Prevention of post-thrombotic syndrome with rosuvastatin: A multicenter randomized controlled pilot trial (SAVER).

BACKGROUND: Post-thrombotic syndrome (PTS) is one of the most frequent complications of venous thromboembolism (VTE) leading to considerable morbidity and cost. Apart from appropriate anticoagulation, there is no drug or medical intervention that helps to prevent PTS. We conducted a multicenter randomized controlled trial to determine whether rosuvastatin can prevent PTS. METHODS: 312 patients receiving standard anticoagulation for a newly diagnosed VTE were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days (n = 155) or no rosuvastatin (n = 157). At the last study visit (Day 180 ± 21), an independent observer who was blinded to study treatment performed a PTS assessment using the Villalta scale. The primary clinical outcome of the trial was mean Villalta score at Day 180. We also explored the presence of PTS as defined by Villalta score > 4 at Day 180. Patients mean age was 46.7 ± 10.8 years, 55.8% were female. RESULTS: At Day 180, the Villalta score was 3.5 ± 0.3 in the rosuvastatin arm vs. 3.3 ± 0.3 in the control arm (p = 0.59), and presence of PTS (Villalta >4) was 29.7% in the rosuvastatin arm vs. 25.5% in the control arm (p = 0.41). Secondary analyses showed no difference between trial arms for presence of severe PTS at Day 180 (2.0% vs. 2.7%, p = 1) and for changes in Villalta score between baseline and Day 180 (-3.7 ± 4.4 vs. -4.0 ± 5.0, p = 0.59). CONCLUSION: This randomized controlled pilot trial did not demonstrate efficacy of rosuvastatin to reduce Villalta score. Further studies with longer duration of exposure to rosuvastatin are needed. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02679664.

Meta-analyses of sulodexide and other drugs in prevention and treatment of post-thrombotic syndrome.

OBJECTIVE: Post-thrombotic syndrome (PTS) is a common chronic complication of deep vein thrombosis. Elastic compression (ECS) is the common pillar for PTS prevention and treatment, while the pharmacological approach for PTS includes direct oral anticoagulants (DOACs) and venoactive drugs (VADs) for prevention and treatment, respectively. Sulodexide can be used both in long-term prevention and in the treatment of PTS. To better understand the efficacy of the main drugs used in the prevention (sulodexide or DOACs) and treatment of PTS (sulodexide or VADs), pairwise meta-analyses of observational studies and RCTs were conducted. MATERIALS AND METHODS: A literature search in MEDLINE, Embase, and Cochrane Library for observational studies and RCTs was performed. Incidence of PTS, reduction in PTS signs or symptoms and proportion of patients with complete venous ulcers healing were the primary outcomes for prevention and treatment of PTS, respectively. Fixed and Random effect model meta-analyses were performed. Heterogeneity and publication bias were assessed. R® software was used for the analysis. RESULTS: 893 articles were identified during the search. 8 observational studies (6 for DOACs and 2 for sulodexide) and 2 RCTs for sulodexide, out of the 11 studies included in the qualitative synthesis, were included for the prevention and treatment of PTS, respectively. Meta-analyses of observational studies showed an overall incidence of PTS of 15% (95% CI, 11-19) for sulodexide, and a 50% reduction of PTS signs and/or symptoms for rivaroxaban compared to warfarin (OR, 0.50; 95% CI, 0.38-0.65). The overall estimate of the two sulodexide RCTs showed a significant improvement in complete ulcer healing, with an OR of 2.32 (95% CI, 1.49-3.63). CONCLUSIONS: In prevention of PTS, sulodexide and rivaroxaban showed a low incidence and reduced risk of PTS respectively, while in PTS treatment, sulodexide was significantly effective in the complete ulcers healing. These results confirm the need to move from the traditional single-pillar approach with elastic compression stockings to a more effective multi-pillar approach, tailoring the treatment to each individual patient.

Efficacy of rivaroxaban in prevention of post-thrombotic syndrome: A systematic review and meta-analysis.

OBJECTIVE: Direct oral anticoagulants (DOACs) have been recommended for the treatment of deep vein thrombosis (DVT). However, the benefits are uncertain for the prevention of post-thrombotic syndrome (PTS). We performed a systematic review and meta-analysis of reported studies to assess the efficacy of DOACs vs vitamin K antagonists for the risk reduction of PTS in patients with DVT. METHODS: We searched PubMed, Medline, the Cochrane Library, Embase, and the Web of Science for studies reporting on the development of PTS after acute DVT. The outcomes were the risk reduction of PTS, PTS severity, the presence of residual vein thrombosis, and the incidence of recurrent venous thromboembolic (VTE) events. RESULTS: A total of 59,199 patients from six retrospective and two randomized controlled studies had received DOAC treatment and were followed up for the development of PTS. In all studies, rivaroxaban had been compared with initial low-molecular-weight heparin followed by warfarin. Of the 59,199 patients, 19,840 (33.5%) had received rivaroxaban and 39,377 (66.5%), warfarin. The rivaroxaban group had a significant reduction in PTS development compared with the warfarin group (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.43-0.63; P < .001). Severe PTS was less common in the rivaroxaban group than in the warfarin group (3.7% vs 6.4%; OR, 0.55; 95% CI, 0.36-0.85; P = .024). Additionally, rivaroxaban was associated with a significant reduction in VTE recurrence (OR, 0.83; 95% CI, 0.59-1.18; P = .03) and low rates of residual vein thrombosis compared with warfarin (36.5% vs 51.8%; P = .037). CONCLUSIONS: Rivaroxaban after acute DVT was associated with a reduced risk of PTS compared with warfarin. Patients treated with rivaroxaban more rarely developed severe PTS and recurrent VTE events compared with patients treated with warfarin.

