Noémie Kraaijpoel

The original and simplified Wells rules and age-adjusted D-dimer testing to rule out pulmonary embolism: an individual patient data meta-analysis

Essentials Evidence for the simplified Wells rule in ruling out acute pulmonary embolism (PE) is scarce. This was a post‐hoc analysis on data from 6 studies comprising 7268 patients with suspected PE. The simplified Wells rule combined with age‐adjusted D‐dimer testing may safely rule out PE. Given its ease of use, the simplified Wells rule is to be preferred over the original Wells rule.

The diagnostic management of upper extremity deep vein thrombosis: A review of the literature

Upper extremity deep vein thrombosis (UEDVT) accounts for 4% to 10% of all cases of deep vein thrombosis. UEDVT may present with localized pain, erythema, and swelling of the arm, but may also be detected incidentally by diagnostic imaging tests performed for other reasons. Prompt and accurate diagnosis is crucial to prevent pulmonary embolism and long-term complications as the post-thrombotic syndrome of the arm. Unlike the diagnostic management of deep vein thrombosis (DVT) of the lower extremities, which is well established, the work-up of patients with clinically suspected UEDVT remains uncertain with limited evidence from studies of small size and poor methodological quality. Currently, only one prospective study evaluated the use of an algorithm, similar to the one used for DVT of the lower extremities, for the diagnostic workup of clinically suspected UEDVT. The algorithm combined clinical probability assessment, D-dimer testing and ultrasonography and appeared to safely and effectively exclude UEDVT. However, before recommending its use in routine clinical practice, external validation of this strategy and improvements of the efficiency are needed, especially in high-risk subgroups in whom the performance of the algorithm appeared to be suboptimal, such as hospitalized or cancer patients. In this review, we critically assess the accuracy and efficacy of current diagnostic tools and provide clinical guidance for the diagnostic management of clinically suspected UEDVT.

A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts

BACKGROUND Venous thromboembolism is a common complication of cancer, but the risk of developing venous thromboembolism varies greatly among individuals and depends on numerous factors, including type of cancer. We aimed to develop and externally validate a clinical prediction model for cancer-associated venous thromboembolism. METHODS We used data from the prospective Vienna Cancer and Thrombosis Study (CATS) cohort (n=1423) to select prognostic variables for inclusion in the model. We then validated the model in the prospective Multinational Cohort Study to Identify Cancer Patients at High Risk of Venous Thromboembolism (MICA) cohort (n=832). We calculated c-indices to show how the predicted incidence of objectively confirmed venous thromboembolism at 6 months compared with the cumulative 6-month incidences observed in both cohorts. FINDINGS Two variables were selected for inclusion in the final clinical prediction model: tumour-site risk category (low or intermediate vs high vs very high) and continuous D-dimer concentrations. The multivariable subdistribution hazard ratios were 1·96 (95% CI 1·41-2·72; p=0·0001) for high or very high versus low or intermediate and 1·32 (95% CI 1·12-1·56; p=0·001) per doubling of D-dimer concentration. The cross-validated c-indices of the final model were 0·66 (95% CI 0·63-0·67) in CATS and 0·68 (0·62-0·74) in MICA. The clinical prediction model was adequately calibrated in both cohorts. INTERPRETATION An externally validated clinical prediction model incorporating only one clinical factor (tumour-site category) and one biomarker (D-dimer) predicted the risk of venous thromboembolism in ambulatory patients with solid cancers. This simple model is a considerable improvement on previous models for predicting cancer-associated venous thromboembolism, and could aid physicians in selection of patients who will likely benefit from thromboprophylaxis. FUNDING Austrian Science Fund, Austrian National Bank Memorial Fund, and participating hospitals.

Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting.

Clinical Impact and Course of Anticoagulant-Related Major Bleeding in Cancer Patients

Cancer patients with venous thromboembolism (VTE) have a two- to six-fold increased risk of anticoagulant-related major bleeding events compared with VTE patients without cancer. It is unknown whether major bleeding events are more severe in cancer patients than in those without cancer. Individual patient data from four randomized phase III trials that compared factor Xa inhibitors and vitamin K antagonists for the treatment of VTE were used to compare the severity of major bleeding events in patients with and without cancer. Using predefined criteria, the severity of the clinical presentation and course of major bleeding events were classified into four categories of increasing severity. A one-stage meta-analysis was used to evaluate the effect of cancer on the severity of the clinical presentation and course by estimating crude odds ratios (ORs) and ORs adjusted for age, sex and anticoagulant type with 95% confidence intervals (CIs). The study group comprised 290 patients with major bleeding, of whom 50 (17%) had cancer. The clinical presentation was judged to be severe (category 3 or 4) in 38% of patients with cancer and 44% of patients without cancer (adjusted OR, 0.90; 95% CI, 0.47-1.72). The clinical course was found to be severe in 20 and 25% of patients with and without cancer, respectively (adjusted OR, 0.75; 95% CI, 0.35-1.61). The present study suggests that the clinical presentation and course of anticoagulant-related major bleeding events are not more severe in cancer patients than in patients without cancer. This may be reassuring for physicians who treat cancer patients with anticoagulant-related bleeding.

Incidental pulmonary embolism in cancer patients: Interobserver agreement on the diagnosis and extent with a focus on distal clots.

