Measurement of High-Sensitivity Cardiac Troponin in Pulmonary Embolism: Useful Test or a Clinical Distraction

2019 ◽  
Vol 45 (08) ◽  
pp. 784-792
Author(s):  
Giuseppe Lippi ◽  
Emmanuel J. Favaloro ◽  
Peter Kavsak
Keyword(s):  
Pulmonary Embolism ◽  
Risk Stratification ◽  
Cardiac Troponin ◽  
Laboratory Tests ◽  
High Sensitivity ◽  
Severity Index ◽  
Adverse Outcomes ◽  
Incremental Value ◽  
Risk Patients ◽  
Acute Pe

AbstractThe ability to predict death or other unfavorable outcomes after an acute pulmonary embolism (PE) is challenging, with current available risk score models having relatively unsatisfactory prognostic performance in this area. For example, the simplified pulmonary embolism severity index (sPESI), the most frequently used stratification tool, misclassifies a significant percentage of low- and high-risk patients. This gap in care, along with the increasing clinical availability of high-sensitivity cardiac troponin (hs-cTn) laboratory tests and the recent emphasis on detecting myocardial injury, may foster further evaluation of hs-cTn testing in patients with acute PE. Our analysis of the current scientific literature on hs-cTn in patients with acute PE identified that hs-cTn testing may provide valuable information for predicting future adverse outcomes and mortality, independently from baseline clinical risk assessment. Although the risk of an adverse event is indeed higher in patients with higher sPESI scores, cTns retain their prognostic value also in those at low risk, suggesting that a combination of hs-cTn with sPESI may provide an incremental value over assessment of either variable alone. Accordingly, the future development of updated risk stratification models, with the inclusion of laboratory tests such as hs-cTn, may represent an enhanced approach for risk stratification in patients with acute PE. Additional research, however, is needed to verify whether the combination of cTns, specifically as measured with hs-cTn assays, with other biomarkers may further improve the current capacity to efficiently manage patients with acute PE.

scholarly journals High-sensitivity troponin I for risk stratification in normotensive pulmonary embolism

2020 ◽  
Vol 6 (4) ◽  
pp. 00625-2020
Author(s):  
Matthias Ebner ◽  
Niklas Guddat ◽  
Karsten Keller ◽  
Marie Christine Merten ◽  
Markus H. Lerchbaumer ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Risk Stratification ◽  
Troponin I ◽  
Adverse Outcome ◽  
High Sensitivity ◽  
Adverse Outcomes ◽  
Prognostic Role ◽  
High Sensitivity Troponin ◽  
All Cause Mortality

While numerous studies have confirmed the prognostic role of high-sensitivity troponin T (hsTnT) in pulmonary embolism (PE), high-sensitivity troponin I (hsTnI) is inappropriately studied. This study aimed to investigate the prognostic relevance of hsTnI in normotensive PE, establish the optimal cut-off value for risk stratification and to compare the prognostic performances of hsTnI and hsTnT.Based on data from 459 consecutive PE patients enrolled in a single-centre registry, receiver operating characteristic analysis was used to identify an optimal hsTnI cut-off value for prediction of in-hospital adverse outcomes (PE-related death, cardiopulmonary resuscitation or vasopressor treatment) and all-cause mortality.Patients who suffered an in-hospital adverse outcome (4.8%) had higher hsTnI concentrations compared with those with a favourable clinical course (57 (interquartile range (IQR) 22–197) versus 15 (IQR 10–86) pg·mL−1, p=0.03). A hsTnI cut-off value of 16 ng·mL−1 provided optimal prognostic performance and predicted in-hospital adverse outcomes (OR 6.5, 95% CI 1.9–22.4) and all-cause mortality (OR 3.7, 95% CI 1.0–13.3). Between female and male patients, no relevant differences in hsTnI concentrations (17 (IQR 10–97) versus 17 (IQR 10–92) pg·mL−1, p=0.79) or optimised cut-off values were observed. Risk stratification according to the 2019 European Society of Cardiology algorithm revealed no differences if calculated based on either hsTnI or hsTnT (p=0.68).Our findings confirm the prognostic role of hsTnI in normotensive PE. HsTnI concentrations >16 pg·mL−1 predicted in-hospital adverse outcome and all-cause mortality; sex-specific cut-off values do not seem necessary. Importantly, our results suggest that hsTnI and hsTnT can be used interchangeably for risk stratification.

