Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism.

RATIONALE: Concomitant deep vein thrombosis (DVT) in patients with acute pulmonary embolism (PE) has an uncertain prognostic significance. OBJECTIVES: In a cohort of patients with PE, this study compared the risk of death in those with and those without concomitant DVT. METHODS: We conducted a prospective cohort study of outpatients diagnosed with a first episode of acute symptomatic PE. Patients underwent bilateral lower extremity venous compression ultrasonography to assess for concomitant DVT. MEASUREMENTS AND MAIN RESULTS: The primary study outcome, all-cause mortality, and the secondary outcome of PE-specific mortality were assessed during the 3 months of follow-up after PE diagnosis. Multivariate Cox proportional hazards regression was done to adjust for significant covariates. Of 707 patients diagnosed with PE, 51.2% (362 of 707) had concomitant DVT and 10.9% (77 of 707) died during follow-up. Patients with concomitant DVT had an increased all-cause mortality (adjusted hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.24 to 3.38; P = 0.005) and PE-specific mortality (adjusted HR, 4.25; 95% CI, 1.61 to 11.25; P = 0.04) compared with those without concomitant DVT. In an external validation cohort of 4,476 patients with acute PE enrolled in the international multicenter RIETE Registry, concomitant DVT remained a significant predictor of all-cause (adjusted HR, 1.66; 95% CI, 1.28 to 2.15; P < 0.001) and PE-specific mortality (adjusted HR, 2.01; 95% CI, 1.18 to 3.44; P = 0.01). CONCLUSIONS: In patients with a first episode of acute symptomatic PE, the presence of concomitant DVT is an independent predictor of death in the ensuing 3 months after diagnosis. Assessment of the thrombotic burden should assist with risk stratification of patients with acute PE.

Organ-specific requirements for Hdac1 in liver and pancreas formation.

Liver, pancreas and lung originate from the presumptive foregut in temporal and spatial proximity. This requires precisely orchestrated transcriptional activation and repression of organ-specific gene expression within the same cell. Here, we show distinct roles for the chromatin remodelling factor and transcriptional repressor Histone deacetylase 1 (Hdac1) in endodermal organogenesis in zebrafish. Loss of Hdac1 causes defects in timely liver specification and in subsequent differentiation. Mosaic analyses reveal a cell-autonomous requirement for hdac1 within the hepatic endoderm. Our studies further reveal specific functions for Hdac1 in pancreas development. Loss of hdac1 causes the formation of ectopic endocrine clusters anteriorly to the main islet, as well as defects in exocrine pancreas specification and differentiation. In addition, we observe defects in extrahepatopancreatic duct formation and morphogenesis. Finally, loss of hdac1 results in an expansion of the foregut endoderm in the domain from which the liver and pancreas originate. Our genetic studies demonstrate that Hdac1 is crucial for regulating distinct steps in endodermal organogenesis. This suggests a model in which Hdac1 may directly or indirectly restrict foregut fates while promoting hepatic and exocrine pancreatic specification and differentiation, as well as pancreatic endocrine islet morphogenesis. These findings establish zebrafish as a tractable system to investigate chromatin remodelling factor functions in controlling gene expression programmes in vertebrate endodermal organogenesis.

Association of anaemia and mortality in patients with acute pulmonary embolism.

This study aimed to evaluate the relationship between anaemia and pulmonary embolism (PE) prognosis. We analysed a cohort of 764 patients with acute PE referred to a single center for diagnosis and management. Patients were divided into groups by quartiles of haemoglobin (Hb): Hb < 11.7 g/dl; Hb 11.7 to 12.9 g/dl; Hb 13.0 to 14.1 g/dl; Hb > 14.1 g/dl. Patients had a mean Hb of 12.9 g/dl, and values ranged from to 4.3 to 19.5 g/dl. Lower Hb was associated with recent bleeding, an impaired haemodynamic profile and higher creatinine. Patients in the lower Hb quartiles more commonly had female gender (p < 0.001), a diagnosis of cancer (p < 0.001), and an indication for an inferior vena cava (IVC) filter (p < 0.002), compared to patients in the higher Hb quartiles. Patients in higher Hb quartiles had higher survival at three months (75%, 86%, 90% and 91% for lowest to highest quartiles, respectively). On multivariate analysis, adjusting for known PE prognostic factors, low Hb proved to be an independent predictor of mortality (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.05 to 1.28 for each decrease of 1 g/dl). Hb level remained an independent predictor of all-cause mortality when cancer patients were excluded from the analysis (adjusted HR 0.81; 95% CI, 0.66 to 0.99; p = 0.04). Moreover, patients with anaemia showed a higher risk of fatal PE (unadjusted HR 1.19, 95% CI 1.04 to 1.37). In conclusion, in patients with acute symptomatic PE, anaemia severity is associated with worsened survival.

