Validation of the Predictive Model of the European Society of Cardiology for Early Mortality in Acute Pulmonary Embolism.

Background Acute pulmonary embolism (PE) is burdened by high mortality, especially within 30 days from the diagnosis. The development and the validation of predictive models for the risk of early mortality allow to differentiate patients who can undergo home treatment from those who need admission into intensive care units. Methods To validate the prognostic model for early mortality after PE diagnosis proposed by the European Society of Cardiology (ESC) in 2014, we analyzed data of a cohort of 272 consecutive patients with acute PE, observed in our hospital during a 10-year period. Moreover, we evaluated the additional contribution of D-dimer, measured at PE diagnosis, in improving the prognostic ability of the model. All cases of PE were objectively diagnosed by angiography chest CT scan or perfusion lung scan. Results The overall mortality rate within 30 days from PE diagnosis was 10% (95% confidence interval [CI]: 6.4-13.5%). According to the ESC prognostic model, the risk of death increased 3.23 times in the intermediate-low-risk category, 5.55 times in the intermediate-high-risk category, and 23.78 times in the high-risk category, as compared with the low-risk category. The receiver operating characteristic analysis showed a good discriminatory power of the model (area under the curve [AUC] = 0.77 [95% CI: 0.67-0.87]), which further increased when D-dimer was added (AUC = 0.85 [95% CI: 0.73-0.96]). Conclusion This study represents a good validation of the ESC predictive model whose performance can be further improved by adding D-dimer plasma levels measured at PE diagnosis.

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

Pulmonary embolism in elderly patients: prognostic impact of the Cumulative Illness Rating Scale (CIRS) on short-term mortality.

BACKGROUND: Pulmonary embolism (PE) is associated with high short-term mortality in elderly patients, even when hemodynamically stable. METHODS: One hundred and seventy hemodynamically stable patients with confirmed PE (41<65years and 129≥65years) were prospectively followed for one month in order to assess whether comorbidities can predict short-term mortality in elderly patients. Upon admission, patients' clinical characteristics (including instrumental and laboratory parameters) were evaluated, and two clinical scores were calculated: the Cumulative Illness Rating Scale (CIRS), commonly used to evaluate comorbidities in elderly patients, and the Pulmonary Embolism Severity Index (PESI). RESULTS: Fifteen patients (all elderly) died within one month from their PE diagnosis (mortality rate=8.8%; 95%CI:4.6-13.1%). In these non survivors, arterial partial oxygen pressure (p<0.0001) and saturation (p<0.0001), pH (p=0.001) and systolic blood pressure (p=0.017) at admission were significantly lower than in survivors, whereas their respiratory rate (p<0.0001), white blood cells (p<0.0001), lactate dehydrogenase (p<0.0001), troponin T (p=0.001) and D-dimer (p=0.023) were significantly higher. CIRS correlated with PESI (rho=0.54, p<0.0001), and was higher in non-survivors (p=0.002). The age- and sex-adjusted odds ratio of 1-month mortality was 1.91 (95%CI:1.24-2.95) for every 1-point increase in CIRS. The AUC was 0.78 (95%CI:0.67-0.89) for the logistic model containing CIRS, and 0.88 (95%CI:0.79-0.96) for that containing PESI (p=0.059). CONCLUSIONS: In elderly patients with PE, CIRS demonstrated a fairly good performance in predicting short-term mortality. Its easiness and suitability for use in common clinical practice make CIRS a potentially useful prognostic score for short-term mortality in these patients.

Acute pulmonary embolism: external validation of an integrated risk stratification model.

