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.

Duration of anticoagulation after venous thromboembolism in real world clinical practice.

INTRODUCTION: Venous thromboembolism (VTE) carries a considerable risk of recurrence and anticoagulants should be administered for a minimum of three months. Since little is known about real life management of VTE, we aimed to describe current practice in the secondary prevention of VTE. MATERIALS AND METHODS: Using the database of an international, prospective registry on patients treated for VTE, RIETE, information was collected on risk factors for VTE and bleeding, anticoagulant treatment, and clinical outcomes during follow up. Multivariate analysis using logistic regression was performed to identify predictors of treatment duration. RESULTS: Of 6944 patients with a first episode of VTE 41.1% had unprovoked VTE, 31.8% had transient risk factors, 27.1% had cancer. After the exclusion of patients who died during the first year of observation, the rate of patients treated for >12 months was 55.1%, 41.9%, and 43.2%, respectively (p<0.001). Pulmonary embolism at presentation, recurrence while on treatment, chronic heart failure and age >65 years were independently associated with treatment for >12 months. Body weight <75 kg, anemia, cancer, and the presence of transient risk factors were associated with treatment for 12 months or less. Major bleeding occurred more frequently than recurrent VTE in patients with VTE secondary to transient risk factors and cancer; fatal bleeding was more frequent than fatal recurrent PE in all subgroups. CONCLUSIONS: We observed heterogeneous duration of anticoagulant treatment for the secondary prevention of VTE. A substantial proportion of patients, in particular those with VTE secondary to transient risk factors, may be exposed to a possibly unnecessary risk of bleeding.

Prognostic significance of multidetector CT in normotensive patients with pulmonary embolism: results of the protect study.

BACKGROUND: In patients with acute pulmonary embolism (PE), rapid and accurate risk assessment is paramount in selecting the appropriate treatment strategy. The prognostic value of right ventricular dysfunction (RVD) assessed by multidetector CT (MDCT) in normotensive patients with PE has lacked adequate validation. METHODS: The study defined MDCT-assessed RVD as a ratio of the RV to the left ventricle short axis diameter greater than 0.9. Outcomes assessed through 30 days after the diagnosis of PE included all-cause mortality and 'complicated course', which consisted of death from any cause, haemodynamic collapse or recurrent PE. RESULTS: MDCT detected RVD in 533 (63%) of the 848 enrolled patients. Those with RVD on MDCT more frequently had echocardiographic RVD (31%) than those without RVD on MDCT (9.2%) (p<0.001). Patients with RVD on MDCT had significantly higher brain natriuretic peptide (269±447 vs 180±457 pg/ml, p<0.001) and troponin (0.10±0.43 vs 0.03±0.24 ng/ml, p=0.001) levels in comparison with those without RVD on MDCT. During follow-up, death occurred in 25 patients with and in 13 patients without RVD on MDCT (4.7% vs 4.3%; p=0.93). Those with and those without RVD on MDCT had a similar frequency of complicated course (3.9% vs 2.3%; p=0.30). CONCLUSIONS: The PROgnosTic valuE of CT study showed a relationship between RVD assessed by MDCT and other markers of cardiac dysfunction around the time of PE diagnosis, but did not demonstrate an association between MDCT-RVD and prognosis.

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.

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.

Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) estimates the risk of 30-day mortality in patients with acute pulmonary embolism (PE). We constructed a simplified version of the PESI. METHODS: The study retrospectively developed a simplified PESI clinical prediction rule for estimating the risk of 30-day mortality in a derivation cohort of Spanish outpatients. Simplified and original PESI performances were compared in the derivation cohort. The simplified PESI underwent retrospective external validation in an independent multinational cohort (Registro Informatizado de la Enfermedad Tromboembólica [RIETE] cohort) of outpatients. RESULTS: In the derivation data set, univariate logistic regression of the original 11 PESI variables led to the removal of variables that did not reach statistical significance and subsequently produced the simplified PESI that contained the variables of age, cancer, chronic cardiopulmonary disease, heart rate, systolic blood pressure, and oxyhemoglobin saturation levels. The prognostic accuracy of the original and simplified PESI scores did not differ (area under the curve, 0.75 [95% confidence interval (CI), 0.69-0.80]). The 305 of 995 patients (30.7%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.0% (95% CI, 0.0%-2.1%) compared with 10.9% (8.5%-13.2%) in the high-risk group. In the RIETE validation cohort, 2569 of 7106 patients (36.2%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.1% (95% CI, 0.7%-1.5%) compared with 8.9% (8.1%-9.8%) in the high-risk group. CONCLUSION: The simplified PESI has similar prognostic accuracy and clinical utility and greater ease of use compared with the original PESI.

Home treatment in pulmonary embolism.