scholarly journals Prognostic impact of copeptin in pulmonary embolism: a multicentre validation study

2018 ◽  
Vol 51 (4) ◽  
pp. 1702037 ◽  
Author(s):  
Kristian Hellenkamp ◽  
Piotr Pruszczyk ◽  
David Jiménez ◽  
Anna Wyzgał ◽  
Deisy Barrios ◽  
...  
Keyword(s):  
At Risk ◽  
Pulmonary Embolism ◽  
High Risk ◽  
Risk Stratification ◽  
Adverse Outcome ◽  
Adverse Outcomes ◽  
Prognostic Impact ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

To externally validate the prognostic impact of copeptin, either alone or integrated in risk stratification models, in pulmonary embolism (PE), we performed a post hoc analysis of 843 normotensive PE patients prospectively included in three European cohorts.Within the first 30 days, 21 patients (2.5%, 95% CI 1.5–3.8) had an adverse outcome and 12 (1.4%, 95% CI 0.7–2.5) died due to PE. Patients with copeptin ≥24 pmol·L−1 had a 6.3-fold increased risk for an adverse outcome (95% CI 2.6–15.5, p<0.001) and a 7.6-fold increased risk for PE-related death (95% CI 2.3–25.6, p=0.001). Risk classification according to the 2014 European Society of Cardiology (ESC) guideline algorithm identified 248 intermediate-high-risk patients (29.4%) with 5.6% (95% CI 3.1–9.3) at risk of adverse outcomes. A stepwise biomarker-based risk assessment strategy (based on high-sensitivity troponin T, N-terminal pro-brain natriuretic peptide and copeptin) identified 123 intermediate-high-risk patients (14.6%) with 8.9% (95% CI 4.5–15.4) at risk of adverse outcomes. The identification of patients at higher risk was even better when copeptin was measured on top of the 2014 ESC algorithm in intermediate-high-risk patients (adverse outcome OR 11.1, 95% CI 4.6–27.1, p<0.001; and PE-related death OR 13.5, 95% CI 4.2–43.6, p<0.001; highest risk group versus all other risk groups). This identified 85 patients (10.1%) with 12.9% (95% CI 6.6–22.0) at risk of adverse outcomes and 8.2% (95% CI 3.4–16.2) at risk of PE-related deaths.Copeptin improves risk stratification of normotensive PE patients, especially when identifying patients with an increased risk of an adverse outcome.

A comparison of the original and simplified Pulmonary Embolism Severity Index

2011 ◽  
Vol 106 (09) ◽  
pp. 423-428 ◽  
Author(s):  
Carmen Venetz ◽  
David Jiménez ◽  
Marie Méan ◽  
Drahomir Aujesky
Keyword(s):  
Pulmonary Embolism ◽  
Characteristic Curve ◽  
Severity Index ◽  
Adverse Outcomes ◽  
Low Risk ◽  
Discriminatory Power ◽  
University Hospital ◽  
Likelihood Ratios ◽  
Predictive Values ◽  
Risk Patients

SummaryThe Pulmonary Embolism Severity Index (PESI) is a validated clinical prognostic model for patients with pulmonary embolism (PE). Recently, a simplified version of the PESI was developed. We sought to compare the prognostic performance of the original and simplified PESI. Using data from 15,531 patients with PE, we compared the proportions of patients classified as low versus higher risk between the original and simplified PESI and estimated 30-day mortality within each risk group. To assess the models’ accuracy to predict mortality, we calculated sensitivity, specificity, and predictive values and likelihood ratios for low-versus higher-risk patients. We also compared the models’ discriminative power by calculating the area under the receiver-operating characteristic curve. The overall 30-day mortality was 9.3%. The original PESI classified a significantly greater proportion of patients as low-risk than the simplified PESI (40.9% vs. 36.8%; p<0.001). Low-risk patients based on the original and simplified PESI had a mortality of 2.3% and 2.7%, respectively. The original and simplified PESI had similar sensitivities (90% vs. 89%), negative predictive values (98% vs. 97%), and negative likelihood ratios (0.23 vs. 0.28) for predicting mortality. The original PESI had a significantly greater discriminatory power than the simplified PESI (area under the ROC curve 0.78 [95% CI: 0.77–0.79] vs. 0.72 [95% CI: 0.71–0.74]; p<0.001). In conclusion, even though the simplified PESI accurately identified patients at low-risk of adverse outcomes, the original PESI classified a higher proportion of patients as low-risk and had a greater discriminatory power than the simplified PESI.Institution where the work was carried out: Division of General Internal Medicine, Bern University Hospital, Bern, Switzerland.