BACKGROUND: In hemodynamically stable patients with acute pulmonary embolism, risk stratification is essential to drive clinical management. In these patients, risk stratification for in-hospital adverse outcomes based on markers of right ventricular dysfunction and injury has been proposed. METHODS: The aim of this study was to validate a model based on the incremental prognostic value of right ventricular dysfunction and injury in hemodynamically stable patients with acute pulmonary embolism. Patients from the prospective Italian Pulmonary Embolism Registry were included in the study. Study outcomes were in-hospital death and the composite of in-hospital death or clinical deterioration. RESULTS: Among 1,515 hemodynamically stable patients, 869 had both echocardiography and troponin assessments. The risk for in-hospital death or clinical deterioration was higher in patients with right ventricular dysfunction and elevated troponin level (8.8%; hazard ratio [HR], 14.2 [95% CI, 1.94-104.16]; P < .01) and with either right ventricular dysfunction or elevated troponin level (4.7%; HR, 7.9 [95% CI, 1.1-59.9]; P < .05) compared with patients without dysfunction and normal troponin levels. The negative predictive value of the model was 100% for in-hospital death and 99% for death or clinical deterioration. C statistics showed an improvement of the discriminatory power for in-hospital death or clinical deterioration by using the overall model (0.66; 95% CI, 0.60-0.73) over either echocardiography (0.59; 95% CI, 0.53-0.67) or troponin level (0.61; 95% CI, 0.53-0.69) alone. CONCLUSIONS: A model that includes both dysfunction and injury of the right ventricle has an incremental prognostic value for risk stratification in hemodynamically stable patients with acute pulmonary embolism. Patients with no dysfunction or injury have a favorable outcome. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01604538; URL: www.clinicaltrials.gov.

Differential diagnosis of pulmonary embolism in outpatients with non-specific cardiopulmonary symptoms.

Most cardiopulmonary diseases share at least one symptom with pulmonary embolism (PE). The aim of this study was to identify the most common acute causes of dyspnea, chest pain, fainting or palpitations, which diagnostic procedures were performed and whether clinicians investigate them appropriately. An Italian multicenter collaboration gathered 17,497 Emergency Department (ED) records of patients admitted from January 2007 to June 2007 in six hospitals. A block random sampling procedure was applied to select 800 hospitalised patients. Results of the overall 17,497 patients were obtained by weighting sampled cases according to the probability of the randomisation block variables in the whole population. The case-mix of enrolled patients was assessed in terms of cardiopulmonary symptoms, and the prevalence of acute disorders. The actual performance of procedures was compared with a measure of their accuracy as expected in the most common clinical presentations. PE occurred in less than 4% of patients with cardiopulmonary symptoms. Acute heart failure, pneumonia and chronic obstructive pulmonary disease exacerbation were the most likely diagnoses in patients with dyspnea. Acute myocardial infarction was present in roughly 10% of patients with chest pain. Atrial fibrillation was the prevalent diagnosis in patients with palpitations. Echocardiography, computed tomographic pulmonary angiography, perfusion lung scan, D-dimer test and B-type natriuretic peptide were performed less than expected from their accuracy. Diagnostic strategies, starting from non-specific symptoms and coping with the eventuality of PE, are likely to benefit from an increased awareness of the examination's accuracy in discriminating among several competing hypotheses, rather than in testing the single PE suspicion.

[A new Emergency Department case management model for nonurgent patients]. / Un nuovo modello di gestione dei pazienti "non urgenti" in Pronto Soccorso.

Emergency Department visits for nonurgent conditions are very widespread and new strategies to provide timely and appropriate medical care for these patients are required. The "Fondazione IRCCS Ca 'Grande" Hospital in Milan, in collaboration with the local health authorities have evaluated a new case management model in which patients classed as nonurgent at triage are diverted to a "continuity of care" outpatient office within the emergency department. This model, based on the integration of hospital and community-based primary healthcare, was effective and led to a significant reduction in waiting times in the ED and to a more appropriate use of resources.

The impact of an aging population on the diagnosis of pulmonary embolism: comparison of young and elderly patients.

The influence of age on predisposing factors, diagnostic tests, and clinical presentation of pulmonary embolism was evaluated in 582 subjects with suspected pulmonary embolism (180 aged <65 years; 402 aged > or =65 years) consecutively enrolled at the Emergency Department. Pulmonary embolism was confirmed in 40% of patients, 75% of those were aged >65 years. Age was directly related to the diagnosis, and the observed probability was higher than the expected probability in the 70 to 79 year subgroup. Score at the Cumulative Illness Rating Scale significantly increased as a function of both age and pulmonary embolism. Dyspnea, syncope, jugular distension, and history of previous venous thromboembolism were more frequently observed in elderly patients. In-hospital mortality rate among the elderly and younger patients was 2% and 0.2%, respectively. The authors conclude that age > or =65 years and high comorbidity are risk factors for pulmonary embolism.

Deferral of assessment of pulmonary embolism.

