H.M.A. Hofstee

Performance of 4 Clinical Decision Rules in the Diagnostic Management of Acute Pulmonary Embolism: A Prospective Cohort Study

BACKGROUND Several clinical decision rules (CDRs) are available to exclude acute pulmonary embolism (PE), but they have not been directly compared. OBJECTIVE To directly compare the performance of 4 CDRs (Wells rule, revised Geneva score, simplified Wells rule, and simplified revised Geneva score) in combination with d-dimer testing to exclude PE. DESIGN Prospective cohort study. SETTING 7 hospitals in the Netherlands. PATIENTS 807 consecutive patients with suspected acute PE. INTERVENTION The clinical probability of PE was assessed by using a computer program that calculated all CDRs and indicated the next diagnostic step. Results of the CDRs and d-dimer tests guided clinical care. MEASUREMENTS Results of the CDRs were compared with the prevalence of PE identified by computed tomography or venous thromboembolism at 3-month follow-up. RESULTS Prevalence of PE was 23%. The proportion of patients categorized as PE-unlikely ranged from 62% (simplified Wells rule) to 72% (Wells rule). Combined with a normal d-dimer result, the CDRs excluded PE in 22% to 24% of patients. The total failure rates of the CDR and d-dimer combinations were similar (1 failure, 0.5% to 0.6% [upper-limit 95% CI, 2.9% to 3.1%]). Even though 30% of patients had discordant CDR outcomes, PE was not detected in any patient with discordant CDRs and a normal d-dimer result. LIMITATION Management was based on a combination of decision rules and d-dimer testing rather than only 1 CDR combined with d-dimer testing. CONCLUSION All 4 CDRs show similar performance for exclusion of acute PE in combination with a normal d-dimer result. This prospective validation indicates that the simplified scores may be used in clinical practice. PRIMARY FUNDING SOURCE Academic Medical Center, VU University Medical Center, Rijnstate Hospital, Leiden University Medical Center, Maastricht University Medical Center, Erasmus Medical Center, and Maasstad Hospital.

Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study

Summary.  Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non‐randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. Patients and Methods: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24 h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow‐up. Results: Of 297 included patients, who all completed the follow‐up, six (2.0%; 95% confidence interval [CI] 0.8–4.3) had recurrent VTE (five PE [1.7%] and one DVT [0.3%]). Three patients (1.0%, 95% CI 0.2–2.9) died during the 3 months of follow‐up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08–2.4). Conclusion: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319; http://www.trialregister.nl/trialreg/index.asp).

Hestia criteria can safely select patients with pulmonary embolism for outpatient treatment irrespective of right ventricular function.

There has been debate over how patients with pulmonary embolism (PE) can be safely selected for outpatient treatment.

Hestia criteria can discriminate high- from low-risk patients with pulmonary embolism

We investigated whether the clinical criteria used in the Hestia study for selection of pulmonary embolism (PE) patients for outpatient treatment could discriminate PE patients with high and low risk for adverse clinical outcome. We performed a cohort study with PE patients who were triaged with 11 criteria for outpatient treatment. Patients not eligible for outpatient treatment were treated in hospital. Study outcomes were recurrent venous thromboembolism, major bleeding and all-cause mortality during 3 months. In total, 530 patients were included, of which 297 were treated at home. In the outpatient group, six patients (2.0%, 95% CI 0.7–4.3%) had recurrent venous thromboembolism versus nine in-patients (3.9%, 95% CI 1.9–7.0%). Three patients (1.0%, 95% CI 0.2–2.9) died during the 3-months follow-up in the outpatient group versus 22 patients (9.6%, 95% CI 6.3–14) in the in-patient group (p<0.05). None of the outpatients died as a result of fatal PE versus five (2.2%) in-patients (p<0.05). In the outpatient group, 0.7% (95% CI 0.08–2.4) had major bleeding events versus 4.8% (95% CI 2.4–8.4) of in-patients (p<0.05). This study showed that the Hestia criteria can discriminate PE patients with low risk from patients with high risk for adverse clinical outcome. The low-risk patients can safely be treated at home.

