Postthrombotic syndrome and quality of life after deep vein thrombosis in patients treated with edoxaban versus warfarin.

Background: Postthrombotic syndrome (PTS) is a long-term complication after deep vein thrombosis (DVT) and can affect quality of life (QoL). Pathogenesis is not fully understood but inadequate anticoagulant therapy with vitamin K antagonists is a known risk factor for the development of PTS. Objectives: To compare the prevalence of PTS after acute DVT and the long-term QoL following DVT between patients treated with edoxaban or warfarin. Methods: We performed a long-term follow-up study in a subset of patients with DVT who participated in the Hokusai-VTE trial between 2010 and 2012 (NCT00986154). Primary outcome was the prevalence of PTS, defined by the Villalta score. The secondary outcome was QoL, assessed by validated disease-specific (VEINES-QOL) and generic health-related (SF-36) questionnaires. Results: Between 2017 and 2020, 316 patients were enrolled in 26 centers in eight countries, of which 168 (53%) patients had been assigned to edoxaban and 148 (47%) to warfarin during the Hokusai-VTE trial. Clinical, demographic, and thrombus-specific characteristics were comparable for both groups. Mean (SD) time since randomization in the Hokusai-VTE trial was 7.0 (1.0) years. PTS was diagnosed in 85 (51%) patients treated with edoxaban and 62 (42%) patients treated with warfarin (adjusted odds ratio 1.6, 95% CI 1.0-2.6). Mean differences in QoL scores between treatment groups were not clinically relevant. Conclusion: Contrary to our hypothesis, the prevalence of PTS tended to be higher in patients treated with edoxaban compared with warfarin. No differences in QoL were observed. Further research is warranted to unravel the role of anticoagulant therapy on development of PTS.

Health-related quality-of-life questionnaires for deep vein thrombosis and pulmonary embolism: A systematic review on questionnaire development and methodology.

To improve the quality and accuracy of the patient-reported outcome measures that assess health-related quality of life (HRQoL), guidelines have been developed to standardize the development and validation process. Considering the increasing importance of HRQoL questionnaires in research, we set out to review the literature and evaluate whether existing questionnaires developed for deep vein thrombosis (DVT) and pulmonary embolism (PE) fulfill state-of-the-art requirements. The literature search was conducted in March 2019 and updated in September 2020. Seven databases were searched. No time limit was set for the search to include all available questionnaires. The inclusion criteria were original publications describing the development of disease-specific HRQoL questionnaires specific to DVT or PE in adults and available in English. The questionnaires were assessed to determine whether they fulfill the requirements in the latest guidelines. A total of 3826 references were identified. After the exclusion process, 15 papers were reviewed in full, of which 7 were included. Four questionnaires were developed for chronic venous disease, two were specific to DVT, and one was specific to PE. Most questionnaires we found in this review, fulfilled some but none fulfilled all recommendations in existing guidelines. Because the development of current available HRQoL questionnaires specific to DVT or PE do not fulfil all recommendations of existing guidelines, there is room for improvements within this field. Such improvements could likely enhance the quality associated with the use of these end points in clinical trials and practice.

Safety of a strategy combining D-dimer testing and whole-leg ultrasonography to rule out deep vein thrombosis.

Guidelines for the diagnostic workup of deep vein thrombosis (DVT) recommend assessing the clinical pretest probability before proceeding to D-dimer testing and/or compression ultrasonography (CUS) if the patient has high pretest probability or positive D-dimer. Referring only patients with positive D-dimer for whole-leg CUS irrespective of pretest probability may simplify the workup of DVT. In this prospective management outcome study, we assessed the safety of such a strategy. We included consecutive outpatients referred to the Emergency Department at Østfold Hospital, Norway, with suspected DVT between February 2015 and November 2018. STA-Liatest D-Di Plus D-dimer was analyzed for all patients, and only patients with levels ≥0.5 µg/mL were referred for CUS. All patients with negative D-dimer or negative CUS were followed for 3 months to assess the venous thromboembolic rate. One thousand three hundred ninety-seven patients were included. Median age was 64 years (interquartile range, 52-73 years), and 770 patients (55%) were female. D-dimer was negative in 415 patients (29.7%) and positive in 982 patients (70.3%). DVT was diagnosed in 277 patients (19.8%). Six patients in whom DVT was ruled out at baseline were diagnosed with DVT within 3 months of follow-up for a thromboembolic rate of 0.5% (95% confidence interval, 0.2-1.2). A simple diagnostic approach with initial stand-alone D-dimer followed by a single whole-leg CUS in patients with positive D-dimer safely ruled out DVT. We consider this strategy to be a valuable alternative to the conventional workup of DVT in outpatients. This trial was registered at www.clinicaltrials.gov as #NCT02486445.

Safety and feasibility of rivaroxaban in deferred workup of patients with suspected deep vein thrombosis.

