0.79 (P = 0.002). Overall, 146 patients (18.7%; 95% CI 15.9–21.4%) had TAPSE measurements below the cut-off value of 1.6 cm. As shown in Table 1, patients with a TAPSE of ≤ 1.6 cm were older, were less likely to be male, had a higher prevalence of chronic heart disease or atrial fibrillation and had more signs of clinical severity (syncope, tachycardia, hypoxemia, and hypotension) than those with a TAPSE of > 1.6 cm. Figure 1 summarizes the differences in RV free wall hypokinesis (A), RV end-diastolic diameter (B) and RV/ LV end-diastolic diameter ratio (C) observed between patients with a TAPSE of > 1.6 cm and those with a TAPSE of ≤ 1.6 cm. Patients with a TAPSE of ≤ 1.6 cm also had significantly higher systolic pulmonary artery pressure (53.7 16.7 mmHg) than those with a TAPSE of > 1.6 cm (40.0 15.5 mmHg) (P < 0.001). Brain natriuretic peptide (519 790 pg mL 1 vs. 168 292 pg mL 1, P < 0.001) and cardiac troponin I (cTnI) (0.17 0.57 ng mL 1 vs. 0.06 0.32 ng mL 1, P = 0.001) levels were also significantly higher among patients with a TAPSE of ≤ 1.6 cm. Outcome
Results Patients
We used multidetector contrast-enhanced helical chest CT in the emergency department to screen 848 consecutive
Outcome data were available for all patients throughout the 30-day study follow-up. Overall, 35 of 782 patients died (4.5%; 95% CI 3.0–5.9%). Ten patients (10/782; 1.3%; 95% CI 0.5–2.1%) died from definite (n = 4) or possible (n = 6) PE, and 25 (25/782; 3.2%; 95% CI © 2014 International Society on Thrombosis and Haemostasis
Prognostic significance of TAPSE 1023 Table 1 Baseline characteristics and treatment information for normotensive patients with acute symptomatic pulmonary embolism (PE) All patients, N = 782 Clinical characteristics Age (years), median (25–75th percentiles) 73 Age > 65 years, n (%) 511 Male gender, n (%) 382 Risk factors for VTE, n (%) Cancer* 136 Recent surgery† 79 Immobilization‡ 151 Comorbid diseases, n (%) COPD 101 Congestive heart failure 44 Clinical symptoms and signs at presentation, n (%) Syncope 123 Chest pain 378 Dyspnea 623 Heart rate > 100 min 1 230 170 Arterial oxyhemoglobin saturation (SAO2) < 90% SBP < 120 mmHg 201 Concomitant DVT 351 CT, echocardiography, and cardiac biomarkers, n (%) RVD (CT) 501 RVD (echocardiogram) 305 RV free wall hypokinesis 166 RVEDD > 30 mm 359 RVEDD/LVEDD > 1 128 Systolic pulmonary artery pressure > 30 mmHg 403 BNP > 100 pg mL 1 345 cTnI > 0.05 ng mL 1 129 Treatment, n (%) Insertion of an IVC filter 7
(59–80) (65) (49)
TAPSE ≤ 1.6 cm, N = 146
TAPSE > 1.6 cm, N = 636
77 (64–82) 105 (72) 58 (40)
71 (58–79) 406 (64) 324 (51)
0.001 0.06 0.014
P-value
(17) (10) (19)
21 (14) 7 (4.8) 32 (22)
115 (18) 72 (11) 119 (19)
0.29 0.02 0.38
(13) (5.6)
22 (16) 14 (10)
79 (14) 30 (5.2)
0.51 0.03
(16) (48) (80) (29) (22) (26) (45) (64) (39) (21) (46) (16) (52) (44) (16) (0.9)
38 70 125 69 58
(26) (48) (86) (47) (45)
52 (36) 67 (46) 121 113 98 103 57 110 105 48
(83) (77) (68) (72) (41) (93) (72) (33)
1 (0.7)
(13) (48) (78) (25) (20)
< 0.001 0.96 0.03 < 0.001 < 0.001
149 (23) 284 (46)
0.002 0.98
85 308 498 161 112
380 192 68 256 71 293 240 81
(60) (30) (11) (42) (12) (70) (38) (13)
6 (1.0)
< < < < < < <
1.6 cm (absolute difference of 4.6%; 95% CI of the absolute difference, 0.1% to 9.3%; P = 0.03); five deaths in each group resulted from definite or possible PE. Patients with acute PE and a TAPSE of ≤ 1.6 cm had significantly higher cumulative mortality than patients with acute PE and a TAPSE of > 1.6 cm (P = 0.013, log-rank test; Fig. 2). Table 2 shows 30-day mortality rates by quartiles of TAPSE in the PROTECT and the RIETE cohorts. In univariate analyses, patients with cancer (hazard ratio [HR] 2.8; 95% CI 1.4–5.6; P = 0.003), systolic blood pressure of < 120 mmHg (HR 2.5; 95% CI 1.3– © 2014 International Society on Thrombosis and Haemostasis
4.8; P = 0.007), elevated cTnI levels (HR 2.1; 95% CI 1.0–4.5; P = 0.04) and a TAPSE of ≤ 1.6 cm (HR 2.3; 95% CI 1.2–4.7; P = 0.02) at the time of acute PE diagnosis were significantly more likely to die from any cause during follow-up (Table 3). In the multivariate analysis, no variable showed evidence of confounding for the association between TAPSE and all-cause mortality during follow-up (Table 3). Decreasing values of TAPSE were associated with an increase in the risk of all-cause mortality (HR 1.11; 95% CI 1.03–1.21; P < 0.01). When we forced into the full model those variables (i.e. congestive heart failure, heart rate, syncope, and dyspnea) with an imbalance between TAPSE groups at baseline, none of them showed evidence of confounding for the effect of TAPSE on the outcome being analyzed. TAPSE measurement remained an independent predictor of all-cause mortality when patients with prior cardiopulmonary disease (n = 136) were excluded from the analysis (HR 2.2; 95% CI 1.0–5.2; P = 0.05). A TAPSE of ≤ 1.6 cm at the time of presentation was also independently and signifi-
1024 J. L. Lobo et al A
100
70 60
Probability of suruvival (%)
RV free wall hypokinesis (%)
80
50 40 30 20 10 0 TAPSE > 1.6 cm
95
TAPSE > 1.6 cm
90
TAPSE ≤ 1.6 cm
85
TAPSE ≤ 1.6 cm
B
80 5
0
RVEDD (mm)
60.00
10
15
20
25
30
Time (days) No. at risk TAPSE > 1.6 cm TAPSE ≤ 1.6 cm
40.00
636 146
628 136
626 130
624 123
Log rank P = 0.013
Fig. 2. Kaplan–Meier estimates of survival (primary endpoint: allcause mortality) in patients stratified by tricuspid annular plane systolic excursion (TAPSE) values.