scholarly journals The Diagnostic Role of Uric Acid to Creatinine Ratio for the Identification of Patients with Adverse Pulmonary Embolism Outcomes

Diagnostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 193
Author(s):  
Konstantinos Bartziokas ◽  
Christos Kyriakopoulos ◽  
Dimitrios Potonos ◽  
Konstantinos Exarchos ◽  
Athena Gogali ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Uric Acid ◽  
Risk Stratification ◽  
Multivariable Analysis ◽  
Area Under The Curve ◽  
Composite Endpoint ◽  
Severity Index ◽  
Pulmonary Angiography ◽  
Adverse Outcomes ◽  
Creatinine Ratio

Background: Uric acid (UA) is the final product of purine metabolism and a marker of oxidative stress that may be involved in the pathophysiology of cardiovascular and thromboembolic disease. The aim of the current study is to investigate the potential value of UA to creatinine ratio (UA/Cr) as a diagnostic tool for the outcome of patients admitted with acute pulmonary embolism (PE) and the correlations with other parameters. Methods: We evaluated 116 patients who were admitted for PE in a respiratory medicine department. PE was confirmed with computed tomography pulmonary angiography. Outcomes evaluated were hospitalization duration, mortality or thrombolysis and a composite endpoint (defined as mortality or thrombolysis). Patients were assessed for PE severity with the PE Severity Index (PESI) and the European Society of Cardiology (ESC) 2019 risk stratification. Results: The median (interquartile range) UA/Cr level was 7.59 (6.3–9.3). UA/Cr was significantly associated with PESI (p < 0.001), simplified PESI (p = 0.019), and ESC 2019 risk stratification (p < 0.001). The area under the curve (AUC) for prediction of 30-day mortality by UA/Cr was 0.793 (95% CI: 0.667–0.918). UA/Cr levels ≥7.64 showed 87% specificity and 94% negative predictive value for mortality. In multivariable analysis UA/Cr was an independent predictor of mortality (HR (95% CI): 1.620 (1.245–2.108), p < 0.001) and composite outcome (HR (95% CI): 1.521 (1.211–1.908), p < 0.001). Patients with elevated UA/Cr levels (≥7.64) had longer hospitalization (median (IQR) 7 (5–11) vs. 6 (5–8) days, p = 0.006)), higher mortality (27.3% vs. 3.2%, p = 0.001) and worse composite endpoint (32.7% vs. 3.4%, p < 0.001). Conclusion: Serum UA/Cr ratio levels at the time of PE diagnosis are associated with disease severity and risk stratification, and may be a useful biomarker for the identification of patients at risk of adverse outcomes.

scholarly journals Contemporary Clinical Management and Course of ACUTE Pulmonary Embolism: The COPE Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3230-3230
Author(s):  
Cecilia Becattini ◽  
Giancarlo Agnelli ◽  
Aldo P Maggioni ◽  
Francesco Dentali ◽  
Andrea Fabbri ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
High Risk ◽  
Risk Stratification ◽  
Major Bleeding ◽  
Acute Pulmonary Embolism ◽  
Low Risk ◽  
Intermediate Risk ◽  
Bayer Healthcare ◽  
Risk Patients ◽  
Acute Pe