BACKGROUND: Limited data exist on the feasibility of providing outpatient care to patients with acute pulmonary embolism (PE). METHODS: We conducted a multicenter randomized clinical trial in acute symptomatic PE to compare the efficacy and safety of early discharge versus standard hospitalization. A clinical prediction rule was used to identify low-risk patients. All patients were followed for three months. The primary outcomes were venous thromboembolic recurrences, major and minor bleeding, and overall mortality. RESULTS: One hundred and thirty two low-risk patients with acute symptomatic PE were randomized to early discharge (n=72) or standard hospitalization (n=60). Overall mortality was 4.2% (95% CI, 0.5-8.9) in the early discharge group and 8.3% (95% CI, 1.1-15) in the standard hospitalization group (Relative Risk (RR) 0.5; 95% confidence interval [CI], 0.12-2.01). Non-fatal recurrences were 2.8% (95% CI, 1.1-6.6) in the early discharge group and 3.3% (95% CI, 1.3-8%) in the standard hospitalization group (RR 0.8; 95% CI, 0.12-5.74). The rates of clinically relevant bleeding were 5.5% in the early discharge group and 5% in the standard hospitalization group (P=0.60). Short-term mortality was 2.8% (95% CI, 0.8-9.6%) in the early discharge group as compared with 0% in the standard hospitalization group. Based on the rate of short-term death in a carefully selected population, the study was suspended. CONCLUSIONS: In spite of the number of complications in patients with acute symptomatic PE randomized to standard hospitalization or early discharge did not differ significantly. The rate of short-term mortality was unexpectedly high in a (a priori) low-risk group of patients with acute PE. The accuracy of clinical prediction scores needs to be validated in well designed clinical trials. (ClinicalTrials.gov number, NCT00214929.).

Troponin-based risk stratification of patients with acute nonmassive pulmonary embolism: systematic review and metaanalysis.

BACKGROUND: Controversy exists regarding the usefulness of troponin testing for the risk stratification of patients with acute pulmonary embolism (PE). We conducted an updated systematic review and a metaanalysis of troponin-based risk stratification of normotensive patients with acute symptomatic PE. The sources of our data were publications listed in Medline and Embase from 1980 through April 2008 and a review of cited references in those publications. METHODS: We included all studies that estimated the relation between troponin levels and the incidence of all-cause mortality in normotensive patients with acute symptomatic PE. Two reviewers independently abstracted data and assessed study quality. From the literature search, 596 publications were screened. Nine studies that consisted of 1,366 normotensive patients with acute symptomatic PE were deemed eligible. Pooled results showed that elevated troponin levels were associated with a 4.26-fold increased odds of overall mortality (95% CI, 2.13 to 8.50; heterogeneity chi(2) = 12.64; degrees of freedom = 8; p = 0.125). Summary receiver operating characteristic curve analysis showed a relationship between the sensitivity and specificity of troponin levels to predict overall mortality (Spearman rank correlation coefficient = 0.68; p = 0.046). Pooled likelihood ratios (LRs) were not extreme (negative LR, 0.59 [95% CI, 0.39 to 0.88]; positive LR, 2.26 [95% CI, 1.66 to 3.07]). The Begg rank correlation method did not detect evidence of publication bias. CONCLUSIONS: The results of this metaanalysis indicate that elevated troponin levels do not adequately discern normotensive patients with acute symptomatic PE who are at high risk for death from those who are at low risk for death.

[Follow-up of pulmonary thromboembolism]. / Seguimiento de la tromboembolia pulmonar.

The aims of follow-up of pulmonary thromboembolism (PTE) are to avoid recurrence and possible sequels, such as pulmonary hypertension and postthrombotic syndrome of the lower limbs. Recurrences are reduced by anticoagulant therapy. In most PTE triggered by a transitory risk factor, without additional risk factors, the duration of oral anticoagulant therapy (OAT) is well established. However, in at least half of all cases, the triggering factors are not clear, the risk of recurrence is higher, and the duration of OAT has not been well-defined. Consequently, the factors that increase the risk of recurrence should be identified and monitored. These factors include cancer, some thrombophilias, and recurrent PTE or deep veinous thrombosis (DVT). In the last few years, idiopathic etiology, residual venous thrombosis, and other factors such as persistent right ventricular dysfunction, have also been demonstrated to be markers of recurrence. In some patients, D-dimers also seem to predict the risk of recurrence. Finally, the duration of OAT will be defined by periodically weighing the risk of recurrence against hemorrhagic risk in each individual patient. Current evidence on the balance of risks indicates a tendency toward indefinite anticoagulation, especially in idiopathic PTE. Moreover, functional monitoring through echocardiography, at least in the first 2 years, is essential to detect pulmonary hypertension associated with chronic pulmonary thromboembolism.

Short-term clinical outcome after acute symptomatic pulmonary embolism.