[Anti-factor Xa activity of enoxaparin for thromboprophylaxis in nonsurgical patients is dependent on body mass]. / La actividad anti-Xa depende del peso en pacientes médicos que reciben tromboprofilaxis con enoxaparina.

OBJECTIVE: Thromboprophylaxis with a fixed dose of low-molecular-weight heparin is recommended for hospitalized acutely ill medical patients. The purpose of this study was to assess whether the anti-factor Xa (anti-Xa) activity of enoxaparin prescribed for venous thromboembolism prophylaxis depends on body mass index (BMI) in patients hospitalized for an acute respiratory disease. PATIENTS AND METHODS: All patients admitted to the respiratory medicine department (January-December 2006) for an acute respiratory disease, and for whom pharmacologic thromboprophylaxis was indicated, were included in the study. Anti-Xa activity was measured 4 hours after administration of enoxaparin on the third day of hospitalization. The primary outcome was anti-Xa activity in relation to BMI. RESULTS: One hundred twelve patients were enrolled. Mean anti-Xa activity decreased with each BMI quartile (0.28, 0.23, 0.15, and 0.13 U/mL for quartiles 1, 2, 3, and 4, respectively). In the multivariate analysis, BMI was the only predictor of inadequate anti-Xa activity (odds ratio, 1.14; 95% confidence interval, 10.5-1.24; P< .002) after adjustment for age, sex, and serum creatinine levels. Two episodes of symptomatic proximal deep vein thrombosis were diagnosed in the month after hospitalization; both occurred in patients who had inadequate anti-Xa activity. CONCLUSIONS: Anti-Xa activity is dependent on BMI in hospitalized acute medical patients receiving enoxaparin for thromboprophylaxis.

Prognostic significance of delays in diagnosis of pulmonary embolism.

STUDY OBJECTIVE: To investigate the prognostic significance of a diagnostic delay of greater than 1 week after symptom onset in patients with pulmonary embolism (PE). DESIGN: Prospective cohort study. LOCATION: Emergency Department of Ramón y Cajal Hospital, a 1500-bed tertiary-care center in Madrid, Spain. PATIENTS: Diagnosed with PE by objective testing between January 1, 2003, and June 30, 2005. INTERVENTIONS: All patients received standard anticoagulation therapy during follow-up. ENDPOINTS: Death from any cause or symptomatic recurrent venous thromboembolism (VTE), confirmed by standard objective testing, within 3 months after PE diagnosis. RESULTS: Of the 397 patients with acute PE, 72 (18%) had a diagnostic delay while 325 (82%) did not. The all-cause mortality rate was 13.1% at 3 months (95% CI=9.8-16.4%); due to 9 (12.5%) deaths in the diagnostic delay group and 43 (13.2%) deaths in the group without diagnostic delay (OR 0.9; 95% CI=0.4-2.0). Though multivariate analysis of clinical variables at the time of PE diagnosis identified active cancer, heart failure and immobility for more than 4 days as independent risk factors for death, diagnostic delay was not predictive. Recurrent VTE was observed in 3 (4.2%) of 72 patients with diagnostic delay and in 15 (4.6%) of 325 patients without diagnostic delay (odds ratio: 0.9; 95% CI=0.2-3.2). None of the variables analysed, including diagnostic delay, was associated with an increased risk of recurrent VTE during follow-up. CONCLUSIONS: Among survivors diagnosed with acute PE in the Emergency Department, we did not detect an association between a delay in diagnosis and an increased risk of death or VTE recurrence during the ensuing 3 months of treatment.

