Short-term prognosis of breakthrough venous thromboembolism in anticoagulated patients

Background: Evidence for guideline recommendations for the treatment of venous thromboembolism (VTE) during anticoagulant therapy is scarce. We aimed to observe and to describe the management of VTE occurring during anticoagulant therapy. Methods: This prospective multi-center, observational study included patients with objectively confirmed VTE during anticoagulant therapy (breakthrough event), with a follow-up of 3 months, after the breakthrough event. Results: We registered 121 patients with a breakthrough event, with a mean age of 56 years (range, 19 to 90); 61 were male (50%). Fifty-eight patients (48%) had an active malignancy. At the time of the breakthrough event, 57 patients (47%) were treated with a vitamin K antagonist (VKA), 53 patients (44%) with low-molecular-weight heparin (LMWH) and 11 patients (9%) with direct oral anticoagulants, unfractionated heparin, or VKA plu

Performance of the 4-Level Pulmonary Embolism Clinical Probability Score (4PEPS) in the diagnostic management of pulmonary embolism:An external validation study

Background: The recently published 4-level Pulmonary Embolism Clinical Probability Score (4PEPS) integrates different aspects from currently available diagnostic strategies to further reduce imaging testing in patients with clinically suspected pulmonary embolism (PE). Aim: To externally validate the performance of 4PEPS in an independent cohort. Methods: In this post-hoc analysis of the prospective diagnostic management YEARS study, the primary outcome measures were discrimination, calibration, efficiency (proportion of imaging tests potentially avoided), and failure rate (venous thromboembolism (VTE) diagnosis at baseline or follow-up in patients with a negative 4PEPS algorithm). Multiple imputation was used for missing 4PEPS items. Based on 4PEPS, PE was considered ruled out in patients with a very low clinical pre-test probability (CPTP) without D-dimer testing, in patients with a low CPTP and D-dimer &lt;1000 μg/L, and in patients with a moderate CPP and D-dimer below the age-adjusted threshold. Results: Of the 3465 patients, 474 (14 %) were diagnosed with VTE at baseline or during 3-month follow-up. Discriminatory performance of the 4PEPS items was good (area under ROC-curve, 0.82; 95%CI, 0.80–0.84) as was calibration. Based on 4PEPS, PE could be considered ruled out without imaging in 58 % (95%CI 57–60) of patients (efficiency), for an overall failure rate of 1.3 % (95%CI 0.86–1.9). Conclusion: In this retrospective external validation, 4PEPS appeared to safely rule out PE with a high efficiency. Nevertheless, although not exceeding the failure rate margin by ISTH standards, the observed failure rate in our analysis appeared to be higher than in the original 4PEPS derivation and validation study. This highlights the importance of a prospective outcome study.</p

Heavy menstrual bleeding on direct factor Xa inhibitors: Rationale and design of the MEDEA study

Background: In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA). Treatment with the direct oral thrombin inhibitor dabigatran appears to be associated with a reduced risk of HMB compared with VKA. These findings come from small observational studies or post hoc analyses of trials in which HMB was not a primary outcome. Use of tranexamic acid during the menstrual period may be effective in patients with HMB, but prospective data regarding efficacy and safety in patients on anticoagulant treatment are lacking. Rationale and Design: A direct comparison of a factor Xa inhibitor and a thrombin inhibitor with HMB as primary outcome, as well as an evaluation of the effects of adding tranexamic acid in women with anticoagulant-associated HMB is highly relevant for clinical practice. The MEDEA study is a randomized, open-label, pragmatic clinical trial to evaluate management strategies in premenopausal women with HMB associated with factor Xa inhibitor therapy. Outcomes: Women using factor Xa inhibitors with proven HMB, as assessed by a pictorial blood loss assessment chart (PBAC) score of >150, will be randomized to one of three study arms: (i) switch to dabigatran; (ii) continue factor Xa inhibitor with addition of tranexamic acid during the menstrual period; or (iii) continue factor Xa inhibitor without intervention. The primary outcome is the difference in PBAC score before and after randomization. Here, we present the rationale and highlight several unique features in the design of the study

