Marc Philip Righini

Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial

BACKGROUND Although practice guidelines recommend outpatient care for selected, haemodynamically stable patients with pulmonary embolism, most treatment is presently inpatient based. We aimed to assess non-inferiority of outpatient care compared with inpatient care. METHODS We undertook an open-label, randomised non-inferiority trial at 19 emergency departments in Switzerland, France, Belgium, and the USA. We randomly assigned patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity index risk classes I or II) with a computer-generated randomisation sequence (blocks of 2-4) in a 1:1 ratio to initial outpatient (ie, discharged from hospital ≤24 h after randomisation) or inpatient treatment with subcutaneous enoxaparin (≥5 days) followed by oral anticoagulation (≥90 days). The primary outcome was symptomatic, recurrent venous thromboembolism within 90 days; safety outcomes included major bleeding within 14 or 90 days and mortality within 90 days. We used a non-inferiority margin of 4% for a difference between inpatient and outpatient groups. We included all enrolled patients in the primary analysis, excluding those lost to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00425542. FINDINGS Between February, 2007, and June, 2010, we enrolled 344 eligible patients. In the primary analysis, one (0·6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2·7%; p=0·011). Only one (0·6%) patient in each treatment group died within 90 days (95% UCL 2·1%; p=0·005), and two (1·2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3·6%; p=0·031). By 90 days, three (1·8%) outpatients but no inpatients had developed major bleeding (95% UCL 4·5%; p=0·086). Mean length of stay was 0·5 days (SD 1·0) for outpatients and 3·9 days (SD 3·1) for inpatients. INTERPRETATION In selected low-risk patients with pulmonary embolism, outpatient care can safely and effectively be used in place of inpatient care. FUNDING Swiss National Science Foundation, Programme Hospitalier de Recherche Clinique, and the US National Heart, Lung, and Blood Institute. Sanofi-Aventis provided free drug supply in the participating European centres.

Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial

BACKGROUND Multislice CT (MSCT) combined with D-dimer measurement can safely exclude pulmonary embolism in patients with a low or intermediate clinical probability of this disease. We compared this combination with a strategy in which both a negative venous ultrasonography of the leg and MSCT were needed to exclude pulmonary embolism. METHODS We included 1819 consecutive outpatients with clinically suspected pulmonary embolism in a multicentre non-inferiority randomised controlled trial comparing two strategies: clinical probability assessment and either D-dimer measurement and MSCT (DD-CT strategy [n=903]) or D-dimer measurement, venous compression ultrasonography of the leg, and MSCT (DD-US-CT strategy [n=916]). Randomisation was by computer-generated blocks with stratification according to centre. Patients with a high clinical probability according to the revised Geneva score and a negative work-up for pulmonary embolism were further investigated in both groups. The primary outcome was the 3-month thromboembolic risk in patients who were left untreated on the basis of the exclusion of pulmonary embolism by diagnostic strategy. Clinicians assessing outcome were blinded to group assignment. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00117169. FINDINGS The prevalence of pulmonary embolism was 20.6% in both groups (189 cases in DD-US-CT group and 186 in DD-CT group). We analysed 855 patients in the DD-US-CT group and 838 in the DD-CT group per protocol. The 3-month thromboembolic risk was 0.3% (95% CI 0.1-1.1) in the DD-US-CT group and 0.3% (0.1-1.2) in the DD-CT group (difference 0.0% [-0.9 to 0.8]). In the DD-US-CT group, ultrasonography showed a deep-venous thrombosis in 53 (9% [7-12]) of 574 patients, and thus MSCT was not undertaken. INTERPRETATION The strategy combining D-dimer and MSCT is as safe as the strategy using D-dimer followed by venous compression ultrasonography of the leg and MSCT for exclusion of pulmonary embolism. An ultrasound could be of use in patients with a contraindication to CT.

Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.

IMPORTANCE D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01134068.

Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies

Summary.  Background: Multiple‐detectors computed tomographic pulmonary angiography (CTPA) has a higher sensitivity for pulmonary embolism (PE) within the subsegmental pulmonary arteries as compared with single‐detector CTPA. Multiple‐detectors CTPA might increase the rate of subsegmental PE diagnosis. The clinical significance of subsegmental PE is unknown. We sought to summarize the proportion of subsegmental PE diagnosed with single‐ and multiple‐detectors CTPA and assess the safety of diagnostic strategies based on single‐ or multiple‐detectors CTPA to exclude PE. Patients and methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE and the Cochrane Register of Controlled Trials. We selected 22 articles (20 prospective cohort studies and two randomized controlled trials) that included patients with suspected PE who underwent a CTPA and reported the rate of subsegmental PE. Two reviewers independently extracted data onto standardized forms. Results: The rate of subsegmental PE diagnosis was 4.7% [95% confidence interval (CI): 2.5–7.6] and 9.4 (95% CI: 5.5–14.2) in patients that underwent a single‐ and multiple‐detectors CTPA, respectively. The 3‐month thromboembolic risks in patients with suspected PE and who were left untreated based on a diagnostic algorithm including a negative CTPA was 0.9% (95% CI: 0.4–1.4) and 1.1% (95% CI: 0.7–1.4) for single‐ and multiple‐detectors CTPA, respectively. Conclusion: Multiple‐detectors CTPA seems to increase the proportion of patients diagnosed with subsegmental PE without lowering the 3‐month risk of thromboembolism suggesting that subsegmental PE may not be clinically relevant.

