Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: A meta-analysis

Introduction

The Wells clinical decision rule (CDR) and D-dimer tests can be used to exclude pulmonary embolism (PE). We performed a meta-analysis to determine the negative predictive value (NPV) of an “unlikely” CDR (≤ 4 points) combined with a normal D-dimer test and the safety of withholding anti-coagulants based on these criteria.

Methods

Prospective studies that withheld anti-coagulant treatment from patients with clinically suspected PE and an “unlikely” CDR in combination with a normal D-dimer concentration without performing further tests were searched for in Medline, Cochrane and Embase. Primary endpoints were the recurrence rate of venous thromboembolism (VTE) and PE-related mortality during 3-months follow-up.

Results

Four studies including 1660 consecutive patients were identified. The pooled incidence of VTE after initial exclusion of acute PE based on an “unlikely” CDR and normal D-dimer was 0.34% (95%CI 0.036-0.96%), resulting in a NPV of 99.7% (95%CI: 99.0-99.9%, random effects-model). The risk for PE related mortality was very low: 1/1660 patients had fatal PE (0.06%, 95%CI 0.0017-0.46%).

Conclusion

Acute PE can be safely excluded in patients with clinically suspected acute PE who have an “unlikely” probability and a negative D-dimer test and anticoagulant treatment can be withheld. There is no need for additional radiological tests in these patients to rule out PE.     

Management of suspected pulmonary embolism patients with low clinical and low V/Q probability

OBJECTIVE: To assess whether guidelines for the management of suspected PE, recommending that ventilation/perfusion (V/Q) scintigraphy should be followed by other imaging in case of non-diagnostic result, and interpreted along with the clinical probability, are applied in daily practice. DESIGN: Two-year audit study SETTING: Tertiary hospital in France. PARTICIPANTS: All patients referred to the nuclear medicine department for a suspected pulmonary embolism (PE), with a low clinical probability, a positive D-Dimer test, and a low V/Q scintigraphy. INTERVENTION: We reviewed medical records to collect data on further diagnostic strategy and therapeutic management. MAIN OUTCOME MEASURE: Thromboembolic risk during a three-month follow up in patients who did not undergo anticoagulation therapy on the basis of a negative diagnostic work up. RESULTS: Of the 456 selected patients, PE was excluded on the basis of a low pretest probability and a low V/Q scintigraphy probability without further testing in 184 (group 1). In the other 272 patients (group 2), 4 venous thromboembolism (VTE) events were diagnosed by leg vein ultrasonography and/or computed tomography pulmonary angiography. In patients who did not receive anticoagulant treatment during follow up, one patient from group 1 (0.6%, 95% confidence interval 0.1 to 3.3) and two patients from group 2 (0.9%, 95% CI 0.2 to 3.2) had an acute venous thromboembolic event. CONCLUSION: Different attitudes are adopted by physicians in patients with a low clinical probability and a low V/Q scintigraphy probability, without impact on safety, as assessed by a non-significant difference in the three-month thromboembolic risks between these two groups.     

D-dimer level is associated with the extent of pulmonary embolism

OBJECTIVES: Our aim was to study the association between the level of D-dimer and the severity of pulmonary embolism (PE) as determined by various biochemical and radiological prognostic markers in order to investigate the potential value of D-dimer as a prognostic marker for the severity of PE. PATIENTS AND METHODS: PE was diagnosed in 100 consecutive out-patients by multi-detector computerized tomography. One patient was excluded and the final cohort consisted of 99 patients. Pulmonary Artery Obstruction Index (PAOI) and Right Ventricular/Left Ventricular (RV/LV) ratio were assessed. RESULTS: The median value for D-dimer was 5.0 mg/L (inter-quartile range: 1.8, 12.2). There was a significant association between log D-dimer, and between log RV/LV (r=0.45), log PAOI (r=0.5), and PaO(2) (r=0.40). The multivariate analysis showed an increased association between log D-dimer and between log RV/LV ratio (r=0.54) and log PAOI (r=0.52) after adjusting for age, gender and for the duration of symptoms. Significant association was found between the level of D-dimer and the most proximal level of PE (p<0.0005). There was a significant dose-response relationship between the level D-dimer and between Troponin-T and the frequency of thrombolysis (p<0.0005). In the subgroup of patients with D-Dimer over the upper quartile (>12.2), 12 (67%) patients had elevated Troponin-T and 8 (32%) patients received thrombolysis, compared to 1 (5%) patient with elevated Troponin-T and none treated with thrombolysis in the subgroup of patients with D-dimer相似文献   