20.00
0.00 TAPSE > 1.6 cm
TAPSE ≤ 1.6 cm
C 2.50
Quartile of TAPSE
2.00 RVEDDLVEDD
Table 2 Thirty-day mortality by quartile of tricuspid annular plane systolic excursion (TAPSE) in the PROTECT and RIETE cohorts
PROTECT cohort < 18 mm 18–20 mm 20–23 mm > 23 mm RIETE cohort < 17 mm 17–20 mm 20–23 mm > 23 mm
1.50
1.00
0.50
Number at risk
Thirty-day all-cause mortality (%)
Thirty-day PE-related mortality (%)
188 160 269 165
7.4 4.4 4.1 1.8
3.2 1.9 0.4 0
306 301 424 295
12.1 7.3 6.4 5.4
4.2 2.3 1.6 1.3
PE, pulmonary embolism.
0.00 TAPSE > 1.6 cm
TAPSE ≤ 1.6 cm
Fig. 1. Bar graphs comparing echocardiographic indices of right ventricular dysfunction in patients with tricuspid annular plane systolic excursion (TAPSE) of > 1.6 cm and ≤ 1.6 cm. (A) Right ventricle (RV) free wall hypokinesis. (B) RV end-diastolic diameter (RVEDD). (C) RVEDD left ventricle end-diastolic diameter (LVEDD).
cantly associated with PE-related death (HR 4.4; 95% CI 1.3–15.3; P = 0.02). We also investigated the optimal combination of echocardiographic findings with regard to risk stratification of acute PE. On multivariate analysis, only TAPSE (HR 1.2; 95% CI 1.0–1.4; P = 0.03) and RV/LV end-diastolic
diameter ratio (HR 8.9; 95% CI 1.1–74.7; P = 0.04) were significantly associated with PE-related mortality during follow-up. The ROC analysis AUC for PE-related mortality of the combination of TAPSE and RV/LV end-diastolic diameter ratio was significantly increased as compared with that for the traditional echocardiographic measures for RVD (0.86 vs. 0.70; P < 0.001). External validation in the RIETE registry
The 1326 eligible patients from the RIETE validation cohort had similar proportions of male gender, chronic pulmonary disease, cancer, previous surgery and immobi© 2014 International Society on Thrombosis and Haemostasis
Prognostic significance of TAPSE 1025 Table 3 Unadjusted and adjusted hazard ratios (HRs) for overall mortality in normotensive patients with acute symptomatic pulmonary embolism Risk factor
Unadjusted HR (95% CI)
P-value
Adjusted HR (95% CI)
P-value
Cancer* SBP < 120 mmHg TAPSE ≤ 1.6 cm cTnI > 0.05 ng mL
2.84 2.50 2.35 2.14
0.003 0.007 0.02 0.04
– – 2.35 (1.17–4.73)† –
– – 0.02 –
1
(1.43–5.64) (1.28–4.85) (1.17–4.73) (1.02–4.47)
CI, confidence interval; cTnI, cardiac troponin I; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion. Only variables found to significantly predict 30-day all-cause mortality by univariable analysis are shown. N = 782 evaluated, with 35 deaths. Final model: chi square = 6.14, P = 0.01. *Active or under treatment in the last year. †No variables showed evidence of confounding.
lization for ≥ 4 days as the 782 patients in the original study cohort (Table 4). Congestive heart failure was significantly more prevalent in the RIETE cohort than in the study cohort. The prevalence of signs of clinical severity (syncope, dyspnea, tachycardia, and hypoxemia) was similar in both cohorts. Systolic pulmonary artery pressure of > 30 mmHg was detected in 58% of patients in the RIETE cohort (764/1326) and in 52% of patients in the study cohort (403/782). Of the 1326 patients included in the RIETE validation cohort, 102 (102/1326; 7.7%; 95% CI 6.3–9.1%) died during follow-up, as compared with 4.5% (35/782; 95% CI 3.0–5.9%) in the original study cohort (absolute risk difference of 3.2%; 95% CI 1.1–5.2%). Thirty-one patients (31/1326; 2.3%; 95% CI 1.5–3.1%) died from PE, and 71 (71/1326; 5.3%; 95% CI 4.1–6.6%) died from other causes. As shown in Table 2, mortality also differed among TAPSE quartiles in the RIETE validation cohort, with the largest differences in outcome being observed between patients with a TAPSE of < 1.7 cm and those with a TAPSE of > 2.3 cm. In the RIETE cohort, decreasing values of TAPSE were associated with an increase in the risk of all-cause mortality (HR 1.06; 95% CI 1.02–1.10; P < 0.01). Patients with a TAPSE of ≤ 1.6 cm at the time of diagnosis of PE had significantly higher all-cause mortality than those with a TAPSE of > 1.6 cm (HR 2.1; 95% CI 1.3–3.2; P = 0.001). A TAPSE of ≤ 1.6 cm at the time of presentation had an independently significant association with PE-specific mortality (HR 2.5; 95% CI 1.2–5.2; P = 0.01). Discussion In the present study, a TAPSE of ≤ 1.6 cm identified normotensive patients with acute PE who had advanced RVD. Patients with a TAPSE of ≤ 1.6 cm had increased all-cause and PE-specific mortality at 30-day follow-up, findings that persisted after adjustment for several previously recognized predictors of outcome. Thus, our results suggest that TAPSE is a robust measure of right ventricular function and a significant predictor of survival in patients with PE. The patient presenting with acute PE with normal blood pressure represents a challenge to the clinician. © 2014 International Society on Thrombosis and Haemostasis
Outcomes for this population are determined by the interaction between the significance of the embolus and specific patient characteristics [25]. This has led to the intense pursuit of a simple but accurate measure of this interaction. RVD, which is most commonly detected with echocardiography, has consistently been associated with adverse clinical outcomes, including mortality [1,9]. Despite the excellent data supporting the use of TTE for risk stratification for the normotensive patient with acute PE, its practical application can be challenging. The RV has a complex contraction mechanism, and the chamber is difficult to visualize in its entirety on any single two-dimensional echocardiographic view [10]. Many of the measurements used to assess its function are subjective in nature. As a result, accurate interpretation has traditionally required an experienced cardiologist. Recent advances in diagnostic technologies and portability have made bedside ultrasound increasingly available to the physician performing the initial assessment of the patient with acute PE [26,27]. As a result, finding a measure of right ventricular function that is valid, reproducible and easy to obtain is more important than ever. TAPSE requires visualization of the tricuspid annulus only, and provides an objective value that is easy to measure and should be comparable across patients. In the largest group of patients studied to date, we have once again confirmed that TAPSE is an excellent surrogate for traditional TTE measures of right ventricular function. Furthermore, we have shown an association with clinical outcomes, and defined an optimal value for performance. The potential prognostic implications of cardiac ultrasound findings for non-high-risk PE remain a subject of debate. One of the main reasons is that echocardiographic criteria for defining RVD are poorly standardized, and may vary widely between hospitals, ultrasound laboratories, and examiners. Therefore, we have provided a uniform set of criteria (i.e. TAPSE and RV/LV end-diastolic diameter ratio) whose accuracy was significantly higher than that of the traditional echocardiographic measures of RVD. Our study has several limitations. We did not adjust for left ventricular function, which is known to have an effect on TAPSE values [28]. Nevertheless, when we excluded patients with prior cardiopulmonary disease,
1026 J. L. Lobo et al Table 4 Comparison of baseline patient characteristics in the study cohort and the RIETE registry validation cohort Original cohort, N = 782