We evaluated a simplified algorithm for safely postponing diagnostic imaging for pulmonary embolism (PE). At the index visit, patients were identified as being at high or low risk of PE; the former received full dosage low molecular weight heparin while the latter were left untreated until performance of diagnostic imaging (max 72 hours). During this period, no thromboembolic events occurred in low-risk patients (0/211, 0.% [upper 95% CI 0.9%]); only one event occurred in those at high-risk (1/125, 0.8% [upper 95% CI, 1.2]). Our study demonstrates that diagnostic imaging for PE can be safely deferred for up to 3 days.

The value of four-detector row spiral computed tomography for the diagnosis of pulmonary embolism.

Although spiral computed tomography (CT) is being used increasingly as the first-line imaging procedure in the diagnostic workup of patients with clinically suspected pulmonary embolism (PE), the diagnostic value of negative findings, at least when using the four-detector row scanners, is still controversial. A total of 702 consecutive patients with clinical symptoms suggestive of PE underwent four-slice CT. Patients with negative findings received the determination of D-dimer. Those with positive D-dimer underwent further diagnostic workup to confirm or rule out the diagnosis of PE. Those with negative D-dimer were followed-up to 6 months to detect the development of symptomatic venous thromboembolism (VTE). The CT test was interpreted as negative in 536 patients (76.3%). These patients had the D-dimer determination, which was positive in 279 and negative in the remaining 257 patients. Of the former, PE subsequently was documented in 55 patients (19.7%). Of the latter, symptomatic VTE in the follow-up period developed in three patients (1.17%; 95% confidence interval, 0.24 to 3.38%). In conclusion, when using the four-detector row, the negative predictive value of CT findings in patients with clinically suspected PE and positive D-dimer is low. In contrast, it is safe to withhold anticoagulation from patients with negative findings and negative D-dimer.

Consentimiento educado vs. Consentimiento informado / Educated consent vs: informed consent

En el artículo se desarrolla la idea de la beneficencia como el principio rector de los cuatro principios que propone la bioética clínica y la importancia de la veracidad, analizando excepciones. Se trata sobre lo imprescindible de un buen proceso de consentimiento informado y el costo impagable de la regla de no influir que impide al médico realizar sus tareas como educador. Se analizan las ventajas del consentimiento educado que no abandona al paciente en el difícil momento de la toma de decisiones y permite intentar modificar en él conductas negativas para la salud. Se analizan los distintos tipos de relación médico-paciente siguiendo la clasificación de Enmanuel E. y Enmanuel L. y cómo en la relación deliberativa es factible el uso del consentimiento educado. Se proponen metas a alcanzar en Cuba.

The article developed the idea of doing good as the ruling principle of the four principles suggested by clinical ethics, and the importance of truth, taking exceptions into account. It dealt with the need of a good process of informed consent and the unaffordable cost of the rule that prevents the physician from influencing the patient and at the same time from fulfilling his/her role as an educator. It further analyzed the advantages of educated consent that does not leave the patient alone at the difficult decision-taking time and allows changing the patient´s negative health behaviours. Several types of physician-patient relationships following Enmanuel E. & Enmanuel L .´s classification and how the use of educated consent is feasible in deliberative relationship were also considered. Some goals that should be attained in Cuba were put forward.

Consentimiento educado vs. Consentimiento informado / Educated consent vs: informed consent

En el artículo se desarrolla la idea de la beneficencia como el principio rector de los cuatro principios que propone la bioética clínica y la importancia de la veracidad, analizando excepciones. Se trata sobre lo imprescindible de un buen proceso de consentimiento informado y el costo impagable de la regla de no influir que impide al médico realizar sus tareas como educador. Se analizan las ventajas del consentimiento educado que no abandona al paciente en el difícil momento de la toma de decisiones y permite intentar modificar en él conductas negativas para la salud. Se analizan los distintos tipos de relación médico-paciente siguiendo la clasificación de Enmanuel E. y Enmanuel L. y cómo en la relación deliberativa es factible el uso del consentimiento educado. Se proponen metas a alcanzar en Cuba(AU)

The heparins and cancer: review of clinical trials and biological properties.