Monotherapy with enoxaparin for the prevention of recurrent venous thromboembolism.

This study aimed to determine whether a weight-adjusted dose of subcutaneous enoxaparin is as effective and safe as oral acenocoumarol for the secondary prophylaxis of pulmonary embolism. Three hundred and eighty consecutive noncancer outpatients hospitalized with an episode of symptomatic pulmonary embolism selected treatment with acenocoumarol or enoxaparin at a dose of 1 mg/kg once daily after being informed of the type of administration and expected frequency of laboratory monitoring for both medicinal products. Endpoints were symptomatic recurrent thromboembolic events evaluated by standard objective testing, and a composite endpoint of recurrent venous thromboembolism, major bleeding, and death from any cause. One hundred and ninety-nine patients (52%) chose acenocoumarol therapy and 181 chose enoxaparin monotherapy. Four patients in the enoxaparin group (2.2%) and six patients in the acenocoumarol group (3%) had an objective thromboembolic recurrence (hazard ratio, 1.35; 95% confidence interval, 0.38-4.79; P = 0.64). Nine patients in the enoxaparin group (5.0%) had a hemorrhagic complication compared with 11 in the acenocoumarol group (5.5%) (P = 0.81). The hospital length of stay was shorter with enoxaparin compared with acenocoumarol (11 versus 16 days, P = 0.0001). Enoxaparin is as effective and safe as acenocoumarol in the secondary prevention of recurrent thromboembolic disease and is associated with shorter hospitalization.

[Prognostic value of transthoracic echocardiography in hemodynamically stable patients with acute symptomatic pulmonary embolism]. / Valor pronóstico de la ecocardiografía transtorácica en pacientes estables hemodinámicamente con tromboembolia de pulmón aguda sintomática.

OBJECTIVE: To determine the prognostic value of transthoracic echocardiography in hemodynamically stable patients diagnosed with acute symptomatic pulmonary embolism. PATIENTS AND METHODS: Hemodynamically stable outpatients diagnosed with acute symptomatic pulmonary embolism at a tertiary university hospital were prospectively included in the study. All patients underwent transthoracic echocardiography within 48 hours of diagnosis. The primary endpoint was all-cause mortality at 1 month. RESULTS: Right ventricular dysfunction was documented by echocardiography in 86 of the 214 patients (40%) in our series. In the first month of follow-up, 7 patients died--4 with positive echocardiographic findings and 3 with negative findings (odds ratio, 2.0; 95% confidence interval, 0.4-9.3; P=.41). For the primary endpoint, the negative predictive value of transthoracic echocardiography was 98%, the positive predictive value was 5%, and the negative likelihood ratio was 0.7. The negative predictive value was 100% and the positive predictive value was 3% when we analyzed death due to pulmonary embolism only. CONCLUSIONS: In our setting, transthoracic echocardiography is not useful for prognostic stratification of hemodynamically stable patients with pulmonary embolism.

The risk of recurrent venous thromboembolism in patients with unprovoked symptomatic deep vein thrombosis and asymptomatic pulmonary embolism.

Patients with a first episode of symptomatic pulmonary embolism (PE) have a higher risk of recurrent venous thromboembolism (VTE) than patients with a first episode of proximal lower extremity deep vein thrombosis (DVT). Patients with symptomatic DVT and silent PE may have a different risk of VTE recurrence than patients that have symptomatic DVT without PE. Therefore, it was the aim of this prospective cohort study to compare the risk of recurrent symptomatic VTE in patients with proximal lower extremity DVT and silent PE to the risk in patients that only have proximal lower extremity DVT. Ninety-one consecutive outpatients presenting to the emergency department of a university hospital subsequently hospitalised with a first episode of unprovoked symptomatic proximal lower extremity DVT, and without new pulmonary symptoms were included. Standard initial treatment consisted of intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin for 5-7 days, overlapped with oral vitamin-K antagonist therapy, with long-term oral vitamin-K antagonist therapy (goal INR 2.5 [2.0-3.0]). Study endpoints were: symptomatic recurrent DVT, new PE, and recurrent PE, evaluated by standard objective testing. At enrollment, 28 of 91 (31%) patients with DVT had silent PE. In the patients with DVT and silent PE, there were 3 VTE recurrences during 20 person-years of follow-up, while there were no VTE recurrences during 61 person-years of follow- up in the patients with isolated DVT. The Kaplan-Meier estimated VTE recurrence rate at 1 year after the diagnosis of DVT was 11% (95% CI: 2-28%) for patients with symptomatic DVT and silent PE, compared to 0% in patients with isolated symptomatic DVT (p=0.0045). In patients with a first episode of unprovoked symptomatic acute proximal lower extremity DVT, the risk of recurrent VTE was significantly higher in those with silent PE compared to those without PE.