Comparing Safety and Efficacy of Rivaroxaban with Warfarin for Patients after Successful Stent Placement for Chronic Iliofemoral Occlusion: A Retrospective Single Institution Study.

OBJECTIVE: The aim was to compare the safety and effectiveness of rivaroxaban and warfarin as anticoagulants for treating patients with post-thrombotic syndrome (PTS) with chronic iliofemoral venous occlusion undergoing iliofemoral venous stenting. METHODS: This single institution retrospective study analysed patients with PTS with chronic iliofemoral venous occlusion who were prescribed rivaroxaban or warfarin for one year after successfully undergoing iliofemoral venous stenting. The primary safety and efficacy endpoints were bleeding complication rate and primary patency rate at one year. Secondary outcomes included Villalta score, symptom recurrence rate, ulcer healing rate, and clinically driven target lesion revascularisation (CD-TLR) rate during follow up. RESULTS: From January 2016 to December 2017, 154 legs from 154 patients were included in this study (69 in rivaroxaban group and 85 in warfarin group). The groups were well matched for patient demographics, clinical characteristics, and procedural details. There was no significant difference between the rivaroxaban group and warfarin group in bleeding complication rate (10% vs. 16%, p = .23, hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.25 - 1.37) at one year, as well as major bleeding complication rate (0% vs. 2%, p = .20, HR 0.16, 95% CI 0.01 - 2.61) and minor bleeding complication rate (10% vs. 14%, p = .40, HR 0.67, 95% CI 0.27 - 1.66). The primary patency rate was higher in the rivaroxaban group at one year (84% vs. 71%, p = .049, HR 0.50, 95% CI 0.26 - 0.96) and at two years (79% vs. 63%, p = .037, HR 0.52, 95% CI 0.29 - 0.93). At a mean follow up of 24 months (range 1 - 42 months), the rivaroxaban group had a significantly lower post-operative Villalta score (4.87 ± 3.51 vs. 6.88 ± 5.85, p = .010, t = 2.64, 95% CI 0.50 - 3.52), lower rate of symptom recurrence (4% vs. 32%, p < .001), lower CD-TLR rates (3% vs. 13%, p = .039), and higher ulcer healing rate (90% vs. 59%, p = .004) than the warfarin group. CONCLUSION: For PTS patients with chronic iliofemoral venous occlusion undergoing iliofemoral venous stenting, rivaroxaban probably exhibited similar safety but superior efficacy to warfarin. However, further prospective control studies with large sample size are necessary to confirm the results.

Low prevalence of Post-thrombotic syndrome in patients treated with rivaroxaban.

Post-thrombotic syndrome (PTS) is a complication of deep vein thrombosis (DVT). Residual vein thrombus (RVT) on Doppler Ultrasound can be associated with PTS. Limited data are available on the effect of direct oral anticoagulants (DOACs) on the long-term outcome of PTS. This study aimed to compare the prevalence of PTS and RVT, in patients with previous DVT treated with rivaroxaban or enoxaparin/warfarin. A total of 129 patients with previous proximal lower limb DVT and treated with rivaroxaban (n = 71) or enoxaparin/warfarin (n = 58) for at least 3 months were included. The Villalta scale for PTS was performed after treatment. The median duration of the DVT symptoms before anticoagulation was 7 days for both groups. The rate of PTS was 50.7% in the patients treated with rivaroxaban and 69% in the enoxaparin/warfarin group. Enoxaparin/warfarin showed an increased prevalence of PTS (P = .018). An analysis in 3 different models showed that the relative risk of PTS decreased by 76% with rivaroxaban use when compared with enoxaparin/warfarin treatment. In addition, 93 of the 129 patients were evaluated regarding the presence of RVT, of which, 11 (24.4%) and 31 (64.6%) presented with RVT for rivaroxaban and enoxaparin/warfarin, respectively (P < .0001). The RVT analysis excluded the possibility of RVT as a mediator of the association between type of treatment and PTS when comparing rivaroxaban with enoxaparin/warfarin (odds ratio (OR) = 0.14; 95% confidence interval (CI): 0.1-1.0, P = .051) with rivaroxaban compared with enoxaparin/warfarin. Rivaroxaban treatment was associated with a lower risk of PTS when compared to enoxaparin/warfarin; RVT however, was not a mediator in the association between PTS and type of treatment.

Comparative outcomes of catheter-directed thrombolysis plus rivaroxaban vs rivaroxaban alone in patients with acute iliofemoral deep vein thrombosis.

BACKGROUND: Since novel oral anticoagulants (NOACs) have been introduced in the past decade, the first option of deep vein thrombosis (DVT) treatment is toward NOACs. However, aggressive and early thrombus removal strategy is widely used for treating acute iliofemoral DVT. Consequently, optimal treatment duration, efficacy, and safety of rivaroxaban alone or in combination with catheter-directed intrathrombus thrombolysis (CDT) in acute iliofemoral DVT patients should be investigated. METHODS: Patients with recent acute iliofemoral DVT treated with combined CDT-rivaroxaban (CDT) or rivaroxaban alone (control) were followed for mean (standard deviation) of 25.7 (2.5) months. DVT evolution, treatment efficacy and safety, and predisposing factors for patency and postthrombotic syndrome (PTS) development were analyzed through duplex ultrasonography, plethysmography, venography, and computed tomographic venography. RESULTS: 43.2%, 64.9%, 75.7%, and 72.2% of the CDT patients showed complete patency at 3, 6, 12, and 24 months of treatment compared with the control patients having 8.5%, 36.2%, 55.3%, and 57.4% of cumulative patency at 3, 6, 12, and 24 months, respectively (p = 0.001, 0.017, 0.088, and 0.081, respectively). The p value of the log-rank test comparing patency rates of the two groups was 0.009. The median (interquartile range, IQR) Villalta scores at 24 months were 3 (2-5) and 6 (4-8) in CDT and control patients, respectively (p = 0·001). PTS and bleeding events during therapy were, respectively, found in 35.1% and 63.8% (p = 0.017) and in 27% and 17% of CDT and control patients (p = 0.4). The Kaplan-Meier curve analysis of cumulative patency at 24 months for 6 months of rivaroxaban treatment was significant (p = 0.016). CONCLUSION: Treatment therapy and treatment duration with rivaroxaban alone or in combination with CDT are potentially associated with vein patency at 24 months, and a 6-month lysis rate and obstructive vein can influence PTS development. A larger randomized trial is warranted to confirm these findings.

