Individually shortened duration versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome: a cost-effectiveness analysis.

BACKGROUND: The IDEAL DVT study showed that it was safe to shorten the duration of elastic compression therapy on an individualised basis after deep vein thrombosis for prevention of post-thrombotic syndrome. In this study, we assessed the cost-effectiveness of this strategy. METHODS: IDEAL DVT was a multicentre, randomised, non-inferiority trial that included patients with acute proximal deep vein thrombosis of the leg. After 6 months of elastic compression therapy, patients were randomly assigned (1:1) to the standard 2 years of elastic stocking compression therapy or shortened duration of compression therapy based on the patient's Villalta score. For our cost-effectiveness analysis, we assessed quality-adjusted life-years (QALYs), measured with the three-level version of EQ-5D (EQ-5D-3L; Dutch and UK tariff) and the 36-item Short Form Health Survey (SF-36), and costs in € (health-care and societal perspective) according to the intention-to-treat approach. Data were collected at 3, 6, 12, and 24 months after diagnosis of thrombosis. We calculated incremental net monetary benefit using a QALY threshold of €30 000, and obtained bootstrapped means and 95% CIs. IDEAL DVT is registered with ClinicalTrials.gov, number NCT01429714. FINDINGS: Between March 22, 2011, and July 1, 2015, 865 patients were enrolled in IDEAL DVT. 437 were assigned to individualised duration of elastic compression therapy and 428 to standard duration of elastic compression therapy. Nine patients were eventually excluded because of recurrent venous thromboembolism within 6 months after the first event. From a societal perspective, for every QALY lost measured with the EQ-5D Dutch tariff, cost savings were €305·992 (incremental net monetary benefit €3205, 95% CI 502-5741), and for every QALY lost based on the Short-Form Six-Dimension (SF-6D) utility score (derived from SF-36), cost savings were €6030·941 (€3540, 95% CI 1174-5953). Using the UK tariff for EQ-5D, the individualised strategy was more effective and less costly (€4071, 1452-6647). The probability that the individualised strategy was cost-effective was 99% at a threshold of €30 000 per QALY (EQ-5D Dutch tariff). INTERPRETATION: Individually shortened duration of elastic compression therapy was cost-effective compared with standard duration elastic compression therapy. Use of an individualised approach to elastic stocking compression therapy for the prevention of post-thrombotic syndrome after deep vein thrombosis could lead to substantial costs savings without loss in health-related quality of life. FUNDING: Netherlands Organisation for Health Research and Development.

Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial.

BACKGROUND: Therapy with elastic compression stockings has been the cornerstone for prevention of post-thrombotic syndrome for decades in patients after acute deep venous thrombosis. It is uncertain who benefits most from therapy, and what the optimum duration of therapy should be. We therefore aimed to assess the safety and efficacy of individualised duration of compression therapy versus the standard duration of 24 months following an initial treatment period of 6 months. METHODS: We did a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial at 12 hospitals in the Netherlands and two in Italy. We randomly assigned patients (1:1) with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (Clinical Etiological Anatomical and Pathophysiological score

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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 DVT.

The IDEAL DVT study, individualised duration elastic compression therapy against long-term duration of therapy for the prevention of post-thrombotic syndrome: protocol of a randomised controlled trial.