[Thromboembolic events in patients after a negative computed tomography pulmonary angiogram: A retrospective study of 165 patients]. / Aparición de episodios tromboembólicos en pacientes con angiotomografía axial computarizada simple negativa. Estudio retrospectivo de 165 pacientes.

OBJECTIVE: To determine the value of computed tomography (CT) angiography of the chest as a diagnostic test to exclude pulmonary embolism and to assess compliance with diagnostic protocols for thromboembolic disease. PATIENTS AND METHODS: We retrospectively studied patients who underwent CT angiography of the chest because of suspected pulmonary embolism in 2004. All the patients were followed for 3 months. The percentage of patients diagnosed with a thromboembolic event based on an objective test during the follow-up period was determined. We analyzed the percentage of patients with a negative CT angiogram on whom additional diagnostic tests (ultrasound of the lower limbs and/or ventilation-perfusion lung scintigraphy) were performed. RESULTS: One hundred sixty-five patients underwent CT angiography of the chest because of suspected pulmonary embolism in 2004. Four of the patients were excluded from the study because they were on chronic anticoagulation therapy and a further 2 were excluded because they had a life expectancy of under 3 months. Of the remaining 159 patients, 60 had CT angiograms that were interpreted as high probability for pulmonary embolism (prevalence of 38%). Thirty-nine of the 99 patients with a negative CT angiogram experienced an objectively confirmed thromboembolic event (63% sensitivity; 95% confidence interval, 53%-73%). Other diagnostic tests were not performed in 46% of the cases. CONCLUSIONS: In our setting, a negative single-detector helical CT angiogram was not sensitive enough to exclude the diagnosis of pulmonary embolism. Furthermore, compliance with internationally accepted diagnostic protocols was far from optimal.

Etiology and prognostic significance of massive pleural effusions.

It has been stated that malignancy is the most common aetiology of massive pleural effusions. To determine the most frequent causes of massive pleural effusions and to assess the diagnostic yield of different diagnostic procedures and survival, we prospectively studied 1084 patients with pleural effusion. Massive pleural effusions were identified in 121 of 1084 patients (11.2%). Compared with non-massive pleural effusions, massive pleural effusions were significantly more likely to be malignant (53.7% vs. 38.3%, P=0.03) or secondary to cirrhosis (9.9% vs. 2.6%, P=0.0000). On the other hand, massive pleural effusions were significantly less likely to be secondary to infection (10.7% vs. 19.2%, P=0.003) or congestive heart failure (0.8% vs. 6.7%, P=0.03). There was a significant increase in the yield of diagnostic studies in patients with massive malignant pleural effusions (56.9% for cytological studies and 36.9% for biopsies). On the other hand, there was no difference in the diagnostic yield of microbiological and histological studies in the group of tuberculous pleural effusions. In our study population, patients with non-massive malignant pleural effusions had a significantly better survival than those with massive malignant pleural effusions, with a median survival of 8 months (95% confidence interval, 7-9) compared with 5 months (95% confidence interval, 4-6) (P=0.0009). We conclude that malignancy is the most common cause of a massive exudative effusion. Massive malignant pleural effusions are associated with worse survival, independent of age and histologic subgroup, than are non-massive malignant pleural effusions.

Report on the incidence of interstitial lung diseases in Spain.