Diagnostic outcome management study in patients with clinically suspected recurrent acute pulmonary embolism with a structured algorithm

INTRODUCTION The value of diagnostic strategies in patients with clinically suspected recurrent pulmonary embolism (PE) has not been established. The aim was to determine the safety of a simple diagnostic strategy using the Wells clinical decision rule (CDR), quantitative D-dimer testing and computed tomography pulmonary angiography (CTPA) in patients with clinically suspected acute recurrent PE. MATERIALS AND METHODS Multicenter clinical outcome study in 516 consecutive patients with clinically suspected acute recurrent PE without using anticoagulants. RESULTS An unlikely clinical probability (Wells rule 4 points or less) was found in 182 of 516 patients (35%), and the combination of an unlikely CDR-score and normal D-dimer result excluded PE in 88 of 516 patients (17%), without recurrent venous thromboembolism (VTE) during 3month follow-up (0%; 95% CI 0.0-3.4%). CTPA was performed in all other patients and confirmed recurrent PE in 172 patients (overall prevalence of PE 33%) and excluded PE in the remaining 253 patients (49%). During follow-up, seven of these 253 patients returned with recurrent VTE (2.8%; 95% CI 1.2-5.5%), of which in one was fatal (0.4 %; 95 % CI 0.02-1.9%). The diagnostic algorithm was feasible in 98% of patients. CONCLUSIONS A diagnostic algorithm consisting of a clinical decision rule, D-dimer test and CTPA is effective in the management of patients with clinically suspected acute recurrent PE. CTPA provides reasonable safety in excluding acute recurrent PE in patients with a likely clinical probability or an elevated D-dimer test for recurrent PE, with a low risk for fatal PE at follow-up.

No added value of the age-adjusted D-dimer cut-off to the YEARS algorithm in patients with suspected pulmonary embolism

Essentials Imaging is warranted in the majority of patients to confirm or rule out pulmonary embolism (PE). The age‐adjusted D‐dimer (ADJUST) reduced the number of required imaging tests in patients ≥ 50 years. The YEARS algorithm was designed to improve the efficiency in patients with suspected PE. There was no added value of implementing ADJUST in the YEARS algorithm in our cohort.

Diagnostic safety of a structured algorithm with use of clinical decision rule, D-dimer and CT scan for clinically suspected recurrent pulmonary embolism

Primary immune thrombocytopenia (ITP) is characterized by isolated thrombocytopenia. The mechanisms leading to a low platelet count include antibody-mediated destruction of platelets and suppression of megakaryocyte and platelet development. The causes of loss of tolerance and autoantibody production are unknown and it is likely that both genetic and environmental factors are involved. Platelet-specific autoantibodies are directed against a restricted number of ‘dominant’ epitopes of GPIIbIIIa, less frequently of GPIbIX or other platelet glycoproteins. There is evidence to suggest that these autoantibodies are produced from a limited number of clonal B cells by antigen-driven selection. Abnormalities of T cells certainly play a role in causing or perpetuating ITP. Chronic ITP is characterized by a Th1 profile and an impaired T-regulatory cell function, both of which are reversed upon successful treatment. Furthermore, cytotoxic T cells have been shown to cause platelet destruction in vitro and can probably suppress megakaryopoiesis. Chronic infections such as HIV, HCV and Helicobacter pylorican present with isolated thrombocytopenia and therefore mimic ITP. Antibodies cross-reacting with platelet antigens have been identified in thrombocytopenia associated with these infections, supporting a role for molecular mimicry in the development of this disorder. Disclosure of Interest: Honararia for participation on advisory boards and as a speaker at medical education events supported by GlaxoSmithKline, Amgen and RocheThe antiphospholipid syndrome (APS) is an autoimmune disease associated with the presence of antiphospholipid antibodies (APL) and the occurrence of thrombosis and pregnancy complications. One of the assays to detect APL is based on the prolongation of phospho-lipid dependent coagulation assays caused by these antibodies; lupus anticoagulant (LAC). To prevent thrombotic complications, APS patients use long-term anticoagulant treatment that could interfere with LAC determination. Rivaroxaban is a new direct factor Xa inhibitor. In this study we assessed whether rivaroxaban interferes with the detection of LAC. We tested normal pooled plasma (NPP), LAC-positive plasma of SLE patients and LAC-negative plasma from SLE patients. These plasmas were spiked with rivaroxaban. LAC ratios were determined by measuring the LAC-dependent and -independent coagulation times (dRVVT screen/dRVVT confirm, aPTT low and high phospho-lipids, taipan venom and ecarin times). Taipan venom and ecarin are snake venoms that directly activate prothrombin. The taipan venom time is LAC sensitive, whereas the ecarin time is not. Rivaroxaban added to plasma of healthy individuals prolonged the dRVVT LAC ratio, leading to a false positive lupus anticoagulant signal. Rivaroxaban had no influence on the aPTT LAC ratio of normal plasma, but slightly increased the ratio in plasma of SLE patients. For some plasmas negative for LAC, the presence of rivar-oxaban lead to a false positive LAC signal in the aPTT. We observed that the ratio of the taipan venom time over ecarin time remained uninfluenced by the presence of rivaroxaban, both in the absence or presence of antiphospholipid antibodies. This study shows that rivaroxaban can interfere with conventional LAC assays. The taipan venom time/ecarin time ratio may be a good alternative for the detection of LAC in patients using rivaroxaban.Introduction: Cancer greatly increases the risk of venous thromboem-bolism (VTE). Here, we investigated the contribution of microparti-cle-dependent procoagulant activity to the prothrombotic state in these patients. Methods: In 43 cancer patients without VTE at entry and 22 healthy volunteers, markers of in vivo and microparticle-dependent coagulation were measured and patients were prospectively followed for 6 months for the development of VTE. Procoagulant activity of microparticles (MPs) was measured using a phospholipid dependent test (STA Procoag PLL), a factor Xa-generation assay (Xa-assay) with and without anti-tissue factor (TF), and a fibrin generation test (FGT) with and without anti-factor VII(a). Results: Markers of in vivo coagulation activation and total number of circulating MPs were elevated in cancer patients compared to controls (F1+2 246 vs. 156 pM, thrombin-antithrombin complexes 4.1 vs. 3.0 mg/L, D-dimer 0.76 vs. 0.22 mg/L and 5.53 x 106 vs. 3.37 x 106 microparticles per mL; all P <0.001). Five cancer patients (12%) developed VTE during follow-up. Patients with VTE had comparable levels of coagulation activation markers and phos-pholipid dependent MP procoagulant activity. However, TF-mediated Xa-generation (0.82 vs. 0.21 pg/mL, P = 0.016) and the VIIa-dependent FGT (13% vs. 0%, P = 0.036) were higher in the VTE group compared with the non-VTE group.