D-Dimer for venous thromboembolism diagnosis: 20 years later

Summary.  Twenty years after its first use in the diagnostic workup of suspected venous thromboembolism (VTE), fibrin D‐dimer (DD) testing has gained wide acceptance for ruling out this disease. The test is particularly useful in the outpatient population referred to the emergency department because of suspected deep vein thrombosis (DVT) or pulmonary embolism (PE), in which the ruling out capacity concerns every third patient clinically suspected of having the disease. This usefulness is based on the high sensitivity of the test to the presence of VTE, at least for some assays. Due to its poor specificity precluding its use for ruling in VTE, DD testing must be integrated in comprehensive, sequential diagnostic strategies that include clinical probability assessment and imaging techniques such as lower limb venous compression ultrasonography for suspected DVT or multi‐slice helical computed tomography for suspected PE. The present narrative review updates the data available on the use of the various commercially available DD assays in the diagnostic approach of clinically suspected VTE in distinct patient populations or situations, including outpatients and inpatients, patients with cancer, older age, pregnancy, a suspected recurrent event, limited thrombus burden, and patients already on anticoagulant treatment.

Effects of age on the performance of common diagnostic tests for pulmonary embolism

PURPOSE The diagnosis of pulmonary embolism in the elderly is often difficult because of comorbid medical conditions, and perhaps also because diagnostic tests have a lower yield. We analyzed the diagnostic performance of common diagnostic tests for pulmonary embolism in different age groups. METHODS We analyzed data from two large studies that enrolled 1,029 consecutive patients presenting to the emergency department with clinically suspected pulmonary embolism. The clinical probability of pulmonary embolism (high [>/=80%], intermediate, or low [</=20%]) was estimated by the treating physician. All patients underwent a sequential diagnostic protocol, including ventilation-perfusion lung scan, measurement of plasma D-dimer level, lower limb venous compression ultrasonography, and pulmonary angiography if the noninvasive work-up was inconclusive. RESULTS The prevalence of pulmonary embolism increased progressively, from 12% in patients <40 years of age to 44% in those >/=80 years of age. The positive predictive value of a high clinical probability of pulmonary embolism was greater in the elderly (71% to 78% in those >/=60 years old versus 40% to 64% in those </=59 years old). The sensitivity of D-dimer testing was 100% in all age groups, but its specificity decreased markedly with age, from 67% in those </=40 years old to 10% in those >/=80 years old. The diagnostic yield of lower limb compression ultrasonography was greater in the elderly. The proportion of lung scans that were diagnostic (normal, near-normal, or high probability) decreased from 68% to 42% with increasing age. CONCLUSIONS Age affects the performance of common diagnostic tests for pulmonary embolism and should be kept in mind when evaluating patients suspected of having this condition.

Prognostic factors for pulmonary embolism: the prep study, a prospective multicenter cohort study.

RATIONALE The short-term prognosis of pulmonary embolism (PE) depends on hemodynamic status and underlying disease. The prognostic value of right ventricular dysfunction and injury is less well established. OBJECTIVES To evaluate prognostic factors of PE in a multicenter prospective cohort study. METHODS Echocardiography, brain natriuretic peptide (BNP), N-terminal-proBNP and cardiac troponin I measurements were done on admission of 570 consecutive patients with an acute PE. A predictive model was based on independent predictors of 30-day adverse events defined as death, secondary cardiogenic shock, or recurrent venous thromboembolism. MEASUREMENTS AND MAIN RESULTS At 30 days, 42 patients (7.4%; 95% confidence interval [CI], 5.5-9.8%) had adverse events. On multivariate analysis, altered mental state (odds ratio [OR] 6.8; 95% confidence interval [CI], 2.0-23.3), shock on admission (OR 2.8; 95% CI, 1.1-7.5), cancer (OR 2.9; 95% CI, 1.2-6.9), BNP (OR 1.3 for an increase of 250 ng/L; 95% CI, 1.1-1.6) and right to left ventricle diameter ratio (OR 1.2 for an increase of 0.1; 95% CI, 1.1-1.4) were associated with 30-days of adverse events. The predictive performance of the model was good (area under receiver operating characteristics curve 0.84 [95% CI, 0.78-0.90]), making it possible to develop a bedside prognostic score. CONCLUSIONS BNP and echocardiography may be useful determinants of the short-term outcome for patients with PE, together with clinical findings. Patients with PE can be stratified according to the initial risk of adverse outcome, using a simple score based on clinical, echocardiographic, and biochemical variables.

Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.

Objectives In older patients, the the D-dimer test for pulmonary embolism has reduced specificity and is therefore less useful. In this study a new, age dependent cut-off value for the test was devised and its usefulness with older patients assessed. Design Retrospective multicentre cohort study. Setting General and teaching hospitals in Belgium, France, the Netherlands, and Switzerland. Patients 5132 consecutive patients with clinically suspected pulmonary embolism. Intervention Development of a new D-dimer cut-off point in patients aged >50 years in a derivation set (data from two multicentre cohort studies), based on receiver operating characteristics (ROC) curves. This cut-off value was then validated with two independent validation datasets. Main outcome measures The proportion of patients in the validation cohorts with a negative D-dimer test, the proportion in whom pulmonary embolism could be excluded, and the false negative rates. Results The new D-dimer cut-off value was defined as (patient’s age×10) μg/l in patients aged >50. In 1331 patients in the derivation set with an “unlikely” score from clinical probability assessment, pulmonary embolism could be excluded in 42% with the new cut-off value versus 36% with the old cut-off value (<500 μg/l). In the two validation sets, the increase in the proportion of patients with a D-dimer below the new cut-off value compared with the old value was 5% and 6%. This absolute increase was largest among patients aged >70 years, ranging from 13% to 16% in the three datasets. The failure rates (all ages) were 0.2% (95% CI 0% to 1.0%) in the derivation set and 0.6% (0.3% to 1.3%) and 0.3% (0.1% to 1.1%) in the two validation sets. Conclusions The age adjusted D-dimer cut-off point, combined with clinical probability, greatly increased the proportion of older patients in whom pulmonary embolism could be safely excluded.

Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism

Practice guidelines recommend outpatient care for selected patients with non-massive pulmonary embolism (PE), but fail to specify how these low-risk patients should be identified. Using data from U.S. patients, we previously derived the Pulmonary Embolism Severity Index (PESI), a prediction rule that risk stratifies patients with PE. We sought to validate the PESI in a European patient cohort. We prospectively validated the PESI in patients with PE diagnosed at six emergency departments in three European countries. We used baseline data for the rules 11 prognostic variables to stratify patients into five risk classes (I-V) of increasing probability of mortality. The outcome was overall mortality at 90 days after presentation. To assess the accuracy of the PESI to predict mortality, we estimated the sensitivity, specificity, and predictive values for low- (risk classes I/II) versus higher-risk patients (risk classes III-V), and the discriminatory power using the area under the receiver operating characteristic (ROC) curve. Among 357 patients with PE, overall mortality was 5.9%, ranging from 0% in class I to 17.9% in class V. The 186 (52%) low-risk patients had an overall mortality of 1.1% (95% confidence interval [CI]: 0.1-3.8%) compared to 11.1% (95% CI: 6.8-16.8%) in the 171 (48%) higher-risk patients. The PESI had a high sensitivity (91%, 95% CI: 71-97%) and a negative predictive value (99%, 95% CI: 96-100%) for predicting mortality. The area under the ROC curve was 0.78 (95% CI: 0.70-0.86). The PESI reliably identifies patients with PE who are at low risk of death and who are potential candidates for outpatient care. The PESI may help physicians make more rational decisions about hospitalization for patients with PE.

Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.

Summary.  Background: Pretest probability assessment is necessary to identify patients in whom pulmonary embolism (PE) can be safely ruled out by a negative D‐dimer without further investigations. Objective: Review and compare the performance of available clinical prediction rules (CPRs) for PE probability assessment. Patients/methods: We identified studies that evaluated a CPR in patients with suspected PE from Embase, Medline and the Cochrane database. We determined the 95% confidence intervals (CIs) of prevalence of PE in the various clinical probability categories of each CPR. Statistical heterogeneity was tested. Results: We identified 9 CPR and included 29 studies representing 31215 patients. Pooled prevalence of PE for three‐level scores (low, intermediate or high clinical probability) was: low, 6% (95% CI, 4–8), intermediate, 23% (95% CI, 18–28) and high, 49% (95% CI, 43–56) for the Wells score; low, 13% (95% CI, 8–19), intermediate, 35% (95% CI, 31–38) and high, 71% (95% CI, 50–89) for the Geneva score; low, 9% (95% CI, 8–11), intermediate, 26% (95% CI, 24–28) and high, 76% (95% CI, 69–82) for the revised Geneva score. Pooled prevalence for two‐level scores (PE likely or PE unlikely) was 8% (95% CI,6–11) and 34% (95% CI,29–40) for the Wells score, and 6% (95% CI, 3–9) and 23% (95% CI, 11–36) for the Charlotte rule. Conclusion: Available CPR for assessing clinical probability of PE show similar accuracy. Existing scores are, however, not equivalent and the choice among various prediction rules and classification schemes (three‐ versus two‐level) must be guided by local prevalence of PE, type of patients considered (outpatients or inpatients) and type of D‐dimer assay applied.