Though studies have identified clinical variables that predict adverse events in patients with acute pulmonary embolism (PE), they have typically not differentiated short-term from long-term predictors. This multicenter prospective cohort study included consecutive outpatients with objectively confirmed symptomatic acute PE. We analyzed the incidence and time course of death, venous thromboembolism (VTE) recurrence, and major bleeding, and we compared event rates during short-term (first week) and long-term (3 months) follow-up after the diagnosis of PE. We also assessed risk factors for short-term mortality. During the first three months after diagnosis of PE, 142 of 1,338 (10.6%) patients died. Thirty-six deaths (2.7%) occurred during the first week after diagnosis of PE, and 61.1% of these were due to PE. Thirty-eight patients (2.8%) had recurrent VTE during the three-month follow-up, though none of the recurrences occurred during the first week after diagnosis of PE. During the three-month follow-up, major bleeding occurred in 48 patients (3.6%). Twenty-one (1.6%) major bleeds occurred during the first week of follow-up, and nine of these were fatal. Short-term mortality was significantly increased in patients who initially presented with systolic arterial hypotension (odds ratio [OR] 3.35; 95% CI, 1.51-5.41) or immobilization due to a medical illness (OR 2.89; 95% confidence interval [CI], 1.31-6.39). In conclusion, during the first week after the diagnosis of PE, death and major bleeding occur more frequently than recurrent VTE. Patients with systolic arterial hypotension and immobilization at the time of PE diagnosis had an increased risk of short-term mortality.

Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry.

BACKGROUND: Clinical predictors for fatal pulmonary embolism (PE) in patients with venous thromboembolism have never been studied. METHODS AND RESULTS: Using data from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry about patients with objectively confirmed symptomatic acute venous thromboembolism, we determined independent predictive factors for fatal PE. Between March 2001 and July 2006, 15 520 consecutive patients (mean age+/-SD, 66.3+/-16.9 years; 49.7% men) with acute venous thromboembolism were included. Symptomatic deep-vein thrombosis without symptomatic PE was observed in 58.0% (n=9008) of patients, symptomatic nonmassive PE in 40.4% (n=6264), and symptomatic massive PE in 1.6% (n=248). At 3 months, the cumulative rates of overall mortality and fatal PE were 8.65% and 1.68%, respectively. On multivariable analysis, patients with symptomatic nonmassive PE at presentation exhibited a 5.42-fold higher risk of fatal PE compared with patients with deep-vein thrombosis without symptomatic PE (P<0.001). The risk of fatal PE was multiplied by 17.5 in patients presenting with a symptomatic massive PE. Other clinical factors independently associated with an increased risk of fatal PE were immobilization for neurological disease, age >75 years, and cancer. CONCLUSIONS: PE remains a potentially fatal disease. The clinical predictors identified in the present study should be included in any clinical risk stratification scheme to optimally adapt the treatment of PE to the risk of the fatal outcome.

[A clinical prediction rule for identifying short-term risk of adverse events in patients with pulmonary thromboembolism]. / Escala de riesgo de eventos adversos a corto plazo en pacientes con tromboembolia pulmonar.

OBJECTIVE: To identify patients with a low short-term risk of complications following acute pulmonary thromboembolism. PATIENTS AND METHODS: A prospective multicenter study was conducted in 8 Spanish hospitals; 681 consecutive outpatients diagnosed with pulmonary thromboembolism were enrolled. Clinically significant variables were weighted using coefficients derived from a logistic regression model in order to optimize the diagnostic performance of a clinical prediction rule to predict the following complications within 10 days of acute pulmonary thromboembolism: death, recurrent thromboembolism, and major or minor bleeding. RESULTS: Forty-three patients (6.3%) had 51 complications. These included 33 deaths, 12 major bleeding episodes, and 6 minor bleeding episodes. The clinical variables used in the prediction rule were assigned the following scores: recent major bleeding episode and cancer with metastasis, 4 points each; creatinine levels of over 2 mg/dL, 3 points; cancer without metastasis and immobility due to a recent medical condition, 2 points each; and absence of surgery in the past 2 months and an age of over 60 years, 1 point each. A risk score of 2 or less, obtained by 47.8% of patients, indicated a low short-term risk of developing complications following pulmonary thromboembolism. The area under the receiver operating characteristic curve for the prediction rule was 0.75 (95% confidence interval [CI], 0.67-0.83). For this cutoff point, sensitivity was 82.9% (95% CI, 68.7-91.5) and the likelihood ratios for a positive and negative test result were 1.63 (95% CI, 1.39-1.92), and 0.35 (95% CI, 0.18-0.69), respectively. CONCLUSIONS: Our clinical prediction rule could be useful for identifying patients with a low risk of complications in the 10 days following acute pulmonary thromboembolism. Those patients would be eligible for consideration for outpatient treatment.