Performance of four clinical decision rules in the diagnostic management of acute pulmonary embolism; The prometheus diagnostic accuracy study

Background: Four different clinical decision rules (CDRs) (Wells score, Revised Geneva score (RGS), simplified Wells score and simplified RGS) safely exclude pulmonary embolism (PE), when combined with a normal D-dimer test. Recently, an age adjusted cut-off of the D-dimer (patients age x 10 ig/L) greatly increased the number of patients in whom PE could safely be excluded. We validated the age-adjusted D-dimer test and assessed its performance in combination with the four CDRs in patients with suspected PE. Methods: Eight hundred and thirty-four consecutive patients with suspected PE were included of whom 414 were > 50 years (50%). The proportion of patients in whom PE could be excluded with an unlikely CDR combined with a normal age-adjusted D-dimer test was calculated and compared with the conventional D-dimer cut-off. We assessed VTE failure rates during 3-months follow-up. Results: Compared to the conventional D-dimer cut-off level, a normal age-adjusted D-dimer level substantially increased the number of patients in whom PE could be safely excluded. All CDRs performed equally well. This difference was nearly fourfold in patients > 70 years, where the Wells rule excluded more patients than the other CDRs. Conclusion: The age-adjusted D-dimer increases the number of older patients in whom PE can be safely excluded, irrespective of the Wells score or RGS, thereby avoiding unnecessary imaging tests.

The age-adjusted D-dimer safely excludes a high number of pulmonary embolisms in combination with four different clinical decision rules

Background: Four different clinical decision rules (CDRs) (Wells score, Revised Geneva score (RGS), simplified Wells score and simplified RGS) safely exclude pulmonary embolism (PE), when combined with a normal D-dimer test. Recently, an age adjusted cut-off of the D-dimer (patients age x 10 ig/L) greatly increased the number of patients in whom PE could safely be excluded. We validated the age-adjusted D-dimer test and assessed its performance in combination with the four CDRs in patients with suspected PE. Methods: Eight hundred and thirty-four consecutive patients with suspected PE were included of whom 414 were > 50 years (50%). The proportion of patients in whom PE could be excluded with an unlikely CDR combined with a normal age-adjusted D-dimer test was calculated and compared with the conventional D-dimer cut-off. We assessed VTE failure rates during 3-months follow-up. Results: Compared to the conventional D-dimer cut-off level, a normal age-adjusted D-dimer level substantially increased the number of patients in whom PE could be safely excluded. All CDRs performed equally well. This difference was nearly fourfold in patients > 70 years, where the Wells rule excluded more patients than the other CDRs. Conclusion: The age-adjusted D-dimer increases the number of older patients in whom PE can be safely excluded, irrespective of the Wells score or RGS, thereby avoiding unnecessary imaging tests.