Biomarkers in pulmonary embolism

Purpose of review Controversy exists about the precise role of thrombolytic therapy in normotensive patients with pulmonary embolism. To resolve this controversy two major questions must be addressed. First, can a subgroup of normotensive pulmonary embolism patients with a high risk for adverse outcomes, such as in-hospital mortality or early recurrent venous thromboembolism, be identified? Second, is there convincing evidence that the benefits of more aggressive therapy counterbalance its risks? Troponin I and T as well as brain natriuretic peptide (BNP) have recently been introduced as promising tools in the risk assessment of patients with pulmonary embolism. Recent findings The studies in series of patients with pulmonary embolism showed prevalences of elevated cardiac biomarkers of 16 to 84%. Positive predictive values for in-hospital mortality varied from 6 to 44%, whereas negative predictive values for uneventful outcome were above 93% in all studies. Summary Although a correlation between elevated biomarkers and in-hospital mortality in pulmonary embolism patients is present in most of the studies, the positive predictive value appears to be insufficient to extend the indication for thrombolytic therapy to all patients with elevated biomarkers. Future research is necessary to show whether combining different biomarkers with echocardiography is more usefu

The clinical usefulness of D-dimer testing in cancer patients with suspected deep venous thrombosis

Background: Little is known about the diagnostic value of a D-dimer test in cancer patients with clinically suspected deep venous thrombosis (DVT). Objective: To evaluate the clinical utility of a whole blood rapid D-dimer test (SimpliRED) in cancer patients compared with noncancer patients. Methods: In consecutive patients with suspected lower limb DVT, a D-dimer test and ultrasonogram were performed. Cancer status was recorded at presentation. If the D-dimer test and ultrasonogram results were normal, DVT was considered absent. If the D-dimer result was abnormal, ultrasonography was performed again 1 week later. Anticoagulant therapy was only instituted in those patients with an abnormal ultrasonography result. All patients were followed up for 3 months to record subsequent thromboembolic events. The accuracy of the D-dimer test was assessed, and the efficiency and safety of withholding additional ultrasonography in cancer patients with normal results on both D-dimer and ultrasonography was compared with noncancer patients. Results: A total of 1739 consecutive patients were studied, 217 (12%) of whom had cancer. The negative predictive value of the D-dimer test was 97% in both cancer and noncancer patients. In 63 (29%) of all 217 cancer patients, the D-dimer and ultrasonography results were normal at referral; therefore, the diagnosis of DVT was refuted and anticoagulant treatment was withheld. In these 63 patients, one thromboembolic event occurred during follow-up (1.6%; 95% confidence interval, 0.04%-8.53%). Conclusions: The negative predictive value of a whole blood D-dimer test in cancer patients seems as high as in noncancer patients. In a substantial proportion of cancer patients, the diagnosis can likely be refuted at referral, based on normal D-dimer test and ultrasonogram results. Furthermore, it seems safe to withhold anticoagulant therapy in these patient

Prognostic value of echocardiographically assessed right ventricular dysfunction in patients with pulmonary embolism

Background: Echocardiographically assessed right ventricular dysfunction is increasingly used to guide more aggressive therapy in hemodynamically stable patients with acute pulmonary embolism (PE). However, the prognostic value of right ventricular dysfunction in these patients is still unclear. Methods: We systemically reviewed the literature to assess the prevalence of echocardiographic right ventricular dysfunction and the association with adverse outcomes in patients with PE who had this condition. The methodologic quality of each study was scored. Absolute risks of the outcome events were calculated for each study separately, and positive predictive values of PE-related mortality were determined for normotensive patients. Results: Seven studies were included. All had methodologic shortcomings, but they suggested an at least 2-fold increased risk of PE-related mortality in patients with right ventricular dysfunction, the prevalence of which varied from 40% to 70%. However, this seems to be less convincing in hemodynamically stable patients. The only 2 studies that allowed for an estimation of the accuracy in normotensive patients showed low positive predictive values of echo cardiographic right ventricular dysfunction for PE-related in-hospital mortality (positive predictive value, 4% and 5% in the 2 studies). Conclusion: It remains unclear whether echocardiographic right ventricular dysfunction is a prevalent and reliable predictor of adverse outcomes in hemodynamically stable patients with acute P

