Varicose vein surgery after acute isolated superficial vein thrombosis in daily practice: INSIGHTS-SVT study.

OBJECTIVE: The aim of this study was to assess the utilization of surgical interventions in patients diagnosed with superficial vein thrombosis (SVT) and its potential association with the occurrence of venous thromboembolism (VTE) and bleeding events. METHODS: INSIGHTS-SVT, a prospective, non-interventional, multicenter study in Germany, investigated the management and outcomes of patients with acute SVT who received conservative and/or invasive treatments at the discretion of the treating physician. RESULTS: Among the 872 patients with 12-month data, 657 had medical therapy only, and 215 patients underwent vascular surgery (70 within 3 months of SVT diagnosis, 136 between months 4 and 12, and nine had an intervention in both periods). The most commonly performed procedures included endovenous thermal ablation, ligation of the saphenofemoral or saphenopopliteal junction, and vein stripping. The primary outcome of symptomatic VTE was observed in 5.8% of conservatively treated patients and 6.3% of those who underwent surgical intervention. Additionally, the secondary outcome of recurrent or extended SVT was documented in 4.7% of conservatively treated patients and 5.3% of invasively treated patients. Bleeding events occurred in 1.4% of conservatively treated patients and 2.1% of surgically treated patients. These differences were statistically not significant. Furthermore, our analysis indicated a potential protective effect associated with surgical treatments, such as ligation of the saphenofemoral or saphenopopliteal junction, stripping and endovenous thermal ablation, concerning the endpoint of VTE for patients when applied after 3 months from the index SVT event. CONCLUSIONS: In line with previous research, our study suggests that surgical interventions are not frequently employed in the management of SVT, although they may be warranted in select cases. Nevertheless, additional research is essential to gain a deeper understanding of the indications, criteria, and benefit of surgical interventions in the treatment of SVT.

Determinants of Late Venous Thromboembolic Events After Acute Isolated Superficial Vein Thrombosis in Daily Practice: 12 Month Results of the INSIGHTS-SVT Study.

OBJECTIVE: Long term incidence of symptomatic venous thromboembolism (VTE) and bleeding events in patients with superficial vein thrombosis (SVT) was investigated. METHODS: In this prospective, observational study, patients with acute SVT were treated at the discretion of the responsible physician. The primary efficacy outcome was symptomatic VTE including deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent or extending SVT. The primary safety outcome was clinically relevant bleeding, recorded at periodic clinic visits over a 12 month period. RESULTS: The mean age of 872 patients with 12 month follow up was 60.6 ± 14.5 years, 64.5% were female, 80.1% had chronic venous disease (defined as chronic venous insufficiency and or varicose veins), and 41.9% had a history of VTE. They were receiving fondaparinux in 62.1% (mean duration 34.9 ± 15.7 days), low molecular weight heparin (LMWH) in 25.0% (mean duration 26.2 ± 23.2 days), any other anticoagulants in 6.2%, and no anticoagulant in 6.7%. At 12 months, 108 patients (14.3%) achieved the primary efficacy outcome. The most common VTE event was recurrent or extending SVT in 11.0%, followed by symptomatic DVT in 2.7%, symptomatic PE in 2.4%, hospitalisation due to VTE in 1.8%, and death in 1.1%. Clinically relevant bleeding events occurred in 2.1% of patients, and major bleedings in 0.3%. By drug, the rate of the primary efficacy outcome was highest in the LMWH group (22.4%) and lowest in the fondaparinux group (10.4%). In a multivariable model, patients with events between three months and 12 months were significantly more likely to have higher BMI (hazard ratio [HR] 1.06; p = .002), history of VTE (HR 2.89; p = .002), and severe systemic infections (HR 7.59; p = .006). CONCLUSION: The risk of symptomatic VTE remained elevated over 12 months of follow up. Therefore, anticoagulation beyond 45 days may be considered in patients with risk factors. [ClinicalTrials.gov identifier: NCT02699151.].

Management and Outcomes of Patients with Isolated Superficial Vein Thrombosis under Real Life Conditions (INSIGHTS-SVT).