BACKGROUND AND AIM OF THE WORK: Almost no epidemiological data are available on a worldwide basis on the prevalence, incidence or relative frequency of interstitial lung diseases (ILD). We report the results of a registration of ILD by 23 centers of pulmonary medicine in Spain over one year (from October 2000 to September 2001). METHODS: A standardized questionnaire was sent to the centers, together with guidelines for classification and diagnostic evaluation. This questionnaire included questions about the explorations performed to establish the diagnosis. RESULTS: A total of 511 cases were registered. The mean age of the patients was 61 +/- 0.7 (x +/- SEM) yrs. The male to female ratio was 1.2:1. The estimated incidence of ILD was 7.6 per 100,000/year. The most frequent disease was idiopathic pulmonary fibrosis (38.6%), followed in decreasing order by sarcoidosis (14.9%), cryptogenic organizing pneumonia (10.4%), ILD associated with collagen vascular diseases (9.9%) and hypersensitivity pneumonitis (6.6%). In 5.1% of cases ILD was unclassified. HRCT scan was performed in 91.9% of cases, bronchoalveolar lavage in 67.9%, transbronchial lung biopsy in 59.9%, and surgical lung biopsy in 22.7%. CONCLUSIONS: This registration provides interesting information on the occurrence of ILD in Spain and on the procedures used to establish the diagnosis.

Dramatic response to inhaled dobesilate in a patient with lung squamous cell cancer.

The effectiveness of local application, by inhalation, of dobesilate, an inhibitor of fibroblast growth factor signalling, in a patient with squamous cell lung carcinoma is reported. To our knowledge, these are the first published data on the efficacy of dobesilate in the treatment of this disease. The antimitotic, antiangiogenic, proapoptotic and anti-inflammatory activities of dobesilate can be important factors to consider, in explaining the efficacy of the treatment. Dobesilate administration can be a therapeutic option in patients with lung cancer having poor performance status or severe complications.

[Incidence of symptomatic and asymptomatic chronic thromboembolic pulmonary hypertension]. / Incidencia de hipertensión pulmonar tromboembólica crónica sintomática y asintomática.

INTRODUCTION AND OBJECTIVES: To assess the incidence of long-term symptomatic and asymptomatic chronic thromboembolic pulmonary hypertension (CTEPH) in a cohort of patients with acute symptomatic pulmonary embolism (PE), and the potential risk factors for its diagnosis. METHODS: We conducted a prospective, long-term, follow-up study in 110 consecutive patients with an acute episode of pulmonary embolism (PE). All patients underwent transthoracic echocardiography (TTE) two years after the diagnosis of PE was made. If systolic pulmonary artery pressure exceeded 40 mm Hg and there was evidence of residual PE either by ventilation-perfusion or CT scan, patients underwent right heart catheterisation to confirm the diagnosis. In asymptomatic patients, right heart catheterisation was performed if a repeated TTE still demonstrated persistent pulmonary hypertension six months after the first. RESULTS: CTEPH was diagnosed in 10 (6 patients during follow-up, and 4 at the end of the study) of the 110 patients (9.1%; 95% confidence interval [CI], 3.7 to 14.5%). All patients showed symptoms related to the disease according to a structured questionnaire. In the multivariate regression analysis, only concomitant age (relative risk [RR] 1.2 per age; 95% CI, 1.0 to 1.3; P=0.03) and previous PE (RR 5.7; IC 95%, 1.5 a 22.0; P=0.01) were independent predictors of CTEPH. CONCLUSIONS: CTEPH cumulative incidence appears to be higher than previously reported. All patients had symptoms related to the disease.

[Risk factors in chronic thromboembolic pulmonary hypertension]. / Factores de riesgo de la hipertensión pulmonar tromboembólica crónica.

Although preoccupation with chronic thromboembolic pulmonary hypertension (CTEPH) among the scientific community is constantly increasing, the pathogenesis of this disease has not been completely elucidated and factors predisposing to its development are not precisely known. Some patients may be genetically conditioned to develop CTEPH, but only a few fibrinogen mutations and an increase in the frequency of polymorphisms of human leukocyte antigens have been described. Hereditary coagulation defects are no more prevalent in patients with CTEPH than in controls, except for factor VIII and antiphospholipid antibodies. Some studies have analyzed differences in the expression of type 1 tissue plasminogen activator inhibitor in the thrombus of patients with CTEPH (compared with thrombi of acute pulmonary thromboembolism [PTE]) and suggest that thrombosis in situ can contribute to the persistence of the coagulum and disease progression. Some characteristics of acute PTE have been associated with its progression to CTEPH, such as idiopathic PTE, large perfusion defects, massive PTE, recurrent PTE and pulmonary hypertension persisting at 5 weeks after the thrombotic event. Several clinical factors that increase the risk of CTEPH have been described, such as splenectomy, ventricular shunts, and chronic inflammatory diseases. Thyroid replacement therapy and cancer have also emerged as new predictors of CTEPH. Identification of new predisposing factors will provide clues to the pathogenic mechanisms of the disease and will facilitate early diagnosis and more effective treatment.