Use of Micronized Purified Flavonoid Fraction Together with Rivaroxaban Improves Clinical and Ultrasound Outcomes in Femoropopliteal Venous Thrombosis: Results of a Pilot Clinical Trial.

INTRODUCTION: The aim of this study was to assess the impact of adding long-term micronized purified flavonoid fraction (MPFF) to standard treatment of femoropopliteal deep vein thrombosis (DVT). METHODS: This pilot, comparative, open-label study with blinded outcome assessor enrolled patients with a first episode of femoropopliteal DVT confirmed by duplex ultrasound scanning (DUS). All participants were randomly allocated to one of two treatment groups: (1) control that received a standard treatment with oral rivaroxaban, and (2) experimental that involved additional treatment with MPFF 1000 mg/day. Both drugs were used for 6 months. Patients were followed for the whole treatment period and underwent DUS every 2 months to determine the degree of recanalization by popliteal (PV), femoral vein (FV), and common femoral vein (CFV) compressibility. Thrombi extension were assessed by the modified Marder score. At the end of the follow-up period, patients were assessed with Villalta and venous clinical severity scales (VCSS). Patients with a Villalta score ≥ 5 were diagnosed with post-thrombotic syndrome (PTS). RESULTS: Sixty patients were randomized to the control or MPFF groups (n = 30 in each group). There were 40 men and 20 women with a mean age ± SD of 56.3 ± 13.4 years. Clinically unprovoked DVT was recognized in 65% of cases and left side localization in 45%. The mean baseline Marder score was 15.0 ± 4.8 and 11.1 ± 4.3 in the experimental and control groups, respectively (p = 0.002). At 6 months, the mean Villalta score in the MPFF group was significantly lower compared with control (2.9 ± 2.7 versus 5.8 ± 3.0; p < 0.0001). PTS was diagnosed in six patients (20%) and 17 patients (57%) in the experimental and control groups respectively (p = 0.007). A significant difference between the groups was also observed for the VCSS value (2.3 ± 1.9 versus 4.9 ± 1.9; p < 0001). After 6 months of treatment the Marder score decreased to 0.8 ± 1.6 and 2.8 ± 3.5 in the experimental and control groups, respectively (p = 0.006). In the MPFF group, there was a greater reduction in the Marder score (p < 0.0001) and more rapid rate of recanalization for the FV (p < 0.0001), with a non-significant trend for the CFV (p = 0.130) and PV (p = 0.204) compared with the control group. Full recanalization of the PV at 6 months was observed in 24 patients (80%) who had received MPFF, and only 17 patients (57%) in the control group (p = 0.095). CONCLUSION: The addition of MPFF to standard therapy for DVT in the form of oral rivaroxaban can reduce the incidence of PTS at 6 months in patients with proximal DVT and increase the speed of deep vein recanalization. FUNDING: Les Laboratoires Servier funded the article processing fees, editorial assistance, and open access fee for this manuscript.

Treatment of deep vein thrombosis with rivaroxaban and its potential to prevent the post-thrombotic syndrome.

BACKGROUND: The study was initiated following the observation of complete recanalization of thrombus in subjects with DVT treated with rivaroxaban after 1-2 weeks. The aim of this observational retrospective study was to evaluate clinically and by means of echo color Duplex, the fibrinolytic effect of rivaroxaban in patients with recent and previous DVT. To accomplish this two populations of patients were evaluated. METHODS: Group 1 was comprised of 31 patients (ranging in age 52-73 years) with popliteal-femoral DVT (12 months ago) treated with standard anticoagulant therapy. In these patients, we found a complete superficial femoral recanalization and partial recanalization of the popliteal vein (30% of residual thrombus). The patients had normal creatinine clearance and liver function. The patients were switched from warfarin to rivaroxaban due to a lack of compliance with warfarin therapy. Group 2 was comprised of 22 patients (ranging in age 65-82 years) with previous popliteal-femoral DVT and documented complete common femoral veins recanalization who presented with a recent superficial femoral vein re-thrombosis (1 week before). The patients had normal creatinine clearance and liver function. The patients switched from warfarin to rivaroxaban due to a lack of compliance with warfarin therapy. RESULTS: In group 1, all patients exhibited the complete recanalization of the popliteal veins after 4 weeks of rivaroxaban therapy. In group 2, all patients exhibited the complete recanalization of the popliteal veins after 4 weeks, and the complete recanalization of the acute re-thrombosis of the superficial femoral veins after 2 weeks of rivaroxaban therapy. No adverse events for both groups were observed. CONCLUSIONS: Our results suggest that rivaroxaban could have a pro-fibrinolytic effect not only on recent thrombus but also on organized thrombus that results in a complete recanalization of affected veins. It is proposed that this lytic effect will preserve venous valve structure and lead to a reduction of incidence of post-thrombotic syndrome in rivaroxaban treated patients.

