Health‑related quality of life after deep vein thrombosis

Background: Health-related quality of life (HRQoL) is known to be impaired in patients who develop post-thrombotic syndrome (PTS) following deep vein thrombosis (DVT). However, there is limited knowledge of the long-term HRQoL after DVT compared to controls without DVT. The objectives of this study were to evaluate long-term HRQoL following DVT and to compare that with age and sex matched control group and to population norms as well as to investigate possible predictors for reduced HRQoL. Methods: HRQoL was evaluated in 254 patients with confirmed DVT using the generic EQ-5D and the diseases specific VEINES-QOL/Sym questionnaire, whereas PTS was assessed by the Villalta scale. Patients were asked to give the EQ-5D questionnaire to two friends of same age- (±5 years) and sex (buddy controls). Results: Patients scored significantly lower on all dimensions of EQ-5D compared to controls. EQ-5D index value was lower in patients compared with buddy controls; mean 0.79 (SD 0.17; IQR 0.72–1.00) versus 0.9 (SD 0.12; IQR 0.80–1.00), p < 0.001. EQ-5D index value was also significantly lower than age- and sex-adjusted population norms (p 30/m2) were significantly associated with impaired HRQoL assessed by EQ-5D index value (odds ratio [OR] 11.0: 95 % confidence interval [CI] 4.6–29.7; and 2.3: 95 % CI 1.1–4.8, respectively) and VEINES-QOL (OR 28.2: 95 % CI 10.6–75.0; and OR 4.1: 95 % CI 1.7–9.7, respectively). Conclusion: Long-term HRQoL was significantly impaired in DVT patients compared with buddy controls and population norms. PTS and obesity were independently associated with impaired HRQoL

Health-related quality of life after pulmonary embolism: a cross-sectional study

Objectives The psychological effects of acute pulmonary embolism (PE) have scarcely been studied. The aims of this study were to evaluate health-related quality of life (HRQoL) in patients with a history of PE compared with that of the general population and buddy controls, and to explore factors that may predict impaired HRQoL. Design Cross-sectional. Setting Haematology and thrombosis unit in Fredrikstad, Norway. Participants 213 consecutive patients treated for PE were identified from hospital registries. Eligible patients were scheduled for a single study visit, including a functional capacity test (6 min walking test). HRQoL was assessed using the EuroQol 5D dimensions 3-level (EQ-5D-3L) questionnaire, of which the results were compared with Danish population norms and age-matched and sex-matched buddy controls. The buddy controls were recruited by asking every patient to hand over the EQ-5D questionnaire to 2 age-matched and sex-matched friends or relatives. Multivariable regression analyses were used to examine possible determinants of reduced HRQoL. Results Mean age was 61 years (SD 15), 117 (55%) were males, and median time since diagnosis was 3.8 years (range 0.3–9.5). Mean EuroQol visual analogue scale (EQ VAS) was 67 in PE as compared with 81 in the general population (p<0.005) and corresponding EQ-5D index values were 0.80 and 0.86 (p<0.005). Patients reported more problems in all 5 EQ-5D compared with both the buddy controls and the general population, p<0.05. Shorter 6 min walking distance (β=0.09, p<0.005) and patient-reported dyspnoea (β=11.27, p<0.005) were independent predictors of lower EQ VAS scores. Conclusions Our findings show that patients with a history of PE have impaired HRQoL when compared with the general population and buddy controls. Reduced functional capacity and persistent dyspnoea were the main predictors of this impairment

Thiopurine Enhanced ALL Maintenance (TEAM) : study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

Background: A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. Methods: TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0-45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5-12.5 mg/m(2)/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m(2)/day. A total of 778 patients will be included in TEAM during similar to 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse,TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. Discussion: TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms.Peer reviewe