RIETE registry, N = 1326
Clinical characteristics Age (years), median 73 (59–80) 72 (25–75th percentiles) Age > 65 years, n (%) 511 (65) 872 Male gender, n (%) 382 (49) 642 Risk factors for VTE, n (%) Cancer* 136 (17) 222 Recent surgery† 79 (10) 155 Immobilization for 151 (19) 237 ≥ 4 days‡ Comorbid diseases, n (%) COPD 101 (13) 178 Congestive heart failure 44 (5.6) 116 Clinical symptoms and signs at presentation, n (%) Syncope 123 (16) 216 Chest pain 378 (48) 680 Dyspnea 623 (80) 1068 Heart rate > 100 min 1 230 (29) 376 Arterial oxyhemoglobin 170 (22) 264 saturation (SAO2) < 90% SBP < 120 mmHg 201 (26) 379 Echocardiography and cardiac biomarkers, n (%) RVD (echocardiogram) 305 (39) 511 RV free wall hypokinesis 166 (21) 321 RVEDD > 30 mmHg 359 (46) 597 RVEDD/LVEDD > 1 128 (16) 252 Systolic pulmonary artery 403 (52) 764 pressure > 30 mmHg Treatment, n (%) Insertion of an IVC filter 13 (2) 19
P-value
(58–80)
0.19
(67) (48)
0.88 0.88
(17) (12) (18)
0.75 0.29 0.44
(13) (8.7)
0.79 0.01
(16) (51) (81) (28) (20)
0.78 0.30 0.67 0.64 0.34
(29)
0.17
(38) (24) (45) (19) (58)
0.87 0.13 0.73 0.14 0.01
(1.4)
0.82
COPD, chronic obstructive pulmonary disease; IVC, inferior vena cava; LVEDD, left ventricle end-diastolic diameter; RV, right ventricle; RVD, right ventricular dysfunction; RVEDD, right ventricle end-diastolic diameter; SBP, systolic blood pressure; VTE, venous thromboembolism. *Active or under treatment in the last year. †In the previous month. ‡Immobilized patients are defined in this analysis as non-surgical patients who had been immobilized (i.e. total bed rest with bathroom privileges) for ≥ 4 days in the month prior to pulmonary embolism diagnosis.
TAPSE remained a significant predictor of clinical outcomes. Moreover, the similar results from the external validation cohort analysis provided evidence for the robustness of the findings, and further strengthened the soundness of the conclusions. The prevalence of adverse events, and of PE-related mortality in particular, was low. The positive and negative predictive values might be higher and lower, respectively, in a population with a higher prevalence of adverse clinical outcomes. Finally, TAPSE might be easier to measure than traditional RV measures on TTE. However, in this study, the echocardiograms were performed and interpreted by certified cardiologists, and the results may not be generalizable to the measurement of TAPSE by less experienced operators. In conclusion, TAPSE might provide an objective value, and does not require visualization of the RV free
wall for interpretation. We have shown that it is correlated with traditional RV measures on TTE, and that it might predict clinical outcomes. We have defined a cutpoint value for TAPSE and the optimal combination of echocardiographic measures to be used for patients with acute PE. Future studies should clarify the role of TAPSE in a management algorithm to test whether it can improve outcomes in normotensive patients with acute PE. Addendum J. L. Lobo, A. Holley, V. Tapson, L. Moores, R. Yusen, and D. Jimenez: study concept and design. J. L. Lobo, A. Holley, V. Tapson, L. Moores, M. Oribe, M. Barr on, R. Otero, D. Nauffal, R. Valle, M. Monreal, R. Yusen, and D. Jimenez: acquisition of data, analysis and interpretation of data, and statistical analysis. J. L. Lobo, A. Holley, V. Tapson, L. Moores, R. Yusen, and D. Jimenez: drafting of the manuscript. J. L. Lobo, A. Holley, V. Tapson, L. Moores, M. Oribe, M. Barr on, R. Otero, D. Nauffal, R. Valle, M. Monreal, R. Yusen, and D. Jimenez: critical revision of the manuscript for important intellectual content. R. Yusen and D. Jimenez: study supervision. The corresponding author, D. Jimenez, had full access to all of the data in the study, and had final responsibility for the decision to submit for publication. Acknowledgement This work was supported by FIS 2008 (PI 08200), FIS 2011 (PI 110246), and SEPAR 2008. Disclosure of Conflict of Interests The authors state that they have no conflict of interest. References 1 Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386–9. 2 Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecularweight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med 2004; 140: 175–83. 3 Douketis JD, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: 458–62. 4 Jimenez D, Yusen RD, Otero R, Uresandi F, Nauffal D, Laserna E, Conget F, Oribe M, Cabezudo MA, Dıaz G. Prognostic models for selecting patients with acute pulmonary embolism for initial outpatient therapy. Chest 2007; 132: 24–30. 5 Aujesky D, Roy PM, Verschuren F, Righini M, Osterwalder J, Egloff M, Renaud B, Verhamme P, Stone RA, Legall C, Sanchez O, Pugh NA, N’gako A, Cornuz J, Hugli O, Beer HJ, Perrier A, Fine MJ, Yealy DM. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011; 378: 41–8. © 2014 International Society on Thrombosis and Haemostasis
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© 2014 International Society on Thrombosis and Haemostasis
15 Ghio S, Recusani F, Klersy C, Sebastiani R, Laudisa ML, Campana C, Gavazzi A, Tavazzi L. Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000; 85: 837–42. 16 Park JH, Park YS, Park SJ, Lee JH, Choi SW, Jeong JO, Seong IW. Midventricular peak systolic strain and Tei index of the right ventricle correlated with decreased right ventricular systolic function in patients with acute pulmonary thromboembolism. Int J Cardiol 2008; 125: 319–24. 17 Jimenez D, Lobo JL, Monreal M, Otero R, Yusen RD. Prognostic significance of multidetector computed tomography in normotensive patients with pulmonary embolism: rationale, methodology and reproducibility for the PROTECT study. J Thromb Thrombolysis 2012; 34: 187–92. 18 Remy-Jardin M, Remy J, Wattinne L, Giraud F. Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the single-breath-hold-technique – comparison with pulmonary angiography. Radiology 1992; 185: 381–7. 19 Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camaiti A, Santoro G, Conti A, Agnelli G, Berni G. Short term clinical outcome of patients with pulmonary embolism, normal blood pressure and echocardiographic right ventricular dysfunction. Circulation 2000; 101: 2817–22. 20 Samad BA, Alam M, Jensen-Urstad K. Prognostic impact of right ventricular involvement as assessed by tricuspid annular motion in patients with acute myocardial infarction. Am J Cardiol 2002; 90: 778–81. 21 Laporte S, Mismetti P, Decousus H, Uresandi F, Otero R, Lobo JL, Monreal M; RIETE Investigators. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the RIETE registry. Circulation 2008; 117: 1711–16. 22 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81. 23 Harrel FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996; 15: 361–87. 24 Pencina MJ, D’Agostino RB. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Stat Med 2004; 23: 2109–23. 25 Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002; 121: 877–905. 26 Diacon AH, Theron J, Bolliger CT. Transthoracic ultrasound for the pulmonologist. Curr Opin Pulm Med 2005; 11: 307–12. 27 Lichtenstein DA. Ultrasound in the management of thoracic disease. Crit Care Med 2007; 35: S250–61. 28 Lopez-Candales A, Rajagopalan N, Saxena N, Gulyasy B, Edelman K, Bazaz R. Right ventricular systolic function is not the sole determinant of tricuspid annular motion. Am J Cardiol 2006; 98: 973–7.
