Feasibility of a screening algorithm for chronic thromboembolic pulmonary hypertension: The OSIRIS study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term sequel to pulmonary embolism (PE) whose incidence varies according to different published studies. We have carried out this study to determine its incidence within 2 years after index pulmonary embolism and to study limitations to an early diagnosis. MATERIAL AND METHODS: OSIRIS is a multicentre, longitudinal cohort study. Patients were followed for 3, 6, 12, and 24 months after pulmonary embolism using a structured three-step algorithm. A physician-centered questionnaire at least one positive response in a screening proceeded to the second step, transthoracic echocardiography. The third step consisted of ventilation/perfusion lung scintigraphy and right heart catheterisation. A transthoracic echocardiography was performed in patients without positive response in the screening questionnaire after 2 years. CTEPH diagnosis required haemodynamic confirmation by right heart catheterisation and mismatched perfusion defects on lung scintigraphy. RESULTS: A total of 1191 patients were enrolled in 18 Spanish hospitals. Cumulative CTEPH incidence after 2-years PE was: 2.49 % (95 % CI: 1.68-3.56) and the incidence rate of CTEPH was 1.1 cases per 1000 person-months (95 % CI: 0.725; 1.60). The CTEPH algorithm presented a lack of adherence of 29 %; patient and physician preferences posed barriers to the triage algorithm The screening questionnaire, in patients who completed the follow-up, shows a specificity of 91.3 % (89.0-93.2 %) and negative predictive value of 99.4 % (98.4-99.8 %).. CONCLUSIONS: OSIRIS provides practiced clinical based data on the chronic thromboembolic pulmonary hypertension incidence and identified barriers to the implementation of a 3-step triage algorithm for its detection. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03134898.

Biomarkers of Venous Thromboembolism Recurrence after Discontinuation of Low Molecular Weight Heparin Treatment for Cancer-Associated Thrombosis (HISPALIS-Study).

The most appropriate duration of anticoagulant treatment for cancer-associated venous thromboembolism (CAT) remains unclear. We have conducted a prospective multicenter study in CAT patients with more than 6 months of anticoagulant treatment to predict the risk of venous thromboembolism (VTE) recurrence after anticoagulation discontinuation. Blood samples were obtained when patients stopped the anticoagulation, at 21 days and at 90 days. In each sample we assessed different coagulation-related biomarkers: D-dimer (DD), high-sensitivity C-reactive protein (hs-CRP), P-selectin (PS), phospholipids, soluble tissue factor, factor VIII and the thrombin generation test. It was evaluated 325 CAT patients and 166 patients were included in the study, mean age 64 ± 17 years. VTE recurrence until 6 months after stopping anticoagulation treatment was 9.87% [95% confidence interval (CI): 6−15]. The biomarkers sub-distribution hazard ratios were 6.32 for ratio DD basal/DD 21 days > 2 (95% CI: 1.82−21.90), 6.36 for hs-CRP > 4.5 (95% CI: 1.73−23.40) and 5.58 for PS > 40 (95% CI: 1.46−21.30) after 21 days of stopping anticoagulation. This is the first study that has identified the DD ratio, hs-CRP and PS as potential biomarkers of VTE recurrence in cancer patients after the discontinuation of anticoagulation treatment. A risk-adapted strategy may allow the identification of the optimal time to withdraw the anticoagulation in each CAT patient.

Randomised controlled trial of a prognostic assessment and management pathway to reduce the length of hospital stay in normotensive patients with acute pulmonary embolism.

BACKGROUND: The length of hospital stay (LOS) for acute pulmonary embolism (PE) varies considerably. Whether the upfront use of a PE prognostic assessment and management pathway is effective in reducing the LOS remains unknown. METHODS: We conducted a randomised controlled trial of adults hospitalised for acute PE: patients were assigned either to a prognostic assessment and management pathway involving risk stratification followed by predefined criteria for mobilisation and discharge (intervention group) or to usual care (control group). The primary end-point was LOS. The secondary end-points were the cost of prognostic tests and of hospitalisation, and 30-day clinical outcomes. RESULTS: Of 500 patients who underwent randomisation, 498 were included in the modified intention-to-treat analysis. The median LOS was 4.0 days (interquartile range (IQR) 3.7-4.2 days) in the intervention group and 6.1 days (IQR 5.7-6.5 days) in the control group (p<0.001). The mean total cost of prognostic tests was EUR 174.76 in the intervention group, compared with EUR 233.12 in the control group (mean difference EUR -58.37, 95% CI EUR -84.34- to -32.40). The mean total hospitalisation cost per patient was EUR 2085.66 in the intervention group, compared with EUR 3232.97 in the control group (mean difference EUR -1147.31, 95% CI EUR -1414.97- to -879.65). No significant differences were observed in 30-day readmission (4.0% versus 4.8%), all-cause mortality (2.4% versus 2.0%) or PE-related mortality (0.8% versus 1.2%) rates. CONCLUSIONS: The use of a prognostic assessment and management pathway was effective in reducing the LOS for acute PE.