Abstract Background. New management strategies, risk stratification procedures and treatments have become available over the last years for patients with acute pulmonary embolism (PE), leading to changes in clinical practice and potentially influencing patient's course and outcome. Methods: The COntemporary management of Pulmonary Embolism (COPE) is an academical prospective, non-interventional, multicentre study in patients with confirmed acute symptomatic PE. In-hospital and 30-day mortality were the co-primary study outcomes. At first evaluation, patients were categorized at low-risk (simplified PESI [sPESI]=0), intermediate-risk (further classified based presence/absence of increased levels and right ventricle dysfunction [RVD] at echocardiography) and high-risk (shock or cardiac arrest). Results. Among 5213 study patients, PE was confirmed by computed tomography in 96.3% and at least one test for risk stratification was obtained in more than 80% (81% echocardiography, 83% troponin, 56% brain natriuretic peptide/NT-pro BNP). Among 4885 patients entering the Emergency Department for acute PE, 1.2% were managed as outpatients and 5.8% by short-observation. In-hospital, 289 patients underwent reperfusion (5.5%); at discharge, 6.7% received a vitamin K antagonist and 75.6% a direct oral anticoagulant. Median duration of hospitalization was 7 days (IQR 5-12 days). Overall in-hospital mortality was 3.4% (49% due to PE, 16% cancer and 4.5% major bleeding) and 30-day mortality 4.8% (36% PE, 28% cancer and 4% major bleeding). In-hospital major bleeding was 2.6%. Death at 30 days occurred in 22.6% of 177 high-risk patients, in 6% of the 3281 intermediate-risk and in 0.5% of 1702 low-risk patients. Time to death at 30 days in patients at low, intermediate and high risk for death is reported in the Figure. Conclusions: COPE is the largest ever cohort of patients with acute PE. In this contemporary scenario, the majority of patients received CT for diagnosis, at least one test for risk stratification and direct oral anticoagulants as long-term treatment. Short term death remains not negligible in patients with high and intermediate-risk PE. Figure 1 Figure 1. Disclosures Becattini: Bristol Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria; Bayer HealthCare: Honoraria. Agnelli: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria; Bayer HealthCare: Honoraria. Dentali: Daiichi Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Boehringer: Honoraria; Alfa Sigma: Honoraria.

scholarly journals Is the Pulmonary Embolism Severity Index Being Routinely Used in Clinical Practice?

Thrombosis ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Ali Shafiq ◽  
Hamza Lodhi ◽  
Zaheer Ahmed ◽  
Ata Bajwa
Keyword(s):  
Pulmonary Embolism ◽  
High Risk ◽  
Hospital Stay ◽  
Length Of Hospital Stay ◽  
Risk Groups ◽  
Severity Index ◽  
Low Risk ◽  
Significant Difference ◽  
Risk Patients ◽  
Acute Pe

Background. The Pulmonary Embolism Severity Index (PESI) score can risk-stratify patients with PE but its widespread use is uncertain. With the PESI, we compared length of hospital stay between low, moderate, and high risk PE patients and determined the number of low risk PE patients who were discharged early. Methods. PE patients admitted to St. Joseph Mercy Oakland Hospital from January 2005 to August 2010 were screened. PESI score stratified acute PE patients into low (<85), moderate (86–105), and high (>105) risk categories and their length of hospital stay was compared. Patients with low risk PE discharged early (≤3 days) were calculated. Results. Among 315 PE patients, 51.7% were at low risk. No significant difference in hospital stay between low (7.11 ± 3 d) and moderate (6.88 ± 2.9 d) risk, p > 0.05, as well as low and high risk (7.28 ± 3.0 d), p > 0.05, was found. 9% of low risk patients were discharged ≤ 3 days. Conclusions. There was no significant difference in length of hospital stay between low and high risk groups and only a small number of low risk patients were discharged from the hospital early suggesting that risk tools like PESI may not have a widespread use.

scholarly journals Cardiac troponin testing and the simplified Pulmonary Embolism Severity Index

2011 ◽  
Vol 106 (11) ◽  
pp. 978-984 ◽  
Author(s):  
David Spirk ◽  
Drahomir Aujesky ◽  
Marc Husmann ◽  
Daniel Hayoz ◽  
Thomas Baldi ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Cardiac Troponin ◽  
Prognostic Value ◽  
Troponin T ◽  
Characteristic Curve ◽  
Early Death ◽  
Severity Index ◽  
Highly Sensitive ◽  
Risk Patients ◽  
Highly Sensitive Troponin