Long-term consequences of pregnancy-related venous thrombosis

Background: Venous thrombosis (VT) is among the leading causes of maternal mortality in countries with high standards of perinatal care; however the long-term outcomes of pregnancy-related VT are unknown. Aims: To assess the long-term prevalence of post-thrombotic syndrome (PTS), a frequently occurring chronic complication after deep vein thrombosis (DVT), to identify possible predictors for PTS, and to evaluate disease specific quality of life (QOL) after pregnancy-related DVT as compared with a control group. We also aimed to assess the mortality and incidence of cancer after VT in this population. Materials and Methods: The Norwegian Patient Register and the Medical Birth Registry of Norway were used to identify cases of women with a first-ever pregnancy-related VT during 1990-2003 from 18 Norwegian hospitals. Women without VT matched for time of delivery were selected by the Medical Birth Registry as controls. All VTs were validated using the hospital medical records. Total 559 cases and 1229 controls were identified and were invited to answer a comprehensive questionnaire. 313 cases and 353 controls met to participate in 2006. The questionnaire included self-reported Villalta score for the assessment of PTS and the disease specific QOL questionnaire VEINES-QOL/Sym. In 2012, the original study population of 1788 women was linked to the Norwegian Cause of Death Registry and the Cancer Registry of Norway. Results: PTS was found in 42% of 204 women 3-16 years after a lower limb pregnancy-related DVT. Proximal DVT when occurring postnatal was the most important predictor for PTS. Higher age and smoking were also independently associated with PTS. Women with DVT reported reduced disease specific QOL compared with controls. Ten cases (1.8%) and 7 controls (0.6%) died during 13 years of follow-up. Mortality was significantly higher among cases compared with controls (hazard ratio 3.2, 95% confidence interval 1.2-8.5, P=0.018 when adjusted for age). The mortality among cases was also 19 times higher than among the age-adjusted Norwegian female population the first year after VT (standardized mortality ratio (SMR) 18.8, 95% CI 7.8-45.3), but thereafter the mortality was similar (SMR 0.9, 95% CI 0.4-2.0). Fifteen cases (2.7%) and 13 controls (1.1%) were diagnosed with cancer after index pregnancy and subsequent cancer was significantly more frequent among cases compared with controls (hazard ratio 2.6, 95% CI 1.3-5.6, p=0.011). Cases did not have higher incidence of cancer when comparing with the age-and sex-adjusted general population (standardized incidence ratio 1.0, 95% CI 0.6-1.7). Conclusions: PTS was a common long-term complication after pregnancy-related DVT affecting almost half of the women and disease specific QOL in this population was reduced compared with a control group. Cases had significantly higher mortality and incidence of cancer than controls during 13 years of follow-up. When comparing with the age-adjusted Norwegian female population, mortality was increased only the first year after VT and incidence of cancer was similar

Limitations of the Villalta scale in diagnosing post-thrombotic syndrome

Introduction The Villalta scale is currently the recommended tool for diagnosing post-thrombotic syndrome (PTS) in clinical studies, but there is concern that the sensitivity and specificity of the scale might be low. We aimed to evaluate the diagnostic accuracy of the Villata scale using criteria in line with clinical practice as a reference. Material and methods We invited patients with a history of proximal DVT during 2006–09 to participate in a cross-sectional follow-up study of long-term complications after DVT. PTS was diagnosed by the Villalta scale, and by the following four mandatory and predefined clinical criteria used as a reference for PTS: 1. Objectively verified DVT; 2. chronic complaints (>1 month) in the DVT leg; 3. complaints appeared after the DVT; and 4. an alternative diagnosis was unlikely. Results We included 88 of 170 eligible patients (52%). With our clinical criteria as a reference the sensitivity and specificity of the Villalta scale for diagnosing PTS were 75% (95% CI 60–87%) and 66% (95% CI 50–80%), respectively. Fifteen patients were diagnosed with PTS by the Villalta scale only. These patients more often experienced pain or had comorbidity that could explain their leg symptoms and signs. Eleven patients diagnosed with PTS by the clinical criteria only, had more fluctuating heaviness and edema. Conclusions Our findings indicate that the diagnostic accuracy of the Villalta scale has limitations. Incorporating chronicity, whether the leg problems appeared following the DVT, fluctuations of heaviness and edema, and comorbidity in PTS assessment may improve the diagnostic accuracy

Does the Villalta scale capture the essence of postthrombotic syndrome? A qualitative study of patient experience and expert opinion