Effect of patient location on the performance of clinical models to predict pulmonary embolism

INTRODUCTION: Current clinical likelihood models for predicting pulmonary embolism (PE) are used to categorize outpatients into low, intermediate and high clinical pre-test likelihood of PE. Since these clinical prediction rules were developed using outpatients it is not known if they can be applied universally to both inpatients and outpatients with suspected PE. Thus, the purpose of this study was to determine the effect of patient location on the performance of clinical models to predict PE. MATERIALS AND METHODS: Two clinical models (Wells and Wicki) were applied to data from the multi-centered PIOPED study. The Wells score was applied to 1359 patients and the Wicki score was applied to 998 patients. 361 patients (27%) from the PIOPED study did not have arterial gas measurement and were excluded from the Wicki score patient group. Patients were stratified by their location at the time of entry into the PIOPED study as follows: outpatient/emergency, surgical ward, medicine/coronary care unit or intensive care unit. The diagnostic performance of the two clinical models was applied to the various patient locations and the performance was evaluated using the area under a fitted receiver operating characteristic curve (AUC). RESULTS: The prevalence of PE in the three clinical probability categories were similar for the two scoring methods. Both clinical models yielded the lowest diagnostic performance in patients referred from surgical wards. The AUC for both clinical prediction rules decreased significantly when applied to inpatients in comparison to outpatients. CONCLUSIONS: Current clinical prediction rules for determining the pre-test likelihood of PE yielded different diagnostic performances depending upon patient location. The performance of the clinical prediction rules decreased significantly when applied to inpatients. In particular, the rules performed least well when applied to patients referred from surgical wards suggesting these rules should not be used in this patient group. As expected the clinical prediction rules performed best in outpatients with the optimum diagnostic performance in patients referred from emergency and outpatient wards.     

Validation of a new D-dimer microparticle enzyme immunoassay (AxSYM D-Dimer) in patients with suspected pulmonary embolism (PE)

OBJECTIVES: The aim of the study was to evaluate a new automated assay for D-dimer testing (AxSYM D-Dimer) based on microparticle enzyme-immunoassay technology by comparing it with three well established D-dimer assays. PATIENTS AND METHODS: The performance of the new assay was evaluated in 280 plasma samples that were collected prospectively from out-patients included in a management study evaluating a decision based algorithm. RESULTS: 58/280 patients (21%) had PE diagnosed by CT. Median values of AxSYM D-dimer in patients with PE were 3689 ng/mL (range 775-9000). Comparison analysis displayed excellent agreement with VIDAS (kappa=0.84) and Asserachrom (kappa=0.81) D-dimer assays. A strong correlation was found between AxSYM and the VIDAS (r=0.96) and Asserachrom (r=0.89) D-dimer assays. The highest cut-off value for AxSYM that yielded a sensitivity of 100% was 765 ng/mL with a specificity of 50%. At the cut-off level <500 ng/mL, the sensitivity and specificity of AxSYM D-dimer were 100% and 34%; VIDAS 100% and 42%; Asserachrom 100% and 40%; and STALiatest 100% and 37%, respectively. AxSYM D-dimer was negative in 75 patients (33.8%). None of these had PE at the initial work-up or VTE during the 3-month follow-up. CONCLUSIONS: AxSYM D-dimer seems to be safe and effective in ruling out PE in out-patients. The cut-off level can be set at 500 to 750 ng/mL, at which the assay displays a performance that is comparable to that of the ELISA based assays. However, further studies are needed to confirm the safety of the assay and to determine the most optimal cut-off level in patients with venous thromboembolism.     