OBJECTIVE: Management and outcomes of superficial vein thrombosis (SVT) are highly variable and not well described. Therefore, the INvestigating SIGnificant Health TrendS in the management of SVT (INSIGHTS-SVT) study collected prospective data under real life conditions. METHODS: Prospective observational study of objectively confirmed acute isolated SVT. The primary outcome was a composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), and extension or recurrence of SVT at three months. The primary safety outcome was clinically relevant bleeding. RESULTS: A total of 1 150 patients were included (mean age 60.2 ± 14.7 years; 64.9% women; mean BMI 29.4 ± 6.3 kg/m2). SVT was below the knee in 54.5%, above the knee in 26.7%, above and below the knee in 18.8%. At baseline, 93.6% received pharmacological treatment (65.7% fondaparinux, 23.2% heparins, 4.3% direct oral anticoagulants [DOACs], 14.5% analgesics), 77.0% compression treatment, and 1.9% surgery; 6.4% did not receive any anticoagulation. The primary outcome occurred in 5.8%; 4.7% had recurrent or extended SVT, 1.7% DVT, and 0.8% PE. Clinically relevant non-major bleeding occurred in 1.2% and major bleeding in 0.3%. Complete clinical recovery of SVT was reported in 708 patients (62.4%). Primary outcome adjusted by propensity score and for treatment duration was lower with fondaparinux compared with low molecular weight heparin (4.4% vs. 9.6%; hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.3 - 0.9; p = .017). On multivariable analysis, associated factors for primary outcome included another SVT prior to the present SVT event (HR 2.3), age per year (HR 0.97), duration of drug treatment per week (HR 0.92), and thrombus length (HR 1.03). CONCLUSION: At three month follow up, patients with isolated SVT are at risk of thromboembolic complications (mainly recurrent or extended SVT), despite anticoagulation. In this real life study, about one third had received either heparins, oral anticoagulants, or no anticoagulation.

Rationale, design, and methodology of the observational INSIGHTS-SVT study on the current state of care and outcomes of patients with superficial vein thrombosis.

OBJECTIVE: Superficial vein thrombosis (SVT) is a common disease in clinical practice. In terms of pathophysiology and outcomes, the condition is related to venous thromboembolism, bearing a potential for severe thromboembolic complications if it is not treated adequately. A wide range of treatment approaches (including oral and injectable anticoagulants, pain medication, nondrug therapy including compression therapy, and no treatment at all) are applied in clinical practice, but there is sparse information about selection of patients for therapies, current treatment pathways, and drug use as well as outcomes. The INvestigating SIGnificant Health TrendS in the management of Superficial Vein Thrombosis (INSIGHTS-SVT) study aims to close this gap by collecting representative data on the current treatment of SVT. METHODS: The observational prospective study of about 1200 patients is carried out by up to 120 clinical and office-based physicians who regularly treat patients with SVT and are capable of conducting appropriate compression ultrasound diagnostics, such as vascular physicians, phlebologists, internists, vascular surgeons, and general practitioners. Patients are eligible for inclusion if they have ultrasound-confirmed acute, isolated SVT of the lower extremities. Documentation about the characteristics of the patients, diagnostics, comorbidities, and medical and nonmedical treatment is collected at baseline, at 10 ± 3 days or at approximately 45 days (depending on treatment), at approximately 3 months, and at approximately 12 months. Patients are requested to fill in quality of life questionnaires (on pain, Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms [VEINES-QOL/Sym], EuroQol-5 Dimension 5-Level [EQ-5D-5L]) at baseline and at approximately 3 months. Interventions are not stipulated by the trial protocol. RESULTS: The primary efficacy outcome is the incidence of venous thromboembolism at 3 months; the primary safety outcome is the combined incidence of major and clinically relevant bleeding events at 3 months. As quality measures, plausibility checks at data entry, queries based on statistical analyses that focus on outliers and distribution of values, monitoring visits, and adjudication procedures will be applied. CONCLUSIONS: This large study is expected to provide a comprehensive picture of patients with SVT under clinical practice conditions in Germany.

Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial.