Background The Villalta scale is recommended for diagnosing and grading of postthrombotic syndrome (PTS) in clinical studies, but with limitations in specificity and sensitivity. Objectives To explore the typical complaints of PTS through patients experience and expert opinion and relate this to the items of the Villalta scale. Patients/Methods A qualitative study design with focus group interviews including patients with PTS and health care workers experienced in PTS patient care. Results Typical PTS complaints were reflected within four main domains: (a) agonizing discomforts; patients without venous ulcers often described other discomforts than pain; (b) skin changes; these were common and sometimes present before deep vein thrombosis (DVT). Except for venous ulcers, skin changes were considered of less importance; (c) fluctuating heaviness and swelling during the day and with activity; (d) post‐DVT concerns; fear of DVT recurrence, health services failing to meet the patients’ expectations, and psychological and social restrictions. These findings are not necessarily captured or well reflected in the Villalta scale. Conclusion Our findings indicate that the Villalta scale does not capture typical PTS complaints or their importance to the patients. A revision of the diagnosis and grading should be considered

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

Post-thrombotic syndrome in patients with venous thromboembolism treated with dabigatran or warfarin: A long-term cross-sectional follow-up of RE-COVER study patients

Background Studies suggest that the direct factor Xa inhibitor rivaroxaban compared to warfarin reduces the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT), but this has not been evaluated for oral direct thrombin inhibitors. Objectives To compare the long-term prevalence of PTS, recurrent venous thromboembolism (VTE), and health-related quality of life (HRQoL) in patients with acute DVT and/or pulmonary embolism (PE), randomized to treatment with dabigatran or warfarin in the phase III RE-COVER studies. Methods We conducted a cross-sectional follow-up study of patients randomized in Canada, Norway, and Sweden. PTS was assessed by the patient-reported Villalta scale (PRV) and HRQoL by EQ-5D and VEINES-QOL/Sym. Results We included 349 patients between December 2015 and November 2018; 166 were treated with dabigatran and 183 with warfarin. DVT (+/− PE) was index event in 255 patients, whereas 94 patients had PE only. Mean time from index event was 8.7 (standard deviation 1.4) years. PTS was diagnosed in 63% of patients with DVT and in 46% of patients with PE only, and did not differ between the treatment groups; the crude odds ratio (OR) for PTS in patients treated with dabigatran compared with warfarin was 1.1 (95% confidence interval [CI] 0.6–1.8) after DVT and 1.2 (95% CI 0.5–2.6) after PE only. The prevalence of recurrent VTE was 21% in both treatment groups. HRQoL scores did not differ between groups. Conclusion In this long-term cross-sectional study, the prevalence of PTS, recurrent VTE, and HRQoL were similar in patients treated with dabigatran and warfarin

Elevated complement C3 and C4 levels are associated with postnatal pregnancy-related venous thrombosis

High levels of complement C3 are associated with venous thrombosis (VT) in the general population. We investigated if high C3 and C4 levels were associated with pregnancy-related VT. We undertook the Norwegian VIP study, a case–control study of VT in pregnancy or within 3 months postpartum (cases, n = 313) and women without pregnancy-related VT (controls, n = 353). Determinants of C3 and C4 in the control women were investigated with linear regression and the odds ratio (OR) for pregnancy-related VT was calculated with logistic regression. We found that levels of C3 and C4 were associated with body mass index (BMI), C-reactive protein (CRP); with the coagulation factors (F) fibrinogen, FVIII, and FIX; and with the coagulation inhibitors antithrombin, protein C, protein S, and tissue factor pathway inhibitor. These associations were influenced by CRP levels. The crude OR for pregnancy-related VT was 1.8 (95% confidence interval [CI], 1.1–3.0) for C3 above the 90th percentile and 2.0 (95% CI, 1.2–3.2) for C4 above the 90th percentile. Stratification in antenatal and postnatal VT showed that C3 and C4 were only associated with postnatal VT with an OR for high C3 of 3.0 (95% CI, 1.8–5.0), and for high C4 of 2.6 (95% CI, 1.5–4.6). Adjustment for high FIX and BMI reduced the ORs. We conclude that the association between postnatal VT and C3 and C4 suggests that there is clinically relevant crosstalk between the complement and the coagulation system