Análise do grau de recanalização da trombose venosa profunda: estudo comparativo de pacientes tratados com varfarina versus rivaroxabana / Analysis of recanalization of deep venous thrombosis: a comparative study of patients treated with warfarin vs. rivaroxaban

Contexto A trombose venosa profunda (TVP) afeta anualmente cerca de dez milhões de pessoas no mundo e tem como principais complicações a embolia pulmonar e a síndrome pós-trombótica. O tratamento padrão é a anticoagulação, que pode ser realizada com heparinas, antagonistas da vitamina K, fondaparinux ou, mais recentemente, com anticoagulantes orais diretos (direct oral anticoagulants, DOACs). Os anticoagulantes diminuem a progressão do trombo e facilitam os mecanismos trombolíticos naturais, fato conhecido como recanalização, que pode ocorrer em graus e tempos variados, influenciados por diversos fatores, dentre eles o tipo de anticoagulação utilizado. Objetivos Avaliar o grau e o tempo de recanalização através da análise de laudos de eco-Doppler colorido (EDC) de pacientes com TVP tratados com DOACs ou com heparina + varfarina. Métodos Foram avaliados retrospectivamente os dados demográficos e os laudos dos EDC dos pacientes com TVP, tratados entre janeiro de 2009 a dezembro de 2016. Os pacientes foram divididos em dois grupos, de acordo com a terapêutica utilizada: Grupo I (heparina + varfarina): 26 pacientes; Grupo II (rivaroxabana): 51 pacientes. Os principais itens observados foram o grau e o tempo para a recanalização. Resultados Foram observadas taxas de recanalização aos 30, 90 e 180 dias de 10%, 52,5% e 78,9%, respectivamente, no Grupo I, e de 55,3%, 83,5% e 92,4%, respectivamente, no Grupo II, com diferença estatisticamente significativa (p = 0,041). Conclusões Ambos os tratamentos promoveram recanalização. Houve recanalização mais precoce no grupo de pacientes que utilizaram a rivaroxabana

Deep venous thrombosis (DVT) strikes around ten million people worldwide every year and is associated with major complications including pulmonary embolism and post-thrombotic syndrome. Anticoagulation is the standard treatment, with administration of heparins, vitamin K antagonists, fondaparinux, or, more recently, direct oral anticoagulants (DOACs). Anticoagulants reduce thrombus progression and facilitate natural thrombolytic mechanisms, leading to a phenomenon known as recanalization, which can occur in varying degrees and over variable periods of time, under influence from many different factors, including the type of anticoagulation employed. Objectives To evaluate the degree of recanalization and the time taken, by analysis of color Doppler ultrasonography (CDU) reports from patients with DVT treated with DOACs or with heparin + warfarin. Methods A retrospective analysis was conducted of demographic data and CDU reports from patients with DVT who had been treated from January 2009 to December 2016. These patients were classified into two groups, according to the treatment given: Group I (heparin + warfarin): 26 patients; or Group II (rivaroxaban): 51 patients. The primary outcomes assessed were degree of recanalization and time taken. Results Recanalization rates at 30, 90, and 180 days were 10%, 52.5%, and 78.9%, respectively, in Group I, and 55.3%, 83.5%, and 92.4%, respectively, in Group II, with statistically significant difference (p = 0.041). Conclusions Both treatments led to recanalization. Recanalization occurred earlier among patients treated with rivaroxaban

Rivaroxaban or vitamin-K antagonists following early endovascular thrombus removal and stent placement for acute iliofemoral deep vein thrombosis.

BACKGROUND: The optimal anticoagulant following catheter-based therapy of acute iliofemoral deep vein thrombosis (IFDVT) is unknown. METHODS: From the Swiss Venous Stent registry, an ongoing prospective cohort study, we performed a subgroup analysis of patients with acute IFDVT who underwent catheter-based early thrombus removal followed by nitinol stent placement. Duplex ultrasound and Villalta scores were used to determine patency rates and incidence of the post-thrombotic syndrome (PTS) in patients treated with either rivaroxaban (n = 73) or a vitamin K-antagonist (VKA; n = 38) for a minimum duration of 3 months. RESULTS: Mean follow-up duration was 24 ±â€¯19 months (range 3 to 77 months). Anticoagulation therapy was time-limited (3 to 12 months) in 56% of patients (47% in the rivaroxaban group and 58% in the VKA group, p = 0.26), with shorter mean duration of anticoagulation in the rivaroxaban group (180 ±â€¯98 days versus 284 ±â€¯199 days, p = 0.01). Overall, primary and secondary patency rates at 24 months were 82% (95%CI, 71-89%) and 95% (95%CI, 87-98%), respectively, with no difference between the rivaroxaban (87% [95%CI, 76-94%] and 95% [95%CI, 85-98%]) and the VKA group (72% [95%CI, 52-86%] and 94% [95%CI, 78-99%]; p > 0.10 for both). Overall, 86 (86%) patients were free from PTS at latest follow-up, with no difference between the rivaroxaban and the VKA groups (57 [85%] versus 29 [88%]; p = 0.76). Two major bleeding complications (1 in each group) occurred in the peri-interventional period, without any major bleeding thereafter. CONCLUSIONS: In patients with acute IFDVT treated with catheter-based early thrombus removal and venous stent placement, the effectiveness and safety of rivaroxaban and VKA appear to be similar. CLINICAL TRIAL REGISTRATION: The study is registered on the National Institutes of Health website (ClinicalTrials.gov; identifier NCT02433054).