Diagnostic value of D-dimer in patients with suspected pulmonary embolism: results from a multicentre outcome study

BACKGROUND: D-dimer tests are used in various diagnostic strategies to exclude pulmonary embolism (PE). However, their role as an exclusionary first-line test is still uncertain, mainly because accuracy of the test varies according to the assay and the studied population. METHODS: The aim of this multicentre study was to evaluate the accuracy of D-dimer testing in patients with suspected PE. Diagnosis of PE was based on pre-test clinical probability (PCP) evaluation and both single-detector spiral CT (CT) and lower limbs compression ultrasonography (CUS). Lung scanning and/or pulmonary angiography was mandatory when CT or CUS was inconclusive and when both CT and CUS were normal in a patient with a high PCP. All patients were followed-up for 3 months, looking for VTE recurrence. D-dimers were collected within 24 h of inclusion and stored in each local hematology unit, to be analyzed at the end of all inclusions; physicians in charge of the patient were blinded to D-dimer results. RESULTS: Three hundred and fifty two patients were included in 4 centres. Prevalence of PE was 38.6%. PCP was low in 82 (23.3%), intermediate in 176 (50%) and high in 94 (26.7%) patients. Sensitivity of D-dimer was 96.3% (95% CI: 93-99) and negative predictive value reached 94.4% (95% CI: 90-99). Five patients with a confirmed PE had a D-dimer level below 500 ng/ml (two patients with a high PCP). Among 258 patients with low or intermediate PCP, 80 (31%) had a negative D-dimer test result; three of them had a false negative result and the number needed to test was 3.3. Among 94 patients with a high PCP, 9 had a negative D-dimer test result; two of them had a false negative result and the number needed to test was 13.5. CONCLUSION: These results confirm that rapid assays used in this study can safely exclude PE in first-line testing only in non-high CP patients.     

Elevated D-dimer concentration identifies patients with incomplete recanalization of pulmonary artery thromboemboli despite 6 months anticoagulation after the first episode of acute pulmonary embolism

BACKGROUND: Despite long-term anticoagulation in some patients after acute pulmonary embolism (APE) pulmonary thrombi are not completely resolved. We hypothesized that elevated D-dimer concentration reflecting increased endogenous fibrinolysis may indicate incomplete pulmonary thrombi resolution after the first episode of PE. METHODS: 55 patients aged 54.7+/-18.6 years were anticoagulated for 6 months with acenocumarol (74.5% patients) or low molecular weight heparin (25.5% patients) when control spiral computed tomography (sCT), lung perfusion scintigraphy and D-dimer assessment were performed. RESULTS: Incomplete recanalization of pulmonary circulation was found in 39 (70.9%) patients - thrombi at sCT and/or > or =1 wedge-shaped perfusion defect at scintigraphy. Age, sex, rate of unprovoked APE, malignancies, thrombolysis in the acute phase and type of long-term anticoagulation were similar in patients without and with complete recanalization. D-dimer at follow-up but not on admission was higher in patients with then without incomplete recanalization (median 340 (80-2280) vs 160 (60-390) ng/mL, p=0.02). All 11 (20%) patients with D-dimer level >500 ng/mL at follow-up did not resolve thromboemboli completely. ROC analysis showed that D-dimer at follow-up identified patients with incomplete recanalization (AUC 0.709, 95% CI (0.560-0.831), p=0.007). Multivariable analysis confirmed that D-dimer >350 ng/mL at follow-up and right ventricle dysfunction at the diagnosis were independent predictors of incomplete recanalization (OR 18.58 (95% CI 1.97-175.19) and 7.03 (95% CI 1.43-34.6), respectively, p=0.0006). CONCLUSION: Elevated D-dimer after 6 months anticoagulation and right ventricular dysfunction at the diagnosis predict incomplete recanalization of pulmonary circulation after first episode of APE.     

Comparison of the clinical usefulness of two quantitative D-Dimer tests in patients with a low clinical probability of pulmonary embolism

Background

Quantitative D-Dimer tests are established methods in the non-invasive diagnostic management to rule out venous thromboembolism (VTE). The diagnostic performance and the clinical efficiency different D-Dimer assays in the exclusion of pulmonary embolism (PE) have not yet been compared in a clinical outcome study.

Objective

Evaluation of the efficiency and safety of excluding the diagnosis of PE with two different quantitative D-Dimer assays in consecutive patients with clinically suspected PE.

Patients and Methods

We studied the VTE-failure rate of 2206 consecutive patients with an unlikely clinical probability in whom VIDAS or Tinaquant D-Dimer tests were performed.