DOI: 10.1111/jth.12589
ORIGINAL ARTICLE
Prognostic significance of tricuspid annular displacement in normotensive patients with acute symptomatic pulmonary embolism ,** R. OTERO,†† J . L . L O B O , * A . H O L L E Y , † V . T A P S O N , ‡ L . M O O R E S , § M . O R I B E , ¶ M . B A R R ON D . N A U F F A L , ‡ ‡ R . V A L L E , § § M . M O N R E A L , ¶ ¶ R . D . Y U S E N * * * a n d D . J I M EN E Z , † † † F O R T H E PROTECT AND THE RIETE INVESTIGATORS *Respiratory Department, Txagorritxu Hospital, Vitoria, Spain; †Department of Pulmonary, Critical Care, and Sleep Medicine, Walter Reed National Military Medical Center, Bethesda, MD; ‡Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC; §F. Edward Hebert School of Medicine, Uniformed Services University, Bethesda, MD, USA; ¶Respiratory Department, Galdakao ~o; ††Respiratory Department, Virgen del Rocıo Hospital, Sevilla; Hospital, Galdakao; **Respiratory Department, San Pedro Hospital, Logron ‡‡Respiratory Department, La Fe Hospital, Valencia; §§Medicine Department, Hospital Sierrallana, Cantabria; ¶¶Medicine Department, Germans Trias I Pujol Hospital, Badalona, Spain; ***Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, n y Cajal Hospital, IRYCIS, Madrid, Washington University School of Medicine, St Louis, MO, USA; and †††Respiratory Department, Ramo Spain
n M, Otero R, Nauffal D, Valle R, Monreal M, Yusen RD, Jimenez D, To cite this article: Lobo JL, Holley A, Tapson V, Moores L, Oribe M, Barro for the PROTECT and the RIETE investigators. Prognostic significance of tricuspid annular displacement in normotensive patients with acute symptomatic pulmonary embolism. J Thromb Haemost 2014; 12: 1020–7.
Summary. Background: Tricuspid annular plane systolic excursion (TAPSE) is an emerging prognostic indicator in patients with acute symptomatic pulmonary embolism (PE). Methods and Results: We prospectively examined 782 normotensive patients with PE who underwent echocardiography in a multicenter study. As compared with patients with a TAPSE of > 1.6 cm, those with a TAPSE of ≤ 1.6 cm had increased systolic pulmonary artery pressure (53.7 16.7 mmHg vs. 40.0 15.5 mmHg, P < 0.001), right ventricle (RV) end-diastolic diameter (3.5 0.8 cm vs. 3.0 0.6 cm, P < 0.001), and RV to left ventricle end-diastolic diameter ratio (1.0 0.3 vs. 0.8 0.2, P < 0.001), and a higher prevalence of RV free wall hypokinesis (68% vs. 11%, P < 0.001). Patients with a TAPSE of ≤ 1.6 cm at the time of PE diagnosis were significantly more likely to die from any cause (hazard ratio [HR] 2.3; 95% confidence interval [CI] 1.2–4.7; P = 0.02) and from PE (HR 4.4; 95% CI 1.3–15.3; P = 0.02) during follow-up. In an external validation cohort of 1326 patients with acute PE enrolled in the international multicenter Registro Informatizado de la Correspondence: David Jimenez, Respiratory Department, Ram on y Cajal Hospital, IRYCIS, 28034 Madrid, Spain. Tel.: +34 913368314; fax: +34 913369016. E-mail: [email protected] Received 4 February 2014 Manuscript handled by: P. de Moerloose Final decision: F. R. Rosendaal, 21 April 2014
Enfermedad TromboEmb olica, a TAPSE of ≤ 1.6 cm remained a significant predictor of all-cause mortality (HR 2.1; 95% CI 1.3–3.2; P = 0.001) and PE-specific mortality (HR 2.5; 95% CI 1.2–5.2; P = 0.01). Conclusions: In normotensive patients with PE, TAPSE reflects right ventricular function. For these patients, TAPSE is independently predictive of survival. Keywords: echocardiography; prognosis; pulmonary embolism; right ventricular dysfunction; survival.