[Chronic obstructive pulmonary disease in patients with acute symptomatic pulmonary embolism]. / Enfermedad pulmonar obstructiva crónica en pacientes con tromboembolia de pulmón aguda sintomática.

BACKGROUND: The diagnosis of pulmonary embolism (PE) is often complicated by the presence of chronic obstructive pulmonary disease (COPD). Some studies have suggested that patients with PE and concomitant COPD have a worse prognosis than patients without COPD. PATIENTS AND METHODS: Outpatients diagnosed with acute symptomatic PE at a university tertiary care hospital were prospectively included in the study. Clinical characteristics, time between onset of symptoms and diagnosis, and outcome were analyzed according to presence or absence of COPD. The primary endpoint was all-cause deaths at 3 months. RESULTS: Of 882 patients with a confirmed diagnosis of acute symptomatic PE, 8% (95% confidence interval [CI], 6%-9%) had COPD. Patients with COPD were significantly more likely to have a delay in diagnosis of more than 3 days and to have a low pretest probability of pulmonary embolism according to a standardized clinical score. The total number of deaths during 3 months of follow-up was 128 (14%; 95% CI, 12%-17%). Factors significantly associated with mortality from all causes were a history of cancer or immobilization, systolic blood pressure less than 100mm Hg, and arterial oxyhemoglobin saturation less than 90%. COPD was significantly associated with PE-related death in the logistic regression analysis (relative risk, 2.2; 95% CI, 1.0-5.1). CONCLUSIONS: Patients with COPD and PE more often have a lower pretest probability and a longer delay in diagnosis of PE. COPD is significantly associated with PE-related death in the 3 months following diagnosis.

[Prognostic value of electrocardiographic findings in hemodynamically stable patients with acute symptomatic pulmonary embolism]. / Valor pronóstico de los hallazgos electrocardiográficos en pacientes estables hemodinámicamente con tromboembolia de pulmón aguda sintomática.

INTRODUCTION AND OBJECTIVES: The aim of this study was to determine the prognostic value of electrocardiography in hemodynamically stable patients with a diagnosis of acute symptomatic pulmonary embolism (PE). METHODS: This prospective study included all hemodynamically stable outpatients who were diagnosed with PE at a university hospital. The electrocardiographic abnormalities investigated were: a) sinus tachycardia (>100 beats/min); b) ST-segment or T-wave abnormalities; c) right bundle branch block; d) an S1Q3T3 pattern, and e) recent-onset atrial arrhythmia. RESULTS: The study included 644 patients. Overall, 5% of those with an ECG abnormality died due to PE in the 15 days after diagnosis compared with 2% of those with normal ECG findings (relative risk [RR]=2.4; 95% confidence interval [CI], 1-5,8; P=.05). Multivariate analysis showed that sinus tachycardia was associated with a 2.2-fold increased risk of death due to all causes in the month after PE diagnosis. After adjusting for age, a history of cancer, immobility, ECG abnormalities, and sinus tachycardia, the presence of recent-onset atrial arrhythmia was significantly associated with death due to PE in the first 15 days (RR=2.8; 95% CI, 1-8.3; P=.05). The negative predictive value of atrial arrhythmia for 15-day PE-related mortality was 97%, while the negative likelihood ratio was 0.79. CONCLUSIONS: In hemodynamically stable patients with acute symptomatic PE, the presence of sinus tachycardia and atrial arrhythmia were independent predictors of a poor prognosis. However, the usefulness of these factors for stratifying risk in PE patients is limited.