Funduscopy: Yes or no? Hypertensive emergencies and retinopathy in the emergency care setting; a retrospective cohort study

Abstract According to international guidelines, patients with a suspected hypertensive emergency (HE) admitted to the emergency department (ED) should undergo comprehensive evaluation including funduscopic examination. However, funduscopy is not always readily available and little is known about the prevalence of retinopathy among these patients in the ED setting. In order to characterize patients who should undergo funduscopy, we studied the prevalence, characteristics and clinical outcome in patients with a suspected HE and retinopathy grade III/IV. We conducted a retrospective cohort study of consecutive patients with severe elevation of blood pressure (BP) admitted to the ED between 2012 and 2015. Patients with a systolic blood pressure (SBP) ≥180 mm Hg or diastolic blood pressure (DBP) ≥120 mm Hg at time of presentation were included. A total of 271 patients were included, of whom 18 (6.6%; 95%CI 3.9‐10.5) had a HE. In 121 patients (44.6%; 95%CI 37.1‐53.3), funduscopy was performed, of whom 17 (14.0%; 95%CI 8.2‐22.5) had retinopathy grade III/IV. Mean SBP and DBP were significantly higher in patients with retinopathy (P < .001). However, retinopathy was also seen in patients with lower BP (SBP < 200 mm Hg and DBP < 120 mm Hg). No differences in other clinical characteristics, including visual disturbances, were found. One patient with retinopathy suffered an ischemic stroke after taking oral medication. The prevalence of retinopathy is high among examined patients. Except for higher BP, no clinical signs or symptoms are associated with the presence of retinopathy grade III/IV. We therefore conclude that funduscopic examination should be performed in every patient with a suspected HE

Toll-like receptor 9 gene expression in the post-thrombotic syndrome, residual thrombosis and recurrent deep venous thrombosis: A case-control study

Animal models suggest that toll-like receptor 9 (TLR9) promotes thrombus resolution after acute deep venous thrombosis (DVT). We hypothesized that TLR9 expression is lower in patients with post-thrombotic syndrome (PTS) and investigated the role of TLR9 in residual thrombosis (RT) and recurrence. Patients with a history of DVT with PTS (cases, n=30) and without PTS after minimal 24 months follow-up (controls, n=30) were selected. Healthy individuals (HI, n=29) without DVT were included as reference. TLR9 mRNA expression in leukocytes was determined by qPCR and normalized to the housekeeping succinate dehydrogenase subunit A gene using the ΔCt method. Sub analyses were performed to explore the TLR9 expression in patients with and without RT and multiple DVT episodes. The median TLR9 expression was 0.45 (interquartile range 0.31 to 0.93), 0.39 (0.25 to 0.69) and 0.62 (0.32 to 0.75) in cases, controls and HI respectively (p=0.61). The median TLR9 expression was 0.39 (0.26 to 0.51) in patients with RT compared to 0.55 (0.30 to 0.86, p=0.13) in those without. The median TLR9 expression was significantly lower in patients who had one DVT compared to patients with recurrent DVT, 0.37 (0.23 to 0.63) versus 0.55 (0.43 to 0.96) respectively (p <0.01). No significant difference in TLR9 expression was found between cases, controls and HI. However TLR9 expression seems lower in individuals with DVT and RT, albeit not significant. Interestingly, TLR9 might play a role in recurrent DVT, as the TLR9 expression was significantly higher in patients with recurrent DV

Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosis

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