Validación de 2 escalas clínicas pronósticas en pacientes con tromboembolia pulmonar aguda sintomática / Validation of Two Clinical Prognostic Models in Patients With Acute Symptomatic Pulmonary Embolism

Objetivo: El objetivo de este estudio fue validar y comparar 2 escalas pronósticas, la escala española y la escala Pulmonary Embolism Severity Index simplificada (PESIs), en una cohorte de pacientes diagnosticados de tromboembolia de pulmón (TEP) aguda sintomática. Métodos: Se realizó un análisis retrospectivo de una cohorte de 1.447 pacientes diagnosticados consecutivamente de TEP aguda sintomática. Evaluamos el valor predictivo de las 2 escalas para muerte a 30 días y para un episodio compuesto de recurrencia tromboembólica no mortal y hemorragia mayor no mortal mediante el estadístico C , empleando para su cálculo regresión logística y curvas ROC. Resultados: Durante los primeros 30 días de seguimiento fallecieron 138 pacientes (9,5%). Las 2 escalas mostraron un valor predictivo bueno para mortalidad a 30 días (estadístico C, 0,72 y 0,74) y pobre para la predicción del episodio secundario (estadísticos C, 0,60 y 0,59). La escala PESIs clasificó una proporción significativamente menor de pacientes como de bajo riesgo, comparada con la escala española (32% versus 62%; p < 0,001). La mortalidad del grupo de bajo riesgo según la escala PESIs fue menor que la de la escala española (1,1% versus 4,2%). La proporción de episodios no mortales fue similar en el grupo de bajo riesgo de ambos modelos (2,2% versus 2,3%). Conclusiones: La escala española y la escala PESIs presentaron excelente capacidad discriminatoria para la mortalidad a 30 días. La escala PESIs fue más segura para identificar a los pacientes con TEP y bajo riesgo de complicaciones precoces (AU)

Objective: The aim of this study was to compare the predictive value of two clinical prognostic models, the Spanish score and the simplified Pulmonary Embolism Severity Index (sPESI), in an independent cohort of patients diagnosed of acute symptomatic pulmonary embolism (PE). Methods: We performed a retrospective analysis of a cohort composed of 1447 patients with acute symptomatic PE. The Spanish score and the sPESI were calculated for each patient according to different clinical variables. We assessed the predictive accuracy of these scores for 30-day mortality, and a composite of non fatal recurrent venous thromboembolism and non fatal major bleeding, using C statistic, which was obtained by means of logistic regression and ROC curves. Results: Overall, 138 patients died (9.5%) during the first month of follow-up. Both scores showed an excellent predictive value for 30-day all-cause mortality (C statistic, 0.72 and 0.74), but the performance was poor for the secondary endpoint (C statistic, 0.60 and 0.59). The sPESI classified fewer patients as low risk (32% versus 62%; P<0.001). Low-risk patients based on the sPESI had a lower 30-day mortality than those based on the Spanish score (1.1% versus 4.2%), while the 30-day rate of non fatal recurrent VTE or major bleeding was similar (2.2% versus 2.3%). Conclusions: Both scores provide excellent information to stratify the risk of mortality in patients treated of PE. The usefulness of these models for nonfatal adverse events is questionable. The sPESI identified low-risk patients with PE better than the Spanish score (AU)

Validation of two clinical prognostic models in patients with acute symptomatic pulmonary embolism.

OBJECTIVE: The aim of this study was to compare the predictive value of two clinical prognostic models, the Spanish score and the simplified Pulmonary Embolism Severity Index (sPESI), in an independent cohort of patients diagnosed of acute symptomatic pulmonary embolism (PE). METHODS: We performed a retrospective analysis of a cohort composed of 1447patients with acute symptomatic PE. The Spanish score and the sPESI were calculated for each patient according to different clinical variables. We assessed the predictive accuracy of these scores for 30-day mortality, and a composite of non fatal recurrent venous thromboembolism and non fatal major bleeding, using Cstatistic, which was obtained by means of logistic regression and ROC curves. RESULTS: Overall, 138 patients died (9.5%) during the first month of follow-up. Both scores showed an excellent predictive value for 30-day all-cause mortality (Cstatistic, 0.72 and 0.74), but the performance was poor for the secondary endpoint (Cstatistic, 0.60 and 0.59). The sPESI classified fewer patients as low risk (32% versus 62%; P<.001). Low-risk patients based on the sPESI had a lower 30-day mortality than those based on the Spanish score (1.1% versus 4.2%), while the 30-day rate of non fatal recurrent VTE or major bleeding was similar (2.2% versus 2.3%). CONCLUSIONS: Both scores provide excellent information to stratify the risk of mortality in patients treated of PE. The usefulness of these models for nonfatal adverse events is questionable. The sPESI identified low-risk patients with PE better than the Spanish score.