BACKGROUND The incidence of incidental pulmonary embolism (IPE) in cancer patients is increasing. There is scant information on the interobserver agreement among radiologists about the diagnosis of distal incidental clots and the actual radiologic extension of IPE. METHODS A total of 88 contrast-enhanced computed tomography (CT) scans of cancer patients with IPE were reassessed blindly by two expert thoracic radiologists. First, 62 scans were reassessed and the interobserver agreement on most proximal extent of IPE was calculated between the two expert radiologists as well as between the initial and expert reading, using the kappa statistic. The sample was enriched with 26 additional scans for a total of 30 segmental and 29 subsegmental IPE to determine the interobserver agreement on distal clots. RESULTS The level of agreement regarding the most proximal extent of IPE between the expert radiologists was very good (kappa 0.84; 95% CI, 0.73-0.95) and poor between the original radiologist and expert radiologists (kappa 0.39; 95% CI, 0.22-0.56). In the patients with segmental or subsegmental IPE on initial reading, the expert radiologists agreed with the segmental location in 12 out of 30 patients (40%) and with the subsegmental location in 17 out of 29 patients (59%). The interobserver agreement between the expert radiologists was good (kappa 0.68; 95% CI, 0.46-0.90) and moderate (kappa 0.48; 95% CI, 0.25-0.71), respectively. CONCLUSIONS While the interobserver agreement between radiologists on the most proximal location of IPE in cancer patients appears to be fairly good, it decreases significantly for more distally located incidental clots.

Direct oral anticoagulants in patients with liver cirrhosis: A systematic review

INTRODUCTION Anticoagulant treatment in patients with liver cirrhosis is challenging. The aim of this systematic review was to evaluate clinical outcomes of direct oral anticoagulant (DOAC) therapy in cirrhosis patients. MATERIALS AND METHODS A systematic search was performed in MEDLINE, Embase, and conference proceedings up to November 7th, 2017, for studies that evaluated the efficacy and safety of DOACs in cirrhosis patients with venous thromboembolism (VTE), splanchnic vein thrombosis (SVT), or atrial fibrillation (AF). Two authors independently screened titles, abstracts, and full-text articles, and assessed risk of bias. A meta-analysis could not be performed due to heterogeneity of the included studies. RESULTS Of the 2927 articles assessed, five retrospective cohort studies were included (n = 239, including 20 patients overlap). All studies had fair methodological quality. Two studies evaluated DOAC treatment only, and three also evaluated vitamin K antagonists (VKAs) or low-molecular-weight heparins (LMWHs). Recurrent VTE (DOAC n = 12, LMWH/VKA n = 8) or ischemic stroke (DOAC n = 37, LMWH/VKA n = 9) occurred in none of the patients. Progression of VTE was 8% with DOACs (n = 12) and 13% with VKAs and LWWH (n = 8). Recurrent SVT occurred in 0 to 4% with DOACs (n = 31). Progression of SVT was 0 to 5% with DOACs (n = 24) and 0 to 47% with VKAs and LMWH (n = 33). Major bleeding risk ranged from 4 to 15% with DOACs (n = 172) and from 7 to 28% with VKAs and LMWH (n = 67). All-cause mortality risk was 6% with DOACs (n = 36). CONCLUSIONS There is paucity of data on the efficacy and safety of DOACs in patients with cirrhosis. This analysis suggests that DOACs may be effective and safe for treatment of VTE, SVT, and AF in these patients.

Questioning the use of an age-adjusted D-dimer threshold to exclude venous thromboembolism: comment

D-dimer testing is a cornerstone of the diagnostic management of deep vein thrombosis (DVT) and pulmonary embolism (PE). Over the past decade, the threshold used to exclude venous thromboembolism (VTE) has transitioned from a fixed threshold to an age-adjusted threshold [1] and, more recently, to a clinical probability dependent threshold [2]. This transition intended to increase the proportion of patients in whom imaging can be withheld, without jeopardizing safety. In a post-hoc analysis of two prospective diagnostic management studies, Takach Lapner and colleagues found no differences in diagnostic accuracy between an age-adjusted, an increased fixed, and an inverse age-adjusted D-dimer threshold [3]. This article is protected by copyright. All rights reserved.

Ruling out pulmonary embolism across different subgroups of patients and healthcare settings: protocol for a systematic review and individual patient data meta-analysis (IPDMA)

BackgroundDiagnosing pulmonary embolism in suspected patients is notoriously difficult as signs and symptoms are non-specific. Different diagnostic strategies have been developed, usually combining clinical probability assessment with D-dimer testing. However, their predictive performance differs across different healthcare settings, patient subgroups, and clinical presentation, which are currently not accounted for in the available diagnostic approaches.MethodsThis is a protocol for a large diagnostic individual patient data meta-analysis (IPDMA) of currently available diagnostic studies in the field of pulmonary embolism. We searched MEDLINE (search date January 1, 1995, till August 25, 2016) to retrieve all primary diagnostic studies that had evaluated diagnostic strategies for pulmonary embolism. Two authors independently screened titles, abstracts, and subsequently full-text articles for eligibility from 3145 individual studies. A total of 40 studies were deemed eligible for inclusion into our IPDMA set, and principal investigators from these studies were invited to participate in a meeting at the 2017 conference from the International Society on Thrombosis and Haemostasis. All authors agreed on data sharing and participation into this project. The process of data collection of available datasets as well as potential identification of additional new datasets based upon personal contacts and an updated search will be finalized early 2018. The aim is to evaluate diagnostic strategies across three research domains: (i) the optimal diagnostic approach for different healthcare settings, (ii) influence of comorbidity on the predictive performance of each diagnostic strategy, and (iii) optimize and tailor the efficiency and safety of ruling out PE across a broad spectrum of patients with a new, patient-tailored clinical decision model that combines clinical items with quantitative D-dimer testing.DiscussionThis pre-planned individual patient data meta-analysis aims to contribute in resolving remaining diagnostic challenges of time-efficient diagnosis of pulmonary embolism by tailoring available diagnostic strategies for different healthcare settings and comorbidity.Systematic review registrationProspero trial registration: ID 89366.