Rutosides for prevention of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. The current standard care for the prevention of PTS following DVT is elastic compression stockings. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the prevention of PTS. This is the second update of the review first published in 2013. OBJECTIVES: To determine the effectiveness and safety of rutosides for prevention of post-thrombotic syndrome (PTS) in patients with deep vein thrombosis (DVT), compared to placebo, no intervention, or reference medication. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 21 August 2018. SELECTION CRITERIA: We planned to include trials of rutosides versus any alternative (placebo, no intervention, or reference medication) in the prevention of PTS in patients with DVT. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and intended to extract information from the trials. MAIN RESULTS: No studies were identified comparing rutosides versus any alternative in the prevention of PTS. AUTHORS' CONCLUSIONS: As there were no studies identified in this review there is currently insufficient evidence to determine the effectiveness and safety of rutosides for prevention of PTS in patients with DVT. Some studies suggest that rutosides may provide short-term relief of PTS symptoms. However, there is nothing published on their use as a preventative therapy for PTS. High quality randomised controlled trials of rutoside versus any alternative are required to build the evidence base in this area.

Rutosides for treatment of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the treatment of PTS. This is the second update of the review first published in 2013. OBJECTIVES: To determine the effectiveness (improvement or deterioration in symptoms) and safety of rutosides for treatment of post-thrombotic syndrome (PTS) in patients with DVT compared to placebo, no intervention, elastic compression stockings (ECS) or any other treatment. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 21 August 2018. SELECTION CRITERIA: Two review authors independently assessed studies for inclusion. Studies were included to allow the comparison of rutosides versus placebo or no treatment, rutosides versus ECS, and rutosides versus any other treatment. Two review authors extracted information from the trials. Disagreements were resolved by discussion. DATA COLLECTION AND ANALYSIS: Data were extracted using designated data extraction forms. The Cochrane 'Risk of bias' tool was used for all included studies to assist in the assessment of quality. Primary outcome measures were the occurrence of leg ulceration over time (yes or no) and any improvement or deterioration of post-thrombotic syndrome (yes or no). Secondary outcomes included reduction of oedema, pain, recurrence of DVT or pulmonary embolism, compliance with therapy, and adverse effects. All of the outcome measures were analysed using Mantel-Haenzel fixed-effect model odds ratios. The unit of analysis was the number of patients. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. Overall quality of evidence using the GRADE approach was low, predominantly due to the lack of both participant and researcher blinding in the included studies. The quality of the evidence was further limited as only three small studies contributed to the review findings. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention. One study compared rutosides with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was no clear evidence to support a difference in PTS improvement between the rutosides or placebo/no treatment groups (OR 1.29, 95% CI 0.69 to 2.41; 164 participants; 2 studies; low-quality evidence); or between the rutosides and ECS groups (OR 0.80, 95% CI 0.31 to 2.03; 80 participants; 1 study ; low-quality evidence). Results from one small study reported less PTS improvement in the rutosides group compared to an alternative venoactive remedy (OR 0.18, 95% CI 0.04 to 0.94; 29 participants; 1 study; low-quality evidence). There was no clear evidence to support a difference in PTS deterioration when comparing rutosides with placebo/no treatment (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); with ECS (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); or an alternative venoactive remedy (OR 0.19, 95% CI 0.01 to 4.24; 29 participants; 1 study). No clear evidence of a difference in adverse effects between the rutosides and placebo/no treatment groups was seen ('mild side effects' reported in 7/41 and 5/42 respectively). In the study comparing rutosides with ECS, 2/80 could not tolerate ECS and 6/80 stopped medication due to side effects. The study comparing rutosides with an alternative venoactive remedy did not comment on side effects AUTHORS' CONCLUSIONS: There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited low-quality evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence to support the use of rutosides in the treatment of PTS.

Electrical calf muscle stimulation in patients with post-thrombotic syndrome and residual venous obstruction after anticoagulation therapy.

BACKGROUND: The aim of this study was to assess the impact of electrical calf muscle stimulation (EMS) on clinical and ultrasound outcomes in patients with post-thrombotic syndrome (PTS) and residual venous obstruction (RVO). METHODS: This was a prospective, comparative, non-randomized clinical trial involving patients who had completed a standard 6-month course of anticoagulation therapy for a first episode of unprovoked femoro-popliteal DVT and had signs of RVO in the affected veins and PTS as shown by a Villalta Score of >5. A blinded outcome assessor performed the ultrasound evaluations. A total of 60 patients in the age range from 40 to 86 years (mean 58.5±11.4) consisting of 38 men and 22 women were enrolled. They were divided into two groups of 30 participants each. Both groups (experimental and control) were treated by active walking, below-knee graduated compression stockings, and micronized purified flavonoid fraction. In the experimental group, EMS with «Veinoplus VI¼ device (three applications for 30 min every day) was also used. The patients were followed for 12 months with monthly DUS to reveal recurrent DVT and changes in RVO. The clinical criteria for treatment efficacy included changes in Villalta, VCSS and CIVIQ-20 scores. RESULTS: Recurrent DVT was found in seven of 30 patients in the control group and in zero of 30 patients in the experimental group (23.3% versus 0%, P=0.01). Through the follow-up period the degree of RVO decreased in all affected veins in both groups (P<0.01). The most significant changes were found in the popliteal vein; 60.8% decreased to 28.8% in the experimental group and 50.9% to 27.3% in the control group (P<0.01) with significant differences between the groups (P<0.01). VCSS, Villalta and CIVIQ-20 scores also significantly decreased in both groups (P<0.01). In the group with EMS, changes in the current parameters were more intensive (P<0.01). CONCLUSIONS: There is an ongoing process of deep vein recanalization during the 12 months after anticoagulant therapy cessation. Use of EMS in PTS treatment allows for reduction of recurrent DVT rates, increase the speed of deep vein recanalization and leads to additional improvement in the clinical PTS outcomes.