Factors associated with elevated pulmonary arterial pressure levels on the echocardiographic assessment in patients with prior pulmonary embolism.

BACKGROUND: Factors associated with the detection of raised systolic pulmonary artery pressure (sPAP) levels in patients with a prior episode of pulmonary embolism (PE) are not well known. METHODS: We used the RIETE Registry database to identify factors associated with the finding of sPAP levels ≥50 mm Hg on trans-thoracic echocardiography, in 557 patients with a prior episode of acute, symptomatic PE. RESULTS: Sixty-two patients (11.1%; 95% CI: 8.72-14.1) had sPAP levels ≥50 mm Hg. These patients were more likely women, older, and more likely had chronic lung disease, heart failure, renal insufficiency or leg varicosities than those with PAP levels <50mm Hg. During the index PE event, they more likely had recent immobility, and more likely presented with hypoxemia, increased sPAP levels, atrial fibrillation, or right bundle branch block. On multivariate analysis, women aged ≥70 years (hazard ratio [HR]: 2.0; 95% CI: 1.0-3.7), chronic heart or chronic lung disease (HR: 2.4; 95% CI: 1.3-4.4), atrial fibrillation at PE presentation (HR: 2.8; 95% CI: 1.3-6.1) or varicose veins (HR: 1.8; 95% CI: 1.0-3.3) were all associated with an increased risk to have raised sPAP levels. Chronic heart disease, varicose veins, and atrial fibrillation were independent predictors in women, while chronic heart disease, atrial fibrillation, a right bundle branch block or an S1Q3T3 pattern on the electrocardiogram were independent predictors in men. CONCLUSIONS: Women aged ≥70 years more likely had raised sPAP levels than men after a PE episode. Additional variables influencing this risk seem to differ according to gender.

Residual thrombosis after a first episode of proximal deep venous thrombosis.

The aim of this study was to analyse the normalization rate of compression ultrasonography after a first episode of proximal deep venous thrombosis (DVT). Patients underwent compressive ultrasound (C-US) examinations during the 3-6 months following the first proximal DVT episode. Normalization rate of compressive ultrasound (C-US) during the follow-up period was 26.4% [95% confidence interval, 16.3-37.3]. Allelic variation in factor XIII gene (Val34Leu) significantly affected the improvement of popliteal residual thrombi (P = 0.019). We also observed a significant negative correlation between D-dimer levels at 3 months and improvement of popliteal residual thrombi (P = 0.016). There was a significant positive correlation between baseline lumen diameter of the femoral thrombi and IL-8 cytokine (P = 0.015). A significant difference was also found between 1 month-tumor necrosis factor (TNF)-α levels and improvement of residual thrombi (P = 0.047). Our results show that normalization after a standard period of anticoagulation is not frequent and procoagulant and inflammatory biomarkers and also some genetic variations might be related to the resolution of thrombosis.

Echocardiographic assessment of pulmonary arterial pressure in the follow-up of patients with pulmonary embolism.

BACKGROUND: Echocardiography remains a clinically useful screening test for chronic thromboembolic pulmonary hypertension (CTEPH) in patients with a history of pulmonary embolism (PE). To devise an effective screening strategy, the definition of a high-risk group is necessary. METHODS: We examined a total of 744 patients with acute symptomatic pulmonary embolism (PE) who were enrolled in a Spanish multicenter study. Patients were monitored every 6months during the first two years, and then once a year thereafter. Transthoracic echocardiography was used to screen patients with a clinical suspicion of CTEPH during follow-up. Pulmonary arterial hypertension was defined as an estimated pulmonary artery systolic pressure (PAP)>50mm Hg. The index thromboembolic episode was considered severe if: (a) the patient was immobilized for medical reasons; or (b) systolic blood pressure was less than 90mm Hg; or (c) troponin T values were above the reference range. RESULTS: The incidence of PAP>50mm Hg at 36months was 8.3% (95% confidence interval=4.6%-14.5%). Statistical analysis showed a highly significant association between a severe index thromboembolic episode and the subsequent detection of PAP>50mm Hg on echocardiography, with high positive likelihood ratio (2.40) and negative predictive value (>0.97). CONCLUSIONS: Patients with a severe index thromboembolic episode would constitute a high-risk group for the development of CTEPH. This group of patients should be subjected to a strict follow-up protocol.