Results

The prevalence of PE in 1238 patients whose D-Dimer level was analyzed with Tinaquant assay was 11%. The VIDAS assay group consisted of 968 patients with a PE prevalence of 13%. The VIDAS assay had a sensitivity of 99.2% (95%CI; 96- > 99.9%), the Tinaquant assay of 97.3% (95%CI; 93 -99%). The negative predictive value (NPV) in the Tinaquant assay group was 99.4% (95%CI 98-99.8%) in comparison to 99.7% (95%CI 99-> 99.9%) in the VIDAS assay group. During 3 month of follow-up, there were no fatal cases of PE among patients with normal D-Dimer and unlikely clinical probability in both D-Dimer assay groups. In addition, the test efficiency of Tinaquant assay was significantly higher in comparison to VIDAS assay (52% vs 42%, p < 0.001).

Conclusion

Both Tinaquant and VIDAS D-Dimer tests perform equally well in combination with an unlikely clinical probability in excluding PE. The Tinaquant test was shown to be more efficient.     

Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer

We have previously demonstrated that a clinical model can be safely used in a management strategy in patients with suspected pulmonary embolism (PE). We sought to simplify the clinical model and determine a scoring system, that when combined with D-dimer results, would safely exclude PE without the need for other tests, in a large proportion of patients. We used a randomly selected sample of 80% of the patients that participated in a prospective cohort study of patients with suspected PE to perform a logistic regression analysis on 40 clinical variables to create a simple clinical prediction rule. Cut points on the new rule were determined to create two scoring systems. In the first scoring system patients were classified as having low, moderate and high probability of PE with the proportions being similar to those determined in our original study. The second system was designed to create two categories, PE likely and unlikely. The goal in the latter was that PE unlikely patients with a negative D-dimer result would have PE in less than 2% of cases. The proportion of patients with PE in each category was determined overall and according to a positive or negative SimpliRED D-dimer result. After these determinations we applied the models to the remaining 20% of patients as a validation of the results. The following seven variables and assigned scores (in brackets) were included in the clinical prediction rule: Clinical symptoms of DVT (3.0), no alternative diagnosis (3.0), heart rate >100 (1.5), immobilization or surgery in the previous four weeks (1.5), previous DVT/PE (1.5), hemoptysis (1.0) and malignancy (1.0). Patients were considered low probability if the score was <2.0, moderate of the score was 2.0 to 6.0 and high if the score was over 6.0. Pulmonary embolism unlikely was assigned to patients with scores < or =4.0 and PE likely if the score was >4.0. 7.8% of patients with scores of less than or equal to 4 had PE but if the D-dimer was negative in these patients the rate of PE was only 2.2% (95% CI = 1.0% to 4.0%) in the derivation set and 1.7% in the validation set. Importantly this combination occurred in 46% of our study patients. A score of <2.0 and a negative D-dimer results in a PE rate of 1.5% (95% CI = 0.4% to 3.7%) in the derivation set and 2.7% (95% CI = 0.3% to 9.0%) in the validation set and only occurred in 29% of patients. The combination of a score < or =4.0 by our simple clinical prediction rule and a negative SimpliRED D-Dimer result may safely exclude PE in a large proportion of patients with suspected PE.     

Estimating the pretest probability threshold to justify empiric administration of heparin prior to pulmonary vascular imaging for pulmonary embolism

Expertly interpreted pulmonary vascular imaging (either ventilation-perfusion scan or computed tomography chest angiography) is not uniformly available at most hospitals, including those in the US. When evaluating a patient with suspected pulmonary embolism during times when pulmonary vascular imaging is not available, clinicians frequently face the decision of whether to administer heparin while awaiting availability of imaging. In this report, we analyze published data to quantitate the probability of death or disability from untreated pulmonary embolism versus the probability of serious bleeding for one, two and seven days of heparin therapy. For these three time points, we estimate the pretest probability of pulmonary embolism to justify the empiric administration of heparin.     

Performance of the Pulmonary Embolism Rule-out Criteria (the PERC rule) combined with low clinical probability in high prevalence population

Introduction

PERC rule was created to rule out pulmonary embolism (PE) without further exams, with residual PE risk < 2%. Its safety is currently not confirmed in high PE prevalence populations even when combined with low clinical probability assessed by revised Geneva score (RGS). As PERC rule and RGS are 2 similar explicit rules with many redundant criteria, we hypothesized that the combination of PERC rule with gestalt clinical probability could resolve this limitation.

Methods

We collected prospectively documented clinical gestalt assessments and retrospectively calculated PERC rules and RGS from a prospective study of PE suspected patients. We analyzed performance of combinations of negative PERC with low clinical probability assessed by both methods in high overall PE prevalence population.