Considerations for Systemic and Topical Treatment of Morganella morganii Septicemia Arising from Maggot Infestation.

INTRODUCTION: Live maggot infestation (myiasis) of wounds can present a host of ailments. Loosely associated with maggot excreta, Morganella morganii is a widespread, gram-negative rod bacterium commonly found in the intestinal tracts of humans. M morganii has been observed as being pathogenic, particularly in nosocomial and postoperative environments, as well as in immunosuppressed and elderly populations. CASE REPORT: Herein, the authors present a rare, previously unreported case of M morganii septicemia (as confirmed by positive blood culture), secondary to myiasis of the lower extremities. The patient was successfully treated with both systemic and topical interventions. Posttreatment examination revealed resolution of myiasis and negative blood cultures. CONCLUSIONS: Myiasis can be invasive, leading to severe systemic infection. In these cases, a broad-spectrum antibiotic combined with systemic and topical antiparasitic therapy should be considered.

Prevention of recurrent venous thrombosis and post-thrombotic syndrome.

BACKGROUND: This retrospective registry study evaluated different managements on the development of post-thrombotic syndrome (PTS) and recurrent deep venous thrombosis (R-DVT). The effects of aspirin (100 mg/day), added to the "standard management" (SM) (IUA consensus), were observed in patients after a proximal DVT. METHODS: The study started after the anticoagulant period. Comparable groups used the mild-antithrombotic agent Pycnogenol® (200 mg/day), ticlopidine (250 mg/day) or sulodexide (500 ULS/day). RESULTS: The groups were comparable for sex and age distribution and clinical pictures. In the SM group, 222 patients completed the follow-up (72 months). With SM, the percentage of patients with R-DVT (requiring anticoagulants) was 17.2%; 19.8% of SM patients had a PTS. In the aspirin group (202 subjects), R-DVT was observed in 14.8% of patients; 17.32% had a PTS. The reduction in R-DVT and PTS with aspirin was significant (P<0.05) vs. the SM. There was no tolerability problem in subjects using Pycnogenol® (137 patients); they had a much lower incidence of R-DVT (5.8%) and PTS (6.5%) vs. SM and aspirin (P<0.05). Ticlopidine (121 patients) reduced the incidence of R-DVT (12.4%) and PTS (19.8% of patients) (P<0.05 vs. SM). With sulodexide the incidence of R-DVT was 6.7% (P<0.05 vs. SM); the incidence of PTS was 16.6% (P<0.05 vs. SM). The combined R-DVT+PT syndrome was observed in 14.9% of subjects using SM and in 12.9% of subjects using aspirin (P<0.05 vs. SM), in 3.6% of subjects managed with Pycnogenol® (<0.05% vs. aspirin and all other managements). The incidence was 10.74% with ticlopidine and 6.7% with sulodexide (both significantly lower than SM). CONCLUSIONS: Interaction between PTS and R-DVT are complex; recurrences cause more PTSs, and a post-thrombotic limb is prone to R-DVT. Aspirin, for patients that can tolerate it, reduces the occurrence of PTS and R-DVT. In addition, ticlopidine and sulodexide are effective. Pycnogenol® is the most effective and safe for R-DVT and particularly PTS. Its full range of anti-thrombotic activity is now under evaluation.

Rivaroxaban Versus Warfarin and Risk of Post-Thrombotic Syndrome Among Patients with Venous Thromboembolism.

BACKGROUND: The effectiveness of rivaroxaban to reduce post-thrombotic syndrome in patients with venous thromboembolism is largely unknown. We compared rates of post-thrombotic syndrome in patients given rivaroxaban versus warfarin in a cohort of patients with incident venous thromboembolism receiving routine clinical care. METHODS: We linked Danish nationwide registries to identify all patients with incident venous thromboembolism who were new users of rivaroxaban or warfarin and compared rates of post-thrombotic syndrome using an inverse probability of treatment-weighting approach to account for baseline confounding. RESULTS: We identified 19,957 oral anticoagulation-naive patients with incident venous thromboembolism treated with warfarin or rivaroxaban (mean age, 64 years; 48% were female, 45.5% had pulmonary embolism). The propensity-weighted rate of post-thrombotic syndrome at 3 years follow-up was 0.53 incidents per 100 person-years with rivaroxaban versus 0.55 per 100 person-years with warfarin, yielding a hazard rate of 0.88 (95% confidence interval, 0.66-1.17). This association remained consistent across types of venous thromboembolism (deep venous thrombosis vs pulmonary embolism, and provoked vs unprovoked venous thromboembolism) and when censoring patients with recurrent venous thromboembolism. CONCLUSIONS: In this clinical practice setting, rivaroxaban was associated with lower but statistically nonsignificant rates of post-thrombotic syndrome, which did not appear to be mediated only by an effect on recurrent venous thromboembolism.

Rivaroxaban versus warfarin for the prevention of post-thrombotic syndrome.