Introduction Early mortality rates for pulmonary embolism (PE) range from 5% in patients who are clinically stable to 58% in patients with cardiogenic shock [1–3]. Some patients with PE may safely undergo treatment at home and avoid admission to a hospital [4,5], whereas others require hospital admission and even immediate recanalization of the occluded pulmonary arteries. Risk stratification tools may help to distinguish between these different categories of patient [6,7]. In the setting of acute PE, complex hemodynamic changes affect right ventricular function [8]. Mechanical obstruction of the pulmonary arteries and the release of vasoconstrictive mediators may cause abrupt increases in pulmonary vascular resistance and right ventricle (RV) afterload. Increased RV afterload may cause RV dilatation and a subsequent increase in RV regional wall stress. © 2014 International Society on Thrombosis and Haemostasis
Prognostic significance of TAPSE 1021
Localized ischemic effects may also affect the RV free wall. Interventricular septal shifting towards the left ventricle (LV) may affect LV preload and cardiac output. Arrhythmias may also affect cardiac function. Subsequent systemic hypotension may compromise coronary perfusion and cause ischemia. The severity and combination of these events may lead to varying degrees of cardiovascular compromise. Several risk stratification algorithms using different combinations of clinical and laboratory variables have been developed for use in the work-up of PE. Evaluation of right heart function has also proven to be an integral part of the initial evaluation, with transthoracic echocardiography (TTE) being particularly valuable for predicting morbidity and mortality [9]. Despite the documented value of right heart assessment via TTE, the complex geometry of the RV and the subjective nature of the standard measurements routinely obtained often limit its utility [10,11]. Tricuspid annular plane systolic excursion (TAPSE) is a quantitative echocardiographic parameter obtained in M-mode that has been correlated with standard TTE measures and laboratory values in PE [12,13], and with clinical outcomes in pulmonary arterial hypertension [14] and congestive heart failure [15]. Because visualization of the RV free wall is not required and a numerical value is obtained, TAPSE has the potential to provide objective and valuable information that does not require specialized training for measurement and interpretation. Existing data obtained with TAPSE for prognostic purposes in PE are limited by small sample sizes and the absence of correlation with morbidity and mortality [12,13,16]. The purpose of this study was to establish the relationship between TAPSE and clinical outcomes in normotensive patients with acute symptomatic PE. Furthermore, we aimed to determine the optimal combination of echocardiographic findings for risk stratification of acute PE. To achieve these aims, we conducted a prospective cohort study, and we externally and retrospectively validated our findings in a large, independent cohort of patients. Methods PROTECT is a prospective, multicenter observational cohort study designed by the authors and sponsored by the Institute of Health Carlos III, Spain (NCT00880737) [17]. This PROTECT substudy was a priori designed to test the predictive characteristics of TAPSE in normotensive patients (i.e. without hemodynamic instability) with acute symptomatic PE. Local ethics committees approved the study. All patients provided written informed consent. Patients
Only patients diagnosed with acute PE (first symptoms occurring within 14 days) by multidetector computed © 2014 International Society on Thrombosis and Haemostasis
tomography (CT) were eligible [18]. Exclusion criteria consisted of treatment with thrombolytics at the time of PE diagnosis, life-expectancy of < 3 months, pregnancy, geographic inaccessibility precluding follow-up, age of < 18 years, renal insufficiency (creatinine clearance of < 30 mL min 1), inability to complete CT testing (e.g. allergy to intravenous contrast agents, unavailability of CT, or patient too ill), or hemodynamic instability at presentation (defined as cardiogenic shock, systolic blood pressure of < 90 mmHg, or the use of inotropic support). We also excluded patients who did not successfully complete the protocol-required TTE. Baseline examinations
The study protocol required that patients undergo echocardiography (i.e. TTE) within 24 h after diagnosis of PE. Patients underwent testing in the left lateral position. Trained and certified local cardiologists, blinded to the patient’s clinical data and laboratory test results, interpreted each echocardiogram. Echocardiographic right ventricular dysfunction (RVD) was defined as the presence of at least two of the following: dilatation of the RV (end-diastolic diameter of > 30 mm from the parasternal view or the RV appearing larger than the LV from the subcostal or apical view), hypokinesis of the RV free wall (any view), or tricuspid regurgitant jet velocity of > 2.6 m s 1 [19]. To obtain TAPSE, the apical fourchamber view was used, and an M-mode cursor was placed through the lateral tricuspid annulus in real time. TAPSE was measured as the total displacement of the tricuspid annulus (centimeters) from end-diastole to endsystole, with values representing the average TAPSE of three to five beats [20]. Study outcome measures
The study used all-cause mortality 30 days after the diagnosis of PE as the primary outcome. For this substudy, PE-specific mortality was the secondary outcome [17]. An independent Adjudication Committee, whose members were blinded to initial prognostic test results, adjudicated all serious adverse events. Validation cohort
To externally validate the prognostic significance of TAPSE, patient data from the Registro Informatizado de la Enfermedad TromboEmb olica (RIETE) were used. The RIETE is an ongoing, international multicenter, observational registry of consecutively enrolled patients, designed to collect and analyze data on treatment patterns and clinical outcomes in patients with acute symptomatic venous thromboembolism. Study design and patient eligibility criteria of the RIETE have been described elsewhere [21]. The validation cohort for this
1022 J. L. Lobo et al
study consisted of the subgroup of 1326 patients enrolled in the RIETE who had acute symptomatic PE, had undergone TTE, had TAPSE measurement and follow-up data, and had not been included in this study. Statistical analyses
Descriptive statistics were used for baseline data, chi-square or Fisher’s exact tests were used to compare categorical data between groups, and unpaired two-tailed t-tests or the Mann–Whitney U-test were used to compare continuous data between groups. A receiver operating characteristic (ROC) curve was used to assess the accuracy of TAPSE for detecting the primary outcome of all-cause mortality. The optimum cut-off point was established by selecting the point of test values that provided the greatest sum of sensitivity and specificity – i.e. the point closest to the top left-hand corner on the ROC curve. To estimate mortality over time, we used Kaplan– Meier curves [22], with differences between groups being assessed with the log-rank test. Cox proportional hazards regression models were used to test for an independent association between TAPSE at presentation and outcome measures [23]. A manual backward stepwise approach was used to develop the multivariate model. In the full model, variables with an imbalance between groups at baseline were considered for inclusion. When two or more variables were closely related, only one was included in a given multivariate model. Variables that showed evidence of confounding (that is, the coefficient of the variable group changed by > 10% when that variable was removed from the full model) for the effect of TAPSE on the outcome undergoing analysis were not removed from the model. In addition, we performed multivariate analysis, with 30-day PE-related mortality as the outcome, to determine the optimal combination of echocardiographic findings for risk stratification of PE. No adjustments for other baseline parameters were made in this latter model. We assessed the performance of TAPSE and the new combination of echocardiographic criteria with traditional echocardiographic measures for RVD (see Baseline examinations) by evaluating discrimination with the overall c-statistic [24]. Statistical significance was defined as a two-tailed Pvalue of < 0.05 for all analyses. Analyses were performed with SPSS version 14.0 for the PC (SPSS, Chicago, IL, USA).