BACKGROUND: Superficial-vein thrombosis can lead to deep-vein thrombosis and pulmonary embolism. Rivaroxaban, an oral factor Xa inhibitor, might simplify treatment compared with fondaparinux because it does not require daily subcutaneous injection and is cheaper. We compared efficacy outcomes in patients with superficial-vein thrombosis and additional risk factors given either rivaroxaban or fondaparinux to assess whether rivaroxaban is non-inferior to fondaparinux in the prevention of thromboembolic complications. METHODS: In this open-label, masked endpoint, randomised, non-inferiority phase 3b trial, we recruited patients aged 18 years or older with symptomatic superficial-vein thrombosis from 27 sites (academic, community hospitals, and specialist practices) in Germany. We randomly assigned patients (1:1) to receive 10 mg oral rivaroxaban or 2·5 mg subcutaneous fondaparinux once a day for 45 days. Patients were eligible if they had symptomatic thrombosis (at least 5 cm in a supragenual superficial-vein segment) and at least one additional risk factor (older than 65 years, male sex, previous venous thromboembolism, cancer, autoimmune disease, thrombosis of non-varicose veins). Main exclusion criteria were: symptoms for longer than 3 weeks, thrombus within 3 cm of the sapheno-femoral junction, indication for full-dose anticoagulation therapy, and substantial hepatic or renal impairment. Randomisation was done with a central block randomisation process. The primary efficacy outcome was a composite of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality at 45 days in the per-protocol population (all randomly assigned patients without major protocol violations). We used a non-inferiority margin of 4·5% (absolute difference between rivaroxaban and fondaparinux). The main safety outcome was major bleeding. This study is registered with ClinicalTrials.gov, number NCT01499953. FINDINGS: Between April 25, 2012, and Feb 18, 2016, 485 patients were enrolled in the study and 472 were randomly assigned to the rivaroxaban group (n=236) or the fondaparinux group (n=236). In the 435 patients included in the per-protocol analysis set, the primary efficacy outcome occurred in seven (3%) of 211 patients (95% CI 1·6-6·7) in the rivaroxaban group and in four (2%) of 224 patients (0·7-4·5) in the fondaparinux group (hazard ratio [HR] 1·9, 95% CI 0·6-6·4; p=0·0025 for non-inferiority) at day 45. There were no major bleeds in either group. There was one death in the rivaroxaban group; this patient died from cardiogenic shock on day 50 after a type A aortic dissection, not related to treatment. INTERPRETATION: Rivaroxaban was non-inferior to fondaparinux for treatment of superficial-vein thrombosis in terms of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality, and was not associated with more major bleeding. Therefore, rivaroxaban could offer patients with symptomatic superficial-vein thrombosis a less burdensome and less expensive oral treatment option instead of a more expensive subcutaneous injection. FUNDING: GWT-TUD and Bayer Vital.

Superficial vein thrombosis treated for 45 days with rivaroxaban versus fondaparinux: rationale and design of the SURPRISE trial.

Patients with superficial vein thrombosis (SVT) are commonly treated with low-molecular weight heparin or fondaparinux in prophylactic, intermediate or therapeutic dosages for treatment periods of 10-45 days. This practice is also reflected by the current guideline recommendations. However, given the broad range of thromboembolic complication rates in SVT (between 0 and 30 % have been reported) it seems reasonable to suspect that risk stratification is needed to differentiate patients at low risk who may not benefit from anticoagulation from those at high risk who may need higher dosages or a longer duration of anticoagulation. Furthermore, prolonged treatment with injectable anticoagulants has been shown to result in poor patient adherence. Direct oral anticoagulants have recently been approved for venous thromboembolism therapy and these new drugs may offer advantages also for SVT patients. The prospective, randomized, open-label, blinded adjudication trial superficial phlebitis treated for 45 days with rivaroxaban versus fondaparinux (SURPRISE) will evaluate the efficacy and safety of 10 mg rivaroxaban OD compared to fondaparinux 2.5 mg OD for SVT treatment in a subset of high-risk SVT patients over a treatment period of 45 days. The purpose of the study is to demonstrate non-inferiority of rivaroxaban compared to fondaparinux in preventing the combined efficacy endpoint of thrombus progression, SVT recurrence, DVT, PE and death. The results of the SURPRISE trial will provide evidence for the concept of risk stratification in SVT and for the value of rivaroxaban 10 mg in SVT treatment (clinicaltrials.gov NCT01499953).

Post-thrombotic syndrome 3 years after deep venous thrombosis in the Thrombosis and