SummaryA low simplified Pulmonary Embolism Severity Index (sPESI), defined as age ≤80 years and absence of systemic hypotension, tachycardia, hypoxia, cancer, heart failure, and lung disease, identifies low-risk patients with acute pulmonary embolism (PE). It is unknown whether cardiac troponin testing improves the prediction of clinical outcomes if the sPESI is not low. In the prospective Swiss Venous Thromboembolism Registry, 369 patients with acute PE and a troponin test (conventional troponin T or I, highly sensitive troponin T) were enrolled from 18 hospitals. A positive test result was defined as a troponin level above the manufacturers assay threshold. Among the 106 (29%) patients with low sPESI, the rate of mortality or PE recurrence at 30 days was 1.0%. Among the 263 (71%) patients with high sPESI, 177 (67%) were troponin-negative and 86 (33%) troponin-positive; the rate of mortality or PE recurrence at 30 days was 4.6% vs. 12.8% (p=0.015), respectively. Overall, risk assessment with a troponin test (hazard ratio [HR] 3.39, 95% confidence interval [CI] 1.38–8.37; p=0.008) maintained its prognostic value for mortality or PE recurrence when adjusted for sPESI (HR 5.80, 95%CI 0.76–44.10; p=0.09). The combination of sPESI with a troponin test resulted in a greater area under the receiver-operating characteristic curve (HR 0.72, 95% CI 0.63–0.81) than sPESI alone (HR 0.63, 95% CI 0.57–0.68) (p=0.023). In conclusion, although cardiac troponin testing may not be required in patients with a low sPESI, it adds prognostic value for early death and recurrence for patients with a high sPESI.

scholarly journals Validation of the Pulmonary Embolism Severity Index for risk stratification after acute pulmonary embolism in a cohort of patients in Brazil

2019 ◽  
Vol 45 (1) ◽  
Author(s):  
Leonardo de Araujo Soriano ◽  
Talita Tavares Castro ◽  
Kelvin Vilalva ◽  
Marcos de Carvalho Borges ◽  
Antonio Pazin-Filho ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Pulmonary Embolism ◽  
Mortality Rate ◽  
Risk Stratification ◽  
Acute Pulmonary Embolism ◽  
Severity Index ◽  
Original Version ◽  
Risk Class ◽  
Kaplan Meier ◽  
Acute Pe

ABSTRACT Objective: To validate the Pulmonary Embolism Severity Index (PESI), which was developed for risk stratification after acute pulmonary embolism (PE), for use in Brazil. Methods: This was a single-center retrospective study involving patients admitted to the emergency department with acute PE. The original and simplified versions of the PESI were calculated using hospital admission data from medical records. The outcome measure was the overall 30-day mortality rate. Results: We included 123 patients. The mean age was 57 ± 17 years, and there was a predominance of females, who accounted for 60% of the cohort. There were 28 deaths, translating to an overall 30-day mortality rate of 23%. In the cluster analysis by risk class, overall 30-day mortality was 2.40% for classes I-II, compared with 20.00% for classes III-IV-V (relative risk [RR] = 5.9; 95% CI: 1.88-18.51; p = 0.0002). When we calculated overall 30-day mortality using the simplified version (0 points vs. ≥ 1 point), we found it to be 3.25% for 0 points and 19.51% for ≥ 1 point (RR = 2.38; 95% CI: 0.89-6.38; p = 0.06). Using the original version, a survival analysis showed that risk classes I and II presented similar Kaplan-Meier curves (p = 0.59), as did risk classes III, IV, and V (p = 0.25). However, the curve of the clusters based on the original version, showed significantly higher mortality in the III-IV-V classes than in the I-II classes (RR = 7.63; 95% CI: 2.29-25.21; p = 0.0001). The cluster analysis based on the original version showed a greater area under the ROC curve than did the analysis based on the simplified version (0.70; 95% CI: 0.62-0.77 vs. 0.60; 95% CI: 0.51-0.67; p = 0.05). Conclusions: The PESI adequately predicted the prognosis after acute PE in this sample of the population of Brazil. The cluster analysis based on the original version is the most appropriate analysis in this setting.