normotensive patients diagnosed with acute PE for eligibility. The study excluded 66 patients because they did not have the complete baseline echocardiographic data required for analyses (7.8%; 95% confidence interval [CI] 6.0–9.6%). No statistically significant difference was observed between included and excluded patients regarding demographics, medical history, and clinical presentation. A total of 782 patients (382 men and 400 women; 92% of the screened population) were included in the present study. Table 1 shows the patients’ clinical symptoms, predisposing conditions, and relevant findings at presentation. At enrollment, all patients (100%) were receiving anticoagulant treatment. The overall number of patients treated with inferior vena cava filters was small (0.9%; 7/782). TAPSE and right ventricular function
On admission, TAPSE measurements ranged from 0.9 to 4.0 cm, with a median value of 2.0 cm (25–75th percentile, 1.8–2.3 cm). ROC curve analysis revealed that TAPSE was a sensitive and specific indicator of overall mortality (area under the ROC curve [AUC] 0.64, P = 0.005). To identify low-risk patients with PE, ROC curve analysis for TAPSE determined that 1.6 cm was the optimal cut-off. When only PE-related mortality was considered, the AUC was 0.79 (P = 0.002). Overall, 146 patients (18.7%; 95% CI 15.9–21.4%) had TAPSE measurements below the cut-off value of 1.6 cm. As shown in Table 1, patients with a TAPSE of ≤ 1.6 cm were older, were less likely to be male, had a higher prevalence of chronic heart disease or atrial fibrillation and had more signs of clinical severity (syncope, tachycardia, hypoxemia, and hypotension) than those with a TAPSE of > 1.6 cm. Figure 1 summarizes the differences in RV free wall hypokinesis (A), RV end-diastolic diameter (B) and RV/ LV end-diastolic diameter ratio (C) observed between patients with a TAPSE of > 1.6 cm and those with a TAPSE of ≤ 1.6 cm. Patients with a TAPSE of ≤ 1.6 cm also had significantly higher systolic pulmonary artery pressure (53.7 16.7 mmHg) than those with a TAPSE of > 1.6 cm (40.0 15.5 mmHg) (P < 0.001). Brain natriuretic peptide (519 790 pg mL 1 vs. 168 292 pg mL 1, P < 0.001) and cardiac troponin I (cTnI) (0.17 0.57 ng mL 1 vs. 0.06 0.32 ng mL 1, P = 0.001) levels were also significantly higher among patients with a TAPSE of ≤ 1.6 cm. Outcome
Results Patients
We used multidetector contrast-enhanced helical chest CT in the emergency department to screen 848 consecutive
Outcome data were available for all patients throughout the 30-day study follow-up. Overall, 35 of 782 patients died (4.5%; 95% CI 3.0–5.9%). Ten patients (10/782; 1.3%; 95% CI 0.5–2.1%) died from definite (n = 4) or possible (n = 6) PE, and 25 (25/782; 3.2%; 95% CI © 2014 International Society on Thrombosis and Haemostasis
Prognostic significance of TAPSE 1023 Table 1 Baseline characteristics and treatment information for normotensive patients with acute symptomatic pulmonary embolism (PE) All patients, N = 782 Clinical characteristics Age (years), median (25–75th percentiles) 73 Age > 65 years, n (%) 511 Male gender, n (%) 382 Risk factors for VTE, n (%) Cancer* 136 Recent surgery† 79 Immobilization‡ 151 Comorbid diseases, n (%) COPD 101 Congestive heart failure 44 Clinical symptoms and signs at presentation, n (%) Syncope 123 Chest pain 378 Dyspnea 623 Heart rate > 100 min 1 230 170 Arterial oxyhemoglobin saturation (SAO2) < 90% SBP < 120 mmHg 201 Concomitant DVT 351 CT, echocardiography, and cardiac biomarkers, n (%) RVD (CT) 501 RVD (echocardiogram) 305 RV free wall hypokinesis 166 RVEDD > 30 mm 359 RVEDD/LVEDD > 1 128 Systolic pulmonary artery pressure > 30 mmHg 403 BNP > 100 pg mL 1 345 cTnI > 0.05 ng mL 1 129 Treatment, n (%) Insertion of an IVC filter 7
(59–80) (65) (49)
TAPSE ≤ 1.6 cm, N = 146
TAPSE > 1.6 cm, N = 636
77 (64–82) 105 (72) 58 (40)
71 (58–79) 406 (64) 324 (51)
0.001 0.06 0.014
P-value
(17) (10) (19)
21 (14) 7 (4.8) 32 (22)
115 (18) 72 (11) 119 (19)
0.29 0.02 0.38
(13) (5.6)
22 (16) 14 (10)
79 (14) 30 (5.2)
0.51 0.03
(16) (48) (80) (29) (22) (26) (45) (64) (39) (21) (46) (16) (52) (44) (16) (0.9)
38 70 125 69 58
(26) (48) (86) (47) (45)
52 (36) 67 (46) 121 113 98 103 57 110 105 48
(83) (77) (68) (72) (41) (93) (72) (33)
1 (0.7)
(13) (48) (78) (25) (20)
< 0.001 0.96 0.03 < 0.001 < 0.001
149 (23) 284 (46)
0.002 0.98
85 308 498 161 112
380 192 68 256 71 293 240 81
(60) (30) (11) (42) (12) (70) (38) (13)
6 (1.0)
< < < < < < <
1.6 cm (absolute difference of 4.6%; 95% CI of the absolute difference, 0.1% to 9.3%; P = 0.03); five deaths in each group resulted from definite or possible PE. Patients with acute PE and a TAPSE of ≤ 1.6 cm had significantly higher cumulative mortality than patients with acute PE and a TAPSE of > 1.6 cm (P = 0.013, log-rank test; Fig. 2). Table 2 shows 30-day mortality rates by quartiles of TAPSE in the PROTECT and the RIETE cohorts. In univariate analyses, patients with cancer (hazard ratio [HR] 2.8; 95% CI 1.4–5.6; P = 0.003), systolic blood pressure of < 120 mmHg (HR 2.5; 95% CI 1.3– © 2014 International Society on Thrombosis and Haemostasis
4.8; P = 0.007), elevated cTnI levels (HR 2.1; 95% CI 1.0–4.5; P = 0.04) and a TAPSE of ≤ 1.6 cm (HR 2.3; 95% CI 1.2–4.7; P = 0.02) at the time of acute PE diagnosis were significantly more likely to die from any cause during follow-up (Table 3). In the multivariate analysis, no variable showed evidence of confounding for the association between TAPSE and all-cause mortality during follow-up (Table 3). Decreasing values of TAPSE were associated with an increase in the risk of all-cause mortality (HR 1.11; 95% CI 1.03–1.21; P < 0.01). When we forced into the full model those variables (i.e. congestive heart failure, heart rate, syncope, and dyspnea) with an imbalance between TAPSE groups at baseline, none of them showed evidence of confounding for the effect of TAPSE on the outcome being analyzed. TAPSE measurement remained an independent predictor of all-cause mortality when patients with prior cardiopulmonary disease (n = 136) were excluded from the analysis (HR 2.2; 95% CI 1.0–5.2; P = 0.05). A TAPSE of ≤ 1.6 cm at the time of presentation was also independently and signifi-
1024 J. L. Lobo et al A
100
70 60
Probability of suruvival (%)
RV free wall hypokinesis (%)
80
50 40 30 20 10 0 TAPSE > 1.6 cm
95
TAPSE > 1.6 cm
90
TAPSE ≤ 1.6 cm
85
TAPSE ≤ 1.6 cm
B
80 5
0
RVEDD (mm)
60.00
10
15
20
25
30
Time (days) No. at risk TAPSE > 1.6 cm TAPSE ≤ 1.6 cm
40.00
636 146
628 136
626 130
624 123
Log rank P = 0.013
Fig. 2. Kaplan–Meier estimates of survival (primary endpoint: allcause mortality) in patients stratified by tricuspid annular plane systolic excursion (TAPSE) values.