INTRODUCTION: Despite treatment of acute deep vein thrombosis (DVT) with low molecular weight heparin and warfarin, up to 50% of patients develop post-thrombotic syndrome (PTS). Our aims were to assess whether treatment of DVT with rivaroxaban would reduce the rate of subsequent PTS and improve health-related quality of life (HRQoL) as compared to conventional anticoagulation with low molecular weight heparin (LMWH)/warfarin. MATERIALS AND METHODS: Consecutive patients with an objectively confirmed DVT diagnosed between 2011 and 2014 and treated with either rivaroxaban or warfarin were included in this study 24 (±6) months after DVT. PTS was assessed using the Patient Reported Villalta scale. HRQoL was assessed using the EQ-5D-3L and VEINES-QOL/Sym questionnaires. RESULTS: Total 309 patients were included, 161 (52%) treated with rivaroxaban and 148 (48%) with warfarin. Rivaroxaban-treated patients had a lower rate of PTS (45%: 95% confidence interval [CI] 37 to 52) compared to those treated with warfarin (59%: 95% CI 51 to 66, absolute risk difference 14%: 95% CI 3 to 25, odds ratio (OR) 0.6, P = .01). The adjusted OR for development of PTS was 0.5 (95% CI: 0.3 to 0.8, P = .01) in patients treated with rivaroxaban. HRQoL was significantly better in the rivaroxaban-treated patients. HRQoL measured by EQ-VAS (P = .002) and VEINES-QOL/Sym (P = .005/P = .003) remained significantly better after adjustment. CONCLUSIONS: Patients treated with rivaroxaban had lower rate of PTS and better HRQoL after DVT compared to patients treated with warfarin. However, these results should be interpreted with caution due to the limitation imposed by study design.

Neuromuscular electrical stimulation for the prevention of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is a serious but preventable cause of morbidity and mortality. Neuromuscular electrical stimulation systems (NMES) for the prevention of VTE may be beneficial for patients in whom pharmacological or standard mechanical prophylaxis methods are contraindicated or are regarded as unsafe or impractical. Although findings of experimental studies suggest that NMES reduce venous stasis, the clinical utility and effectiveness of NMES in VTE prevention remain controversial. OBJECTIVES: To assess the effectiveness of neuromuscular electrical stimulation in the prevention of venous thromboembolism. SEARCH METHODS: The Cochrane Vascular Group Information Specialist (CIS) searched the Specialised Register (22 March 2017) and the Cochrane Central Register of Controlled Studies (CENTRAL (2017, Issue 2)). The CIS also searched trial registries for details of ongoing and unpublished studies. The review authors searched the bibliographic lists of relevant articles and reviews to look further for potentially eligible trials. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-randomised trials that compared any form of neuromuscular electrical stimulation as an intervention for VTE prophylaxis (alone or combined with pharmacological or other mechanical methods) versus no prophylaxis and other mechanical or pharmacological methods of VTE prophylaxis. DATA COLLECTION AND ANALYSIS: At least two independent review authors were involved in study selection, data extraction, methodological quality assessment of included studies, and data analysis. We resolved disagreements by discussion between the two review authors. If no agreement could be reached, a third review author acted as an adjudicator. The main outcomes of the review were total deep vein thrombosis (DVT), symptomatic and asymptomatic DVT, pulmonary embolism (PE), total VTE and bleeding (major and minor). The quality of evidence was assessed using the GRADE approach and is indicated in italics. MAIN RESULTS: We included in the review five randomised controlled trials and three quasi-randomised trials, enrolling a total of 904 participants. Among these, four studies included patients undergoing major surgical procedures; one study included patients undergoing surgery for hip fracture under spinal anaesthesia; one study included trauma patients with a contraindication for prophylactic heparin; one study included neurosurgical patients who were operated on under general anaesthesia; and one study included patients with non-functional spinal cord injuries. Overall, eight studies investigated 22 treatment arms. Four studies compared the NMES arm with a no prophylaxis arm, and five studies compared the NMES arm with alternative methods of prophylaxis arms. Alternative methods of prophylaxis included low-dose heparin (5000 IU subcutaneously) - two studies, Dextran 40 - one study, graduated compression stockings (GCS) and intermittent pneumatic compression devices (IPCD) - one study. One study compared combined NMES and low-dose heparin versus no prophylaxis or low-dose heparin alone.We found no clear difference in risks of total DVT (odds ratio (OR) 1.01, 95% confidence interval (CI) 0.60 to 1.70, P = 0.98; 6 studies, 415 participants; low-quality evidence), asymptomatic DVT (OR 1.61, 95% CI 0.40 to 6.43, P = 0.50; 1 study, 89 participants; low-quality evidence), symptomatic DVT (OR 0.40, 95% CI 0.02 to 10.07, P = 0.58; 1 study, 89 participants; low-quality evidence), PE (OR 1.31, 95% CI 0.38 to 4.48, P = 0.67; 2 studies, 126 participants;low-quality evidence), and total VTE (OR 0.92, 95% CI 0.34 to 2.52, P = 0.88; 1 study, 72 participants; low-quality evidence) between prophylaxis with NMES and alternative methods of prophylaxis. None of the studies in this comparison reported bleeding.Compared with no prophylaxis, NMES showed lower risks of total DVT (OR 0.40, 95% CI 0.23 to 0.70, P = 0.02; 4 studies, 576 participants; moderate-quality evidence) and total VTE (OR 0.23, 95% CI 0.09 to 0.59, P = 0.002; 1 study, 77 participants; low-quality evidence). Data show no clear differences in risk of asymptomatic DVT (OR 0.32, 95% CI 0.06 to 1.62, P = 0.17; 1 study, 200 participants; low-quality evidence), symptomatic DVT (OR 0.06, 95% CI 0.00 to 1.36, P = 0.08; 1 study, 160 participants;low-quality evidence), or PE (OR 0.36, 95% CI 0.12 to 1.07, P = 0.07; 1 study, 77 participants; low-quality evidence) between prophylaxis with NMES and no prophylaxis. None of the studies in this comparison reported bleeding.In comparison with low-dose heparin, NMES was associated with higher risk of total DVT (OR 2.78, 95% CI 1.19 to 6.48, P = 0.02; 2 studies, 194 participants; low-quality evidence), but data were inadequate for other comparisons (NMES vs Dextran 40, NMES vs GCS, or NMES vs IPCD) and for other clinical outcomes such as symptomatic or asymptomatic DVT, PE, total VTE, and bleeding in individual comparisons.Overall, we judged the quality of available evidence to be low owing to high or unclear risk of bias and imprecise effect estimates due to small numbers of studies and events. AUTHORS' CONCLUSIONS: Low-quality evidence shows no clear difference in the risk of DVT between NMES and alternative methods of prophylaxis but suggest that NMES may be associated with lower risk of DVT compared with no prophylaxis (moderate-quality evidence) and higher risk of DVT compared with low-dose heparin (low-quality evidence). The best available evidence about the effectiveness of NMES in the prevention of VTE is not adequately robust to allow definitive conclusions. Adequately powered high-quality randomised controlled trials are required to provide adequately robust evidence.