The association between cancer and thromboembolic disease is a well-known phenomenon and can contribute significantly to the morbidity and mortality of cancer patients. The spectrum of thromboembolic manifestations in cancer patients includes deep vein thrombosis, pulmonary embolism, but also intravascular disseminated coagulation and abnormalities in the clotting system in the absence of clinical manifestations. Unfractionated heparin (UFH) and particularly low molecular weight heparins (LMWH-s) are widely used for the prevention and treatment of thromboembolic manifestations that commonly accompany malignancies. Malignant growth has also been linked to the activity of heparin-like glycosaminoglycans, to neoangiogenesis, to protease activity, to immune function and gene expression. All these factors contribute in the proliferation and dissemination of malignancies. Heparins may play a role in tumour cell growth and in cancer dissemination. The aims of the study are to review the efficiency of heparins in the prevention and treatment of cancer-related thromboembolic complications, and review the biological effects of heparins. Heparins are effective in reducing the frequency of thromboembolic complications in cancer patients. Meta-analyses comparing unfractionated heparins and LMWH-s for the treatment of deep vein thrombosis have shown better outcome with a reduction of major bleeding complications in patients treated with LMWH-s. LMWH have antitumour effects in animal models of malignancy: heparin oligosaccharides containing less than 10 saccharide residues have been found to inhibit the biological activity of basic fibroblast growth factor (bFGF), whereas heparin fragments with less than 18 saccharide residues have been reported to inhibit the binding of vascular endothelial growth factor (VEGF) to its receptors on endothelial cells. It has been shown that LMWH, in contrast with UFH, can hinder the binding of growth factors to their high-affinity receptors as a result of its smaller size. In vitro heparin fragments of less than 18 saccharide residues reduce the activity of VEGF, and fragments of less than 10 saccharide residues inhibit the activity of bFGF. Small molecular heparin fractions have also been shown to inhibit VEGF- and bFGF-mediated angiogenesis in vivo, in contrast with UFH. Moreover, heparin may influence malignant cell growth through other different interrelated mechanisms: inhibition of (1) heparin-binding growth factors that drive malignant cell growth; (2) tumour cell heparinases that mediate tumour cell invasion and metastasis; (3) cell surface selectin-mediated tumour cell metastasis and blood coagulation. The above evidence, together with favourable pharmaco-properties and with a reduction in major bleeding complications, suggests an important role for LMWH-s in thromboprophylaxis and in the therapy of venous thromboembolism in cancer patients. There is sufficient experimental data to suggest that heparins may interfere with various aspects of cancer proliferation, angiogenesis, and metastasis formation. Large-scale clinical trials are required to determine the clinical impact of the above activities on the natural history of the disease.

Extended oral anticoagulant therapy after a first episode of pulmonary embolism.

BACKGROUND: The optimal duration of oral anticoagulant treatment after a first episode of pulmonary embolism remains uncertain. OBJECTIVE: To evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months (pulmonary embolism associated with temporary risk factors) or to 1 year (idiopathic pulmonary embolism) in patients with a first episode of pulmonary embolism. DESIGN: Multicenter randomized study with independent, blinded assessment of the outcome events. SETTING: 19 Italian hospitals. PATIENTS: 326 patients who had had 3 months of oral anticoagulant therapy without experiencing recurrence or bleeding. MEASUREMENTS: The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism. RESULTS: Among 165 patients assigned to extended anticoagulant therapy, 15 patients (9.1%) had a recurrence of venous thromboembolism (3.1% per patient-year; average follow-up, 34.9 months), as compared with 18 of 161 patients (11.2%) assigned to discontinue treatment (4.1% per patient-year; average follow-up, 32.7 months); the rate ratio was 0.81 (95% CI, 0.42 to 1.56). All but one of the recurrences occurred after anticoagulant treatment was discontinued. Nineteen recurrences (57.6%) were episodes of pulmonary embolism, two of which were fatal. Three major bleeding episodes were observed during extended anticoagulation (1.8%). Among patients with idiopathic venous thromboembolism, 11 of 90 patients assigned to extended anticoagulation and 11 of 91 patients assigned to discontinue treatment experienced a recurrence (relative risk, 0.99 [CI, 0.45 to 2.16]). CONCLUSION: Patients with pulmonary embolism have a substantial risk for recurrence after discontinuation of oral anticoagulation, regardless of treatment duration. Physicians should try to identify patients who are at high risk for recurrent venous thromboembolism and are therefore potential candidates for indefinite oral anticoagulant therapy.