INTRODUCTION: Post-thrombotic syndrome (PTS) is a serious complication of deep vein thrombosis (DVT) of the leg that affects 20-50% of patients. Once a patient experiences PTS there is no treatment that effectively reduces the debilitating complaints. Two randomised controlled trials showed that elastic compression stocking (ECS) therapy after DVT for 24 months can reduce the incidence of PTS by 50%. However, it is unclear whether all patients benefit to the same extent from ECS therapy or what the optimal duration of therapy for individual patients should be. ECS therapy is costly, inconvenient, demanding and sometimes even debilitating. Tailoring therapy to individual needs could save substantial costs. The objective of the IDEAL DVT study, therefore, is to evaluate whether tailoring the duration of ECS therapy on signs and symptoms of the individual patient is a safe and effective method to prevent PTS, compared with standard ECS therapy. METHODS AND ANALYSIS: A multicentre, single-blinded, allocation concealed, randomised, non-inferiority trial. A total of 864 consecutive patients with acute objectively documented proximal DVT of the leg are randomised to either standard duration of 24 months or tailored duration of ECS therapy following an initial therapeutic period of 6 months. Signs and symptoms of PTS are recorded at regular clinic visits. Furthermore, quality of life, costs, patient preferences and compliance are measured. The primary outcome is the proportion of patients with PTS at 24 months. ETHICS AND DISSEMINATION: Based on current knowledge the standard application of ECS therapy is questioned. The IDEAL DVT study will address the central questions that remain unanswered: Which individual patients benefit from ECS therapy and what is the optimal individual treatment duration? Primary ethics approval was received from the Maastricht University Medical Centre. RESULTS: Results of the study will be disseminated via peer-reviewed publications and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: NCT01429714 and NTR 2597.

Biomarkers for post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a serious condition that occurs in 20%-50% of patients following deep venous thrombosis (DVT). Biomarkers can be of use in further exploring the etiology as well as in developing risk stratification tools for PTS. The relationship between PTS and specific biomarkers may help guide prevention and therapy based on a patient's individual risk profile. This review gives an overview of the current knowledge on biomarkers in relation to PTS. METHODS: A systematic search was executed in three databases (Pubmed, Embase/Medline, Cochrane) to identify all publications on biomarkers in relation to PTS. Where possible, results of studies were pooled and a meta-analysis was performed using Review Manager 5.1 (The Cochrane Collaboration). RESULTS: Twenty-four papers were included in this review. In patients after DVT, increased D-dimer appeared to be associated with the development of PTS (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.02-4.08; P = .04). Neither prothrombin G20210A (OR, 0.95; 95% CI, 0.53-1.69; P = .86, nor increased factor VIII (OR, 1.78; 95% CI, 0.88-3.57; P = .11) were associated with PTS. For factor V Leiden (FVL), conflicting results were found. FVL was not associated with PTS within a population of patients with a history of DVT (OR, 0.98; 95% CI, 0.74-1.29; P = .88), but FVL was positively associated with post-thrombotic ulceration in severe PTS, in patients compared with healthy individuals without a history of DVT (OR, 11.42; 95% CI, 6.37-20.48; P < .00001). A meta-analysis could not be performed for markers of inflammation and tissue remodelling in relation to PTS. CONCLUSIONS: Increased D-dimer levels are associated with a twofold increased risk for PTS. Inherited hypercoagulability, including FVL is not associated with PTS in general. In contrast, FVL is strongly associated with post-thrombotic ulceration in severe PTS. The role of inflammation in the etiology of PTS still has to be elucidated.

Platelet dysfunction in thrombosis patients treated with vitamin K antagonists and recurrent bleeding.

BACKGROUND: Recurrent bleeding can complicate the treatment of thrombosis patients with vitamin K antagonists (VKA), even at a well-regulated level of anticoagulation. In this proof-of-principle study, we investigated whether alterations in platelet function or von Willebrand factor (vWf) contribute to a bleeding phenotype in these patients. METHODS: In this case-control study 33 well-regulated patients without bleeding events (controls) and 33 patients with recurrent bleeding (cases) were retrospectively included. Thrombin generation and vWf were determined in plasma. Platelet function was assessed by light transmission aggregometry and flow cytometry using a validated panel of agonists. RESULTS: Thrombin generation was similarly reduced in controls and cases, in comparison to normal plasma. Plasma vWf level was above the normal range in 85% of controls and 67% of the cases. vWf activity was similarly increased in all patients in comparison to healthy volunteers. Platelet aggregation was in the normal range for almost all patients irrespective of the type of agonist. However, in response to a low collagen dose, platelets from 21% of controls and 27% of cases showed diminished responses. Agonist-induced secretion of alpha- and dense-granules or integrin αIIbß3 activation were affected in platelets from neither controls nor cases. CONCLUSION: Recurrent bleeding in well-controlled patients on VKA therapy is not explained by anti-hemostatic changes in platelet or vWf function.