Comparison of 4- and 64-slice ct scanning in the diagnosis of pulmonary embolism

Background: The D-Dimer (DD) test, used to rule out pulmonary embolism (PE), is less useful in elderly patients due to a lower specificity. We retrospectively derived and validated the efficacy of an age- dependent DD cut-off combined with clinical probability for the exclusion of PE in four large management studies. Methods: The derivation set consisted of consecutive outpatients > 50 years with suspected PE. The DD cut-off was based on ROC-curve analyses. The proportion of patients with a normal DD test and the false negative rates were calculated. The age-adjusted DD cut-off was then validated in patients > 50 years with an unlikely Wells score (> 4) or a non-high Revised Geneva Score (> 10) from two independent cohorts of consecutive patients, respectively. The Vidas DD test was used in all cohorts (combined with Tinaquant in validation set 1). Results: The new DD cut-off was defined as patients age x 10 μg/L. Using the new cut-off PE could be excluded in a higher number of patients > 50 years (Table). Among patients > 70 years, the increase in the proportion of patients with a DD below the new cut-off compared to the old cut-off was 2.3-fold in the derivation set, 2.0-fold in validation set 1 and 2.2-fold in validation set 2, respectively. [Table represented ]Conclusion: An age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of elderly patients in whom PE can be safely excluded. Disclosure of interest: none declared.Despite widespread use of the Platelet Function Analyzer-100 closure time (PFA) as alternative to the bleeding time (BT) for the analysis of primary hemostasis defects, the predictive value is highly variable. This may partly be due to the lack of larger studies, especially in children. We assessed the sensitivity and specificity of the PFA and BT in a large number of patients with increased bleeding tendency due to von Willebrand disease (vWD) and other platelet function disorders (PFD). In addition, we analysed the effect of desmopressin on the PFA in these patients. Methods: PFA and/or BT were measured in a total of 1027 patients (484 children) with increased bleeding tendency. The final diagnosis was ascertained by measurement of specific platelet function tests or clotting factor levels. We also analysed the effect of treatment with 0.3 ig/kg desmopressin on the PFA. Results: Sensitivity and specificity of the PFA were moderate, with no clear differences between children and adults with vWD (Table). The detection of PFD with the PFA was better in children than in adults. The sensitivity of the BT was comparable to the PFA, but the specificity in children was very low. In 54 patients, desmopressin treatment significantly shortened PFA except for one patient with M. Glanzmann and one with vWD. Table represented. Conclusion: Based on this large cohort, the predictive value of the PFA and BT for PFD and vWD in children and adults with increased bleeding tendency is insufficient. The BT had a comparable sensitivity, whereas its specificity was lower than that for PFA, especially in children. PFA seems suitable for measuring the effect of desmopressin.Introduction: Circulating procoagulant microparticles (MP) have been associated with a prothrombotic state in many diseases, including cancer. MP can enhance thrombin formation by exposing tissue factor (TF), the initiator of coagulation in vivo. Whether procoagulant TF is really exposed on circulating MP in cancer, however, is still debated. In addition, MP can also expose procoagulant phospholipids, which are essential for propagation of coagulation. In this study, we determined the contribution of circulating MP to phospholipid (PPL)-dependent coagulation in plasma samples from a heterogeneous group of cancer patients and compared them to healthy subjects. Methods: Citrate-anticoagulated blood was collected from healthy subjects (n = 85) and cancer patients (n = 50). The procoagulant activity of circulating MP was measured in fresh plasma using the STA procoag PPL assay (Diagnostica Stago). Results: The mean age of healthy subjects was 54 ± 12 years and 62% was female. The PPL-dependent clotting time (CTPPL) was 77.8 s ± 8.7 (mean ± SD, normal distribution), gender independent (P = 0.97) and not associated with age (r = 0.24, P = 0.83). Both removal of MP by high speed centrifugation or addition of annexin V strongly prolonged the CTPPL, indicating that MP are indeed the main source of PPL under these conditions. With regard to plasma samples from cancer patients, seven patients (14%) showed a faster CTPPL than controls (below 2.5 percentile). Five of these patients had metastatic disease (four gastrointestinal, one pancreatic cancer). The other two had local disease (one breast and one gastrointestinal cancer). Conclusions: The CTPPL is useful in identifying cancer patients with high levels of circulating procoagulant MP.