20.00
0.00 TAPSE > 1.6 cm
TAPSE ≤ 1.6 cm
C 2.50
Quartile of TAPSE
2.00 RVEDDLVEDD
Table 2 Thirty-day mortality by quartile of tricuspid annular plane systolic excursion (TAPSE) in the PROTECT and RIETE cohorts
PROTECT cohort < 18 mm 18–20 mm 20–23 mm > 23 mm RIETE cohort < 17 mm 17–20 mm 20–23 mm > 23 mm
1.50
1.00
0.50
Number at risk
Thirty-day all-cause mortality (%)
Thirty-day PE-related mortality (%)
188 160 269 165
7.4 4.4 4.1 1.8
3.2 1.9 0.4 0
306 301 424 295
12.1 7.3 6.4 5.4
4.2 2.3 1.6 1.3
PE, pulmonary embolism.
0.00 TAPSE > 1.6 cm
TAPSE ≤ 1.6 cm
Fig. 1. Bar graphs comparing echocardiographic indices of right ventricular dysfunction in patients with tricuspid annular plane systolic excursion (TAPSE) of > 1.6 cm and ≤ 1.6 cm. (A) Right ventricle (RV) free wall hypokinesis. (B) RV end-diastolic diameter (RVEDD). (C) RVEDD left ventricle end-diastolic diameter (LVEDD).
cantly associated with PE-related death (HR 4.4; 95% CI 1.3–15.3; P = 0.02). We also investigated the optimal combination of echocardiographic findings with regard to risk stratification of acute PE. On multivariate analysis, only TAPSE (HR 1.2; 95% CI 1.0–1.4; P = 0.03) and RV/LV end-diastolic
diameter ratio (HR 8.9; 95% CI 1.1–74.7; P = 0.04) were significantly associated with PE-related mortality during follow-up. The ROC analysis AUC for PE-related mortality of the combination of TAPSE and RV/LV end-diastolic diameter ratio was significantly increased as compared with that for the traditional echocardiographic measures for RVD (0.86 vs. 0.70; P < 0.001). External validation in the RIETE registry
The 1326 eligible patients from the RIETE validation cohort had similar proportions of male gender, chronic pulmonary disease, cancer, previous surgery and immobi© 2014 International Society on Thrombosis and Haemostasis
Prognostic significance of TAPSE 1025 Table 3 Unadjusted and adjusted hazard ratios (HRs) for overall mortality in normotensive patients with acute symptomatic pulmonary embolism Risk factor
Unadjusted HR (95% CI)
P-value
Adjusted HR (95% CI)
P-value
Cancer* SBP < 120 mmHg TAPSE ≤ 1.6 cm cTnI > 0.05 ng mL
2.84 2.50 2.35 2.14
0.003 0.007 0.02 0.04
– – 2.35 (1.17–4.73)† –
– – 0.02 –
1
(1.43–5.64) (1.28–4.85) (1.17–4.73) (1.02–4.47)
CI, confidence interval; cTnI, cardiac troponin I; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion. Only variables found to significantly predict 30-day all-cause mortality by univariable analysis are shown. N = 782 evaluated, with 35 deaths. Final model: chi square = 6.14, P = 0.01. *Active or under treatment in the last year. †No variables showed evidence of confounding.
lization for ≥ 4 days as the 782 patients in the original study cohort (Table 4). Congestive heart failure was significantly more prevalent in the RIETE cohort than in the study cohort. The prevalence of signs of clinical severity (syncope, dyspnea, tachycardia, and hypoxemia) was similar in both cohorts. Systolic pulmonary artery pressure of > 30 mmHg was detected in 58% of patients in the RIETE cohort (764/1326) and in 52% of patients in the study cohort (403/782). Of the 1326 patients included in the RIETE validation cohort, 102 (102/1326; 7.7%; 95% CI 6.3–9.1%) died during follow-up, as compared with 4.5% (35/782; 95% CI 3.0–5.9%) in the original study cohort (absolute risk difference of 3.2%; 95% CI 1.1–5.2%). Thirty-one patients (31/1326; 2.3%; 95% CI 1.5–3.1%) died from PE, and 71 (71/1326; 5.3%; 95% CI 4.1–6.6%) died from other causes. As shown in Table 2, mortality also differed among TAPSE quartiles in the RIETE validation cohort, with the largest differences in outcome being observed between patients with a TAPSE of < 1.7 cm and those with a TAPSE of > 2.3 cm. In the RIETE cohort, decreasing values of TAPSE were associated with an increase in the risk of all-cause mortality (HR 1.06; 95% CI 1.02–1.10; P < 0.01). Patients with a TAPSE of ≤ 1.6 cm at the time of diagnosis of PE had significantly higher all-cause mortality than those with a TAPSE of > 1.6 cm (HR 2.1; 95% CI 1.3–3.2; P = 0.001). A TAPSE of ≤ 1.6 cm at the time of presentation had an independently significant association with PE-specific mortality (HR 2.5; 95% CI 1.2–5.2; P = 0.01). Discussion In the present study, a TAPSE of ≤ 1.6 cm identified normotensive patients with acute PE who had advanced RVD. Patients with a TAPSE of ≤ 1.6 cm had increased all-cause and PE-specific mortality at 30-day follow-up, findings that persisted after adjustment for several previously recognized predictors of outcome. Thus, our results suggest that TAPSE is a robust measure of right ventricular function and a significant predictor of survival in patients with PE. The patient presenting with acute PE with normal blood pressure represents a challenge to the clinician. © 2014 International Society on Thrombosis and Haemostasis
Outcomes for this population are determined by the interaction between the significance of the embolus and specific patient characteristics [25]. This has led to the intense pursuit of a simple but accurate measure of this interaction. RVD, which is most commonly detected with echocardiography, has consistently been associated with adverse clinical outcomes, including mortality [1,9]. Despite the excellent data supporting the use of TTE for risk stratification for the normotensive patient with acute PE, its practical application can be challenging. The RV has a complex contraction mechanism, and the chamber is difficult to visualize in its entirety on any single two-dimensional echocardiographic view [10]. Many of the measurements used to assess its function are subjective in nature. As a result, accurate interpretation has traditionally required an experienced cardiologist. Recent advances in diagnostic technologies and portability have made bedside ultrasound increasingly available to the physician performing the initial assessment of the patient with acute PE [26,27]. As a result, finding a measure of right ventricular function that is valid, reproducible and easy to obtain is more important than ever. TAPSE requires visualization of the tricuspid annulus only, and provides an objective value