scholarly journals The Use of Transthoracic Echocardiograms in Hospitalized Adult Patients with Acute Pulmonary Embolism

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-43
Author(s):  
Katherine Steckham ◽  
Craig Ainsworth ◽  
Siraj Mithoowani ◽  
Deborah M Siegal
Keyword(s):  
Pulmonary Embolism ◽  
Right Ventricular ◽  
Cardiac Troponin ◽  
Acute Pulmonary Embolism ◽  
Adverse Outcomes ◽  
Adult Patients ◽  
Hospital Death ◽  
Elevated Troponin ◽  
Systemic Thrombolysis ◽  
Acute Pe

Background: The role of inpatient transthoracic echocardiography (TTE) in patients with acute pulmonary embolism (PE) is unclear. Although right ventricular dysfunction (RVD) predicts adverse outcomes in acute PE, there is no consensus on the optimal TTE findings for prognostication and how they influence management, particularly when CT and/or an elevated cardiac troponin already suggest RVD. Understanding current practices regarding inpatient TTE in acute PE can help direct appropriate use. Our objectives were to (i) characterize inpatient TTE use in adult patients hospitalized with acute PE, (ii) describe and compare findings of RVD by TTE, CT and troponin, and (iii) explore differences in outcomes between patients managed with or without TTE. Methods: We conducted a retrospective cohort study of adult patients hospitalized with acute PE at two academic hospitals in Hamilton, Canada between January and December 2018. Patients with suspected PE that was not objectively confirmed, or PE diagnosed prior to hospitalization were excluded. We also excluded patients who had a TTE prior to the diagnosis of PE. Chi-square tests and independent t-tests were used. P-values less than 0.05 were considered significant. Results: We identified 178 adult patients (mean age 66 ± 15 years; 42% male). Patients were admitted to internal medicine (53%), oncology (19%), surgical specialties (13%) and intensive care units (ICU, 11%). Of 146 patients, 134 (92%) had a PE involving segmental or larger vessels. TTE was conducted in 86 (48%) patients. Systemic thrombolysis was administered to 11 (6%) patients. A higher proportion of patients with an elevated troponin (66% vs. 35% p&lt;0.001) or evidence of RV strain on CT (65% vs. 35%, p=0.001) underwent TTE compared to those without these findings. Patients admitted to the ICU more frequently underwent TTE (69% vs. 44%, p=0.012). RV size and function were normal in 49 (59%) and 53 (63%) cases, respectively. Patients with RV strain on CT were more likely to have RV enlargement (58% vs. 30%, p=0.04) and RVD (58% vs. 25%, p=0.011) on TTE. However, right ventricular internal dimension in diastole (RVIDd) (3.9 ± 0.75 cm vs. 3.7 ± 0.78 cm) and tricuspid annular plane systolic excursion (TAPSE) (1.8 ± 0.44 cm vs. 2.0 ± 0.38 cm) were not statistically different between patients with or without RV strain on CT. A higher proportion of patients with an elevated troponin had RV enlargement (58% vs. 14%, p=0.001) and RVD (50% vs. 18%, p=0.018) on TTE. Length of hospital admission (16 ± 28 days vs. 11 ± 23 days) and in-hospital death (7% vs. 11%) were not statistically different between patients with or without TTE. Conclusions: Inpatient TTE is conducted frequently in hospitalized patients with acute PE, especially in those with evidence of RV strain based on CT and/or an elevated cardiac troponin. Our results suggest that patients with findings of RV strain on CT are more likely to have RV enlargement and RVD on TTE. Future studies should evaluate the diagnostic utility of CT and/or troponin for RVD in the setting of acute PE, which may reduce the routine use of inpatient TTE and associated healthcare resources and costs. Disclosures Mithoowani: Leo Pharma: Honoraria. Siegal:Portola: Honoraria; Novartis: Honoraria; Leo Pharma: Honoraria; Bayer: Honoraria; BMS Pfizer: Honoraria.

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