Results

Among the final study population (n = 959), the overall PE prevalence was 29.8%. Seventy-four patients (7.7%) were classified as PERC negative and among them, 4 patients (5.4%) had final diagnosis of PE. When negative PERC was combined with low pretest probability assessed by RGS or gestalt assessment, PE prevalence was respectively 6.2% and 0%. This last combination reaches threshold target of 2% and unnecessary exams could easily have been avoided in this subgroup (6%). However, it confidence interval was still wide (0%; CI 0-5).

Conclusions

PERC rule combined with low gestalt probability seems to identify a group of patients for whom PE could easily be ruled out without additional test.A larger study is needed to confirm this result and to ensure safety.     

Obesity and pulmonary embolism: the mounting evidence of risk and the mortality paradox

Purpose

To determine the prevalence of pulmonary embolism in obese patients according to age, gender and comorbid conditions and explore the relation of obesity to mortality.

Methods

The number of patients discharged from short-stay hospitals throughout the United States from 1998–2008 with pulmonary embolism who were obese or not obese, and in-hospital all-cause mortality were determined from the Nationwide Inpatient Sample.

Results

From 1998–2008, 203,500 of 17,979,200 (1.1%) obese patients were diagnosed with pulmonary embolism compared with 2,034,100 of 346,049,800 (0.6%) non-obese patients [relative risk (RR) = 2.03]. Relative risk for pulmonary embolism was highest among obese patients aged 11–20 years (RR = 5.80) and was higher in obese women (RR = 2.08) than in obese men (RR = 1.74). Mortality was 4.3% in obese patients with pulmonary embolism compared with 9.5% in non-obese patients (RR = 0.45). Obesity had the greatest effect on mortality in older patients and little effect in teenagers and young adults. Among stable patients who did not receive thrombolytic therapy, mortality was 3.8% in obese patients and 8.4% in non-obese patients (RR = 0.45). Among unstable patients, obesity had little effect on mortality.

Conclusions

The prevalence of pulmonary embolism in hospitalized patients was higher in obese patients than in non-obese patients. Mortality in patients with pulmonary embolism was lower in obese patients than in non-obese patients, with the greatest effects in women, older patients and stable patients.     

Evaluation of a rapid qualitative immuno-chromatography D-dimer assay (Simplify D-dimer) for the exclusion of pulmonary embolism in symptomatic outpatients with a low and intermediate pretest probability. Comparison with two automated quantitative assays

The performance of a rapid qualitative solid-phase immuno-chromatography-based D-dimer assay (Simplify D-dimer) for diagnosing pulmonary embolism (PE) was evaluated in 469 outpatients with a low or intermediate pretest probability. They were referred to the emergency department of a university hospital during a 4-month period. Test results were compared to those of two automated quantitative assays. Simplify D-dimer assay result was positive in all 47 patients in whom the diagnosis of PE was retained and in 219 of the 422 patients without PE (51.2%), leading to a sensitivity of 100% (95%CI, 92.5 to 100%), a specificity of 48.8% (95%CI, 44.0 to 53.6%) and a negative predictive value (NPV) of 100% (95%CI, 98.2 to 100%). These results compared favorably with those of the Vidas D-dimer New assay [sensitivity = 100% (95%CI, 92.5 to 100), specificity = 49.8% (95%CI, 45.0 to 54.6%) and NPV = 100% (95%CI, 98.3 to 100%)] and the STA^®-Liatest^® D-DI assay [sensitivity = 100% (95%CI, 92.5 to 100%), specificity = 48.1% (95%CI, 43.3 to 52.9%) and NPV = 100% (95%CI, 98.2 to 100%)]. The inter-observer (n = 2) variability was very good with 1.7% discordant readings and a kappa coefficient (K) value = 0.97 (95%CI, 0.93 to 1.00). In conclusion, the Simplify D-dimer assay could be a valuable tool for ruling out PE in out-patients but a specific learning course of those having to work with is required in order to minimize the number of ambiguous reading and to overcome the inter-observer variability.     