[Endovascular treatment of a patient with post-thrombotic disease and obstruction of a cava filter]. / Éndovaskuliarnoe lechenie bol'nogo s posttromboticheskoi bolezn'iu i obstruktsiei kava-fil'tra.

Balloon angioplasty and stenting have increasingly been gaining widespread application for treatment of post-thrombotic alterations in the system of the vena cava. Endovascular ultrasonographic examination makes it possible with the utmost degree of reliability to determine both the extension and degree of the narrowing of venous segments, thus proving a possibility of choosing a venous stent of an appropriate diameter. Restoration of an adequate venous lumen leads to normalization of blood flow and elimination of venous hypertension. However, unsolved as yet remains the problem concerning proper management of post-thrombotic obstructions of the inferior vena cava at the level of a cava filter. Owing to a wide variety of configurations of cava filters to deploy, there are no common approaches to elimination of such obstruction. Presented herein is a clinical case report regarding successful endovascular treatment of a patient diagnosed with post-thrombotic disease secondary to endured thrombosis. The findings of both phlebography and endovascular ultrasonographic examination made it possible to diagnose obstruction of the left common iliac vein, external iliac vein, and inferior vena cava to the level of the cava filter previously deployed. In the segment of the inferior vena cava at the level of the cava filter also revealed was a pronounced luminal narrowing exceeding 90% of its diameter. We carried out stenting of the common and external iliac veins, inferior vena cava, and the cava filter. Swelling of the left leg subsided spontaneously within 2 weeks and the first postoperative month was accompanied by gradual disappearance of the previously existing feeling of heaviness in the lower limbs and a dramatic decrease in fatigue by the end of the working day.

[Clinical efficacy of electric stimulation of crural muscles in comprehensive treatment of post-thrombotic disease]. / Klinicheskaia éffektivnost' élektricheskoi stimuliatsii myshts goleni v kompleksnom lechenii posttromboticheskoi bolezni.

The purpose of the study was to evaluate clinical efficacy of electromyostimulation (EMS) of the crural muscles as part of comprehensive therapy for post-thrombotic disease in patients with residual venous obstruction in the femoropopliteal segment. We carried out a prospective comparative clinical study enrolling patients having endured a fist episode of clinically unprovoked venous thrombosis of the femoropopliteal segment and completed the standard 6-month course of anticoagulant therapy and presenting with ultrasonographic signs of complete recanalization of the proximal venous segments (stenosis of 20% and more from the vessel's initial diameter), as well as scoring 5 points and more by the Villalta scale. The study included a total of 60 patients (38 men and 22 women, mean age 58.5±11.4 years) subdivided into two groups consisting of 30 patients each. Patients of both the Study and Control Groups underwent comprehensive therapy including wearing a compression knee sock (23-32 mmHg), a course phlebotrophic drugs, and dosed walking (not less than 5,000 steps a day). The Study Group patients were additionally subjected to daily electrical stimulation of the crural muscles with the "Veinoplus VI" unit (three 30-minute sessions a day). The duration of the follow up amounted to 12 months. The criteria for assessing therapeutic efficacy were as follows: severity of the disease by the VCSS and Villalta scales, quality of life as assessed by the CIVIQ-20 questionnaire, and lack of relapses of the venous thrombus. Clinical and instrumental assessment of the patients' condition was carried out monthly, with the disease's severity and quality of life assesses each 6 months. Relapses of venous thrombosis were registered in 7 (23.3%) patients from the Control Group and were not observed in patients undergoing EMS (p=0.011). In 5 cases, thrombosis was asymptomatic and in 4 cases it was presented by reocclusion of the involved venous segments. Patients of the Study Group were found to have a decrease in the disease's severity, reflected in points: VCSS (9.9±1.6 - 7.8 ± 1.6 - 6.1±1.5 (p <0.0001)); Villalta scale (18.9±3.9 - 12.8±4.0 - 8.3±2.7 (p<0.0001)); CIVIQ-20 score (67.8±8.4 - 51.3±8.4 - 40.0±10.5 (p<0.001)). The Control Group patients showed a similar tendency for the disease's severity: 8.1±2.8 - 7.3±2.1 - 7.2±2.1 points by the VCSS (p=0.014); 12.7±6.7 - 10.9±5.6 - 10.2±5.4 points by the Villalta scale (p=0.002), but not for quality of life: 48.2±19.3 - 46.7±17.3 - 47.4±16.2 points by the CIVIQ-20 (p>0.05). On the background of using EMS, the alterations in the studied parameters were characterized by higher velocity and intensity (p<0.05). The use of electromyostimulation as part of comprehensive treatment for post-thrombotic disease makes it possible to efficiently eliminate both subjective and objective signs of venous insufficiency, improve patients' quality of life and decrease the risk for the development of relapsing venous thrombosis.