that is easy to measure and should be comparable across patients. In the largest group of patients studied to date, we have once again confirmed that TAPSE is an excellent surrogate for traditional TTE measures of right ventricular function. Furthermore, we have shown an association with clinical outcomes, and defined an optimal value for performance. The potential prognostic implications of cardiac ultrasound findings for non-high-risk PE remain a subject of debate. One of the main reasons is that echocardiographic criteria for defining RVD are poorly standardized, and may vary widely between hospitals, ultrasound laboratories, and examiners. Therefore, we have provided a uniform set of criteria (i.e. TAPSE and RV/LV end-diastolic diameter ratio) whose accuracy was significantly higher than that of the traditional echocardiographic measures of RVD. Our study has several limitations. We did not adjust for left ventricular function, which is known to have an effect on TAPSE values [28]. Nevertheless, when we excluded patients with prior cardiopulmonary disease,
1026 J. L. Lobo et al Table 4 Comparison of baseline patient characteristics in the study cohort and the RIETE registry validation cohort Original cohort, N = 782
RIETE registry, N = 1326
Clinical characteristics Age (years), median 73 (59–80) 72 (25–75th percentiles) Age > 65 years, n (%) 511 (65) 872 Male gender, n (%) 382 (49) 642 Risk factors for VTE, n (%) Cancer* 136 (17) 222 Recent surgery† 79 (10) 155 Immobilization for 151 (19) 237 ≥ 4 days‡ Comorbid diseases, n (%) COPD 101 (13) 178 Congestive heart failure 44 (5.6) 116 Clinical symptoms and signs at presentation, n (%) Syncope 123 (16) 216 Chest pain 378 (48) 680 Dyspnea 623 (80) 1068 Heart rate > 100 min 1 230 (29) 376 Arterial oxyhemoglobin 170 (22) 264 saturation (SAO2) < 90% SBP < 120 mmHg 201 (26) 379 Echocardiography and cardiac biomarkers, n (%) RVD (echocardiogram) 305 (39) 511 RV free wall hypokinesis 166 (21) 321 RVEDD > 30 mmHg 359 (46) 597 RVEDD/LVEDD > 1 128 (16) 252 Systolic pulmonary artery 403 (52) 764 pressure > 30 mmHg Treatment, n (%) Insertion of an IVC filter 13 (2) 19
P-value
(58–80)
0.19
(67) (48)
0.88 0.88
(17) (12) (18)
0.75 0.29 0.44
(13) (8.7)
0.79 0.01
(16) (51) (81) (28) (20)
0.78 0.30 0.67 0.64 0.34
(29)
0.17
(38) (24) (45) (19) (58)
0.87 0.13 0.73 0.14 0.01
(1.4)
0.82
COPD, chronic obstructive pulmonary disease; IVC, inferior vena cava; LVEDD, left ventricle end-diastolic diameter; RV, right ventricle; RVD, right ventricular dysfunction; RVEDD, right ventricle end-diastolic diameter; SBP, systolic blood pressure; VTE, venous thromboembolism. *Active or under treatment in the last year. †In the previous month. ‡Immobilized patients are defined in this analysis as non-surgical patients who had been immobilized (i.e. total bed rest with bathroom privileges) for ≥ 4 days in the month prior to pulmonary embolism diagnosis.
TAPSE remained a significant predictor of clinical outcomes. Moreover, the similar results from the external validation cohort analysis provided evidence for the robustness of the findings, and further strengthened the soundness of the conclusions. The prevalence of adverse events, and of PE-related mortality in particular, was low. The positive and negative predictive values might be higher and lower, respectively, in a population with a higher prevalence of adverse clinical outcomes. Finally, TAPSE might be easier to measure than traditional RV measures on TTE. However, in this study, the echocardiograms were performed and interpreted by certified cardiologists, and the results may not be generalizable to the measurement of TAPSE by less experienced operators. In conclusion, TAPSE might provide an objective value, and does not require visualization of the RV free
wall for interpretation. We have shown that it is correlated with traditional RV measures on TTE, and that it might predict clinical outcomes. We have defined a cutpoint value for TAPSE and the optimal combination of echocardiographic measures to be used for patients with acute PE. Future studies should clarify the role of TAPSE in a management algorithm to test whether it can improve outcomes in normotensive patients with acute PE. Addendum J. L. Lobo, A. Holley, V. Tapson, L. Moores, R. Yusen, and D. Jimenez: study concept and design. J. L. Lobo, A. Holley, V. Tapson, L. Moores, M. Oribe, M. Barr on, R. Otero, D. Nauffal, R. Valle, M. Monreal, R. Yusen, and D. Jimenez: acquisition of data, analysis and interpretation of data, and statistical analysis. J. L. Lobo, A. Holley, V. Tapson, L. Moores, R. Yusen, and D. Jimenez: drafting of the manuscript. J. L. Lobo, A. Holley, V. Tapson, L. Moores, M. Oribe, M. Barr on, R. Otero, D. Nauffal, R. Valle, M. Monreal, R. Yusen, and D. Jimenez: critical revision of the manuscript for important intellectual content. R. Yusen and D. Jimenez: study supervision. The corresponding author, D. Jimenez, had full access to all of the data in the study, and had final responsibility for the decision to submit for publication. Acknowledgement This work was supported by FIS 2008 (PI 08200), FIS 2011 (PI 110246), and SEPAR 2008. Disclosure of Conflict of Interests The authors state that they have no conflict of interest. References 1 Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386–9. 2 Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecularweight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med 2004; 140: 175–83. 3 Douketis JD, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: 458–62. 4 Jimenez D, Yusen RD, Otero R, Uresandi F, Nauffal D, Laserna E, Conget F, Oribe M, Cabezudo MA, Dıaz G. Prognostic models for selecting patients with acute pulmonary embolism for initial outpatient therapy. Chest 2007; 132: 24–30. 5 Aujesky D, Roy PM, Verschuren F, Righini M, Osterwalder J, Egloff M, Renaud B, Verhamme P, Stone RA, Legall C, Sanchez O, Pugh NA, N’gako A, Cornuz J, Hugli O, Beer HJ, Perrier A, Fine MJ, Yealy DM. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011; 378: 41–8. © 2014 International Society on Thrombosis and Haemostasis
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