Prospective study of the frequency and outcomes of patients with suspected pulmonary embolism administered heparin prior to confirmatory imaging

Objectives

The administration of empiric systemic anticoagulation (ESA) before confirmatory radiographic testing in patients with suspected pulmonary embolism (PE) may improve outcomes, but no data have been published regarding current practice. We describe the use of ESA in a large prospective cohort of emergency department (ED) patients and report the outcomes of those treated with ESA compared with patients not receiving ESA.

Methods

12-center, noninterventional study of ED patients who presented with symptoms concerning for PE. Clinical data including pretest probability and decision to start ESA were recorded at point of care by attending physicians. Patients were followed for adverse in-hospital outcomes and recurrence of venous thromboembolism.

Results

ESA was initiated 342/7932 (4.3%) of enrolled patients, including 142/618 (23%) patients with high pretest probability. Patients receiving ESA had more abnormal vital signs and were more likely to have a history of venous thromboembolism than those who did not receive ESA. Overall, 481/7,932 (6.1%) had PE diagnosed, 72/481 (15.0%) with PE had ESA, and 72/342 (21%) of ESA patients had PE. Three patients (0.9%, 95%CI: 0.2-2.5%) who received ESA suffered hemorrhagic complications compared with 38 patients (0.5%, 95%CI: 0.4-0.7%) who did not receive ESA.

Conclusions

In this multicenter sample, ED physicians administered ESA to a small, generally more acutely ill subset of patients with high pretest probability of PE, and very few had hemorrhagic complications. ESA was not associated with any clear difference in outcomes. More study is needed to clarify the risk versus benefit of ESA.     

Derivation and validation of a multivariate model to predict mortality from pulmonary embolism with cancer: The POMPE-C tool

Background

Clinical guidelines recommend risk stratification of patients with acute pulmonary embolism (PE). Active cancer increases risk of PE and worsens prognosis, but also causes incidental PE that may be discovered during cancer staging. No quantitative decision instrument has been derived specifically for patients with active cancer and PE.

Methods

Classification and regression technique was used to reduce 25 variables prospectively collected from 408 patients with AC and PE. Selected variables were transformed into a logistic regression model, termed POMPE-C, and compared with the pulmonary embolism severity index (PESI) score to predict the outcome variable of death within 30 days. Validation was performed in an independent sample of 182 patients with active cancer and PE.

Results

POMPE-C included eight predictors: body mass, heart rate > 100, respiratory rate, SaO2%, respiratory distress, altered mental status, do not resuscitate status, and unilateral limb swelling. In the derivation set, the area under the ROC curve for POMPE-C was 0.84 (95% CI: 0.82-0.87), significantly greater than PESI (0.68, 0.60-0.76). In the validation sample, POMPE-C had an AUC of 0.86 (0.78-0.93). No patient with POMPE-C estimate ≤ 5% died within 30 days (0/50, 0-7%), whereas 10/13 (77%, 46-95%) with POMPE-C estimate > 50% died within 30 days.

Conclusion

In patients with active cancer and PE, POMPE-C demonstrated good prognostic accuracy for 30 day mortality and better performance than PESI. If validated in a large sample, POMPE-C may provide a quantitative basis to decide treatment options for PE discovered during cancer staging and with advanced cancer.     

A nationwide family study of pulmonary embolism: identification of high risk families with increased risk of hospitalized and fatal pulmonary embolism

Background

Family history is an important risk factor for deep venous thrombosis. However, few studies have determined the importance of family history of pulmonary embolism (PE).

Objective

This nationwide study aimed to determine the familial risks of fatal and hospitalized PE.

Methods

The Swedish Multi-Generation Register for subjects aged 0 to 76 years old born since 1932 were linked to the Hospital Discharge Register and Cause of Death Register for the period 1964-2008. Standardized incidence ratios (SIRs) for first hospitalization or death (without previous hospitalization for PE) with a main diagnosis of PE were calculated for individuals whose parent or siblings were hospitalized with or died from PE, compared to those whose parent or siblings were not affected by PE.

Results

A total of 20,860 individuals were hospitalized for PE and 862 died due to primary fatal PE (without previous hospitalization for PE). The familial SIR for individuals with one sibling with hospitalized PE was 2.49 (95% CI 1.62-3.83). The familial SIR for siblings with two affected probands was 114.29 (95% CI 56.57-223.95). The familial SIRs for individuals with a parent or sibling hospitalized for PE were significantly increased for fatal PE (1.76; 95% CI 1.38-2.21) and hospitalized PE (2.13; 95% CI 2.04-2.23). Spouses had low overall familial risk for PE (1.09; 95% CI, 1.03-1.14).