Guidelines suggest using empiric low-molecular-weight heparin if the diagnostic workup of deep vein thrombosis (DVT) is expected to be delayed. The role of direct oral anticoagulants for deferred compression ultrasound imaging (CUS) in patients with suspected DVT remains unexplored. The main objective of the study was to assess the safety of deferring CUS with therapeutic doses of rivaroxaban. We prospectively included consecutive outpatients referred to the Emergency Department at Østfold Hospital, Norway, with suspected first or recurrent lower-extremity DVT between February 2015 and November 2018. Patients were discharged with rivaroxaban 15 mg twice daily while awaiting CUS within 24 hours if D-dimer level was ≥0.5 mg/L fibrinogen-equivalent units. The primary outcome was the rate of major bleeding incidents from study inclusion until DVT was confirmed and anticoagulation therapy continued, or otherwise up to 48 hours following administration of the last tablet of rivaroxaban. The secondary outcome was the rate of progressive DVT symptoms or symptoms or signs of pulmonary embolism between hospital discharge until venous thromboembolism was diagnosed. Six hundred twenty-four of 1653 patients referred with suspected DVT were included (37.7%; 95% confidence interval [CI], 35.4-40.1). DVT was diagnosed in 119 patients (19.1%; 95% CI, 16.1-22.3). There were no major bleeding incidents, yielding an observed major bleeding rate of 0% (1-sided 95% CI <0.4). No patients experienced major complications in the interval that CUS was deferred (0%; 95% CI, 0.0-0.6). Deferring CUS for up to 24 hours in patients with suspected DVT with therapeutic doses of rivaroxaban is a safe strategy. This trial was registered at www.clinicaltrials.gov as #NCT02486445.

The impact of post-pulmonary embolism syndrome and its possible determinants.

INTRODUCTION: Recent studies suggest that up to 50% of patients surviving pulmonary embolism (PE) may suffer from post-PE syndrome, which is defined by persistent dyspnea, impaired exercise capacity and/or decreased health-related quality of life (HRQoL). The possible determinants of post-PE syndrome are however not fully established. AIMS: To describe the differences between dyspneic and non-dyspneic PE-patients and to explore determinants of dyspnea, 6-min walking test (6MWT) and HRQoL. MATERIAL AND METHODS: In this cross-sectional study, consecutive patients diagnosed with PE between 2002 and 2011 at Østfold Hospital, Norway were identified from hospital registries. Patients were scheduled for clinical examination and a 6MWT. Dyspnea was assessed by the New York Heart Association (NYHA) classification. HRQoL was assessed with PEmb-QoL questionnaire. PE severity was assessed with PESI score, mean bilateral proximal extent of the clot and right-/left ventricle-ratio (RV/LV-ratio). RESULTS: 203 patients participated in this study, of which 96 patients reported dyspnea (47%). Median time from diagnosis was 3.6 years (IQR 1.9-6.5). Patients without dyspnea performed better on 6MWT (488 m vs 413 m, p < 0.005) and had better HRQoL results (p < 0.005). None of the variables we examined, including Charlson comorbidity index, was independently associated with dyspnea. However, higher RV/LV ratio at diagnosis was significantly associated with reduced 6MWT at follow-up. Further, ongoing anticoagulation and unemployment were independently associated with impaired HRQoL. CONCLUSIONS: PE-survivors complaining of dyspnea suffer from impaired HRQoL and reduced exercise capacity. Although PE-severity factors were associated with reduced exercise capacity, none of the examined factors were found to be independent determinants of dyspnea.

Long-term mortality and incidence of cancer after pregnancy-related venous thrombosis: results of a population-based cohort study.

The long-term mortality and incidence of cancer after pregnancy-related venous thrombosis (VT) is not known. In this population-based cohort study we identified women with a first-ever pregnancy-related VT (cases, n = 557)) from 18 Norwegian hospitals during 1990-2003. Hospital controls (n = 1214) were selected among women who gave birth at the same time as a case. All participants were linked to the Norwegian Cause of Death Registry and to the Cancer Registry of Norway in 2012. The general age-adjusted Norwegian female population was used as a second control group to calculate the standardized mortality ratio (SMR) and the standardized incidence ratio (SIR) for cancer. Ten cases (1.8%) and seven hospital controls (0.6%) died during follow-up. Mortality was 3.2 times higher among cases as compared with hospital controls when adjusted for age (HR 3.2, 95% confidence interval 1.2-8.5, p = 0.018). The SMR for the first year of follow-up was 18.8 (7.8-45.3) and for the rest of the study period 0.9 (0.4-2.0). Fifteen cases (2.7%) and 13 hospital controls (1.1%) were diagnosed with cancer after index pregnancy. The incidence of cancer was 2.6 times higher among cases compared with hospital controls when adjusted for age (HR 2.6, 1.3-5.6, p = 0.011), but compared with the age-adjusted female population in Norway there was no excess risk of cancer (SIR 1.0, 95% CI 0.6-1.7). Mortality and incidence of cancer after pregnancy-related VT was low. Both were increased among cases compared with hospital controls, but not when compared with the general population, except for mortality during the first year after VT.