Prognostic models for selecting patients with acute pulmonary embolism for initial outpatient therapy.

OBJECTIVE: To assess the performance of two prognostic models in predicting short-term mortality in patients with pulmonary embolism (PE). SUBJECTS AND METHODS: We compared the test characteristics of two prognostic models for predicting 30-day outcomes (mortality, thromboembolic recurrences, and major bleeding) in a cohort of 599 patients with objectively confirmed PE. Patients were stratified into the PE severity index (PESI) risk classes I-V and the Geneva low-risk and high-risk strata. We compared the discriminatory power of both prognostic models. RESULTS: The PESI classified fewer patients as low risk (strata I and II) [36%; 216 of 599 patients; 95% confidence interval (CI), 32 to 40%] compared to the Geneva prediction rule (84%; 502 of 599 patients; 95% CI, 81 to 87%) [p < 0.0001]. Using either prediction rule, the low-risk groups showed statistically relevant 30-day mortality difference (PESI, 0.9%; 95% CI, 0.3 to 2.2; vs Geneva, 5.6%; 95% CI, 3.6 to 7.6) [p < 0.0001], although nonfatal recurrent venous thromboembolism or major bleeding rates were statistically similar (PESI, 2.8%; 95% CI, 0.6 to 5.0%; vs Geneva, 4.2%; 95% CI, 2.4 to 5.9%). The area under the receiver operating characteristic curve was higher for the PESI (0.76; 95% CI, 0.69 to 0.83) than for the Geneva score (0.61; 95% CI, 0.51 to 0.71) [p = 0.002]. CONCLUSIONS: The PESI quantified the prognosis of patients with PE better than the Geneva score. This study demonstrated that PESI can select patients with very low adverse event rates during the initial days of acute PE therapy and assist in selecting patients for treatment in the outpatient setting.

Clinical syndromes and clinical outcome in patients with pulmonary embolism: findings from the RIETE registry.

INTRODUCTION: The influence of the clinical syndromes of pulmonary embolism (PE) on clinical outcome has not been evaluated. PATIENTS AND METHODS: The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) is an ongoing registry of consecutive patients with acute venous thromboembolism. In this study, all enrolled patients with acute PE without preexisting cardiac or pulmonary disease were classified into three clinical syndromes: pulmonary infarction, isolated dyspnea, or circulatory collapse. Their clinical characteristics, laboratory findings, and 3-month outcomes were compared. RESULTS: As of January 2005, 4,145 patients with acute, symptomatic, objectively confirmed PE have been enrolled in RIETE. Of them, 3,391 patients (82%) had no chronic lung disease or heart failure: 1,709 patients (50%) had pulmonary infarction, 1,083 patients (32%) had isolated dyspnea, and 599 patients (18%) had circulatory collapse. Overall, 149 patients (4.4%) died during the first 15 days of therapy: 2.5% with pulmonary infarction, 6.2% with isolated dyspnea (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7 to 3.8), and 6.5% with circulatory collapse (OR, 2.7; 95% CI, 1.7 to 4.2). From days 16 to 90, 31 patients had recurrent PE; 5 of 14 patients (36%) with pulmonary infarction died of their new PE, compared with 5 of 10 patients (50%) with isolated dyspnea, and all 7 patients (100%) with circulatory collapse. CONCLUSIONS: PE patients with pulmonary infarction (50% of the whole series) had a significantly lower mortality rate both during initial therapy and after discharge.

[Early complications in patients with pulmonary embolism]. / Complicaciones precoces en pacientes con embolia de pulmón.

BACKGROUND AND OBJECTIVE: Mortality, recurrences and hemorrhages are the most serious early complications of pulmonary embolism (PE). We intended to ascertain the frequency and mechanisms of complications within the first 10 days after PE was diagnosed. PATIENTS AND METHOD: We included patients suspected of suffering PE between December 2003 and August 2004 from 8 hospitals. We performed a multicenter observational prospective study of 8 Spanish hospitals with consecutive outpatients diagnosed with PE. Database of clinical variables: computerized Registry of Patients with Venous Thromboembolism (RIETE). Statistic analysis included chi2 and Student's t test to compare the 2 groups of patients (with and without complications). RESULTS: Six hundred eighty one patients were included, 336 men and 345 women (mean age 66 and 70, respectively). During the first 10 days, 33 (4.8%) of them died, and 22 (3.2%) had an hemorrhage yet no recurrences appeared. Previous immobilization and the presence of respiratory failure, cancer or renal failure were significantly associated with early complications while previous surgery and thoracic pain were not associated with those. CONCLUSIONS: Early complications and some of the associated factors were in agreement with published data. Other situations such as previous surgery or thoracic pain appeared to be protective factors.