Conclusion

The high familial risk in multiplex sibling families suggests the existence of strong genetic risk factors for PE. Familial factors and possibly genetic factors are important risk factors for primary fatal pulmonary embolism.     

Comparison of high specificity with standard versions of a quantitative latex D-dimer test in the assessment of community pulmonary embolism: HaemosIL D-dimer HS and Pulmonary Embolism

Background

D-dimer assays are sensitive but have poor specificity. False positive results lead to extra imaging and hospital admissions.

Objectives

To make a pilot comparison of the diagnostic accuracy of the standard quantitative latex HemosIL D-dimer assay with a newer HemosIL D-dimer HS version designed to have improved specificity.

Patients / Methods

Consecutive patients presenting from the community to an Emergency Department that were investigated for suspected pulmonary embolism using a D-dimer test were included in the study. Standard and D-dimer HS tests were performed. Pulmonary Embolism was diagnosed on the basis of imaging studies or post-mortem at any time from presentation to 90 days thereafter.

Results

The prevalence of Pulmonary Embolism was 4.5% (18/402). The sensitivity, specificity, negative predictive value, and positive predictive value for the standard quantitative D-dimer test was 100% (81.5 - 100.0), 49.2% (44.1 - 54.3),100% (98.1 - 100.0), and 8.5% (5.1 - 13.0), respectively, and 100% (81.5 - 100.0), 58.3% (53.2 - 63.3),100% (98.4 - 100.0), and 10.1% (6.1 - 15.5), for the D-dimer HS test. There were 35 (16%) fewer ‘false positives’ using the D-dimer HS assay compared with the standard assay.

Conclusions

D-dimer HS has superior specificity to the standard quantitative D-dimer test without any loss of sensitivity. The generation of fewer false positive results should lead to less unnecessary diagnostic imaging; the use of which is associated with increased hospital admissions and length of stay. The HS assay may therefore have significant health economic benefits.     

Treatment of patients with acute deep vein thrombosis and/or pulmonary embolism: Efficacy and safety of non-VKA oral anticoagulants in selected populations

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), presents a large clinical burden. Prompt, effective and sustained anticoagulation is vital because of the risk of recurrent events, including life-threatening PE, and complications such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. Dual-drug standard therapy is effective; however, parenteral low molecular weight heparin, coupled with routine coagulation monitoring and dose adjustment of vitamin K antagonists (VKAs), presents challenges for patients and healthcare providers. Non-VKA oral anticoagulants provide a simplified option for VTE treatment. Phase III studies have investigated rivaroxaban and apixaban as single-drug approaches, and edoxaban and dabigatran in conjunction with initial heparin therapy. These agents demonstrated non-inferiority to standard therapy, and most showed significant reductions in major bleeding. However, clinical information is limited in patient subgroups, e.g. fragile patients or patients with renal impairment or cancer, who may be at higher risk of bleeding and/or VTE. A prespecified pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies (8281 patients), undertaken to evaluate clinical outcomes with rivaroxaban versus standard therapy, confirmed the non-inferiority of rivaroxaban, with significant reductions in major bleeding and fewer intracranial and retroperitoneal bleeding events. Consistent efficacy and safety were observed with rivaroxaban, irrespective of fragility, cancer or clot severity. The introduction of the non-VKA oral anticoagulants and approval of rivaroxaban in the EU, US and Canada for the treatment and secondary prevention of DVT and PE offer the potential for improvements in effective care across a broad spectrum of patients with VTE.     

Bayesian adaptive non-inferiority with safety assessment: retrospective case study to highlight potential benefits and limitations of the approach

Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design. The objective of this analysis was to demonstrate the potential benefits of Bayesian adaptive designs by shortening the study duration and therefore limiting patient exposure to ineffective placebo or an active comparator with a known side effect. Bayesian methods allowed us to fully leverage historical data along with data observed as the study was ongoing to calculate predictive probabilities of patient response to treatment without experiencing a specified side effect. Using the Bayesian adaptive approach would have required less than half the number of patients as the original study to draw the same conclusion. Sample size was reduced from 311 to 156 patients, thereby decreasing the number of patients exposed to placebo from 54 to 30 and the number exposed to the active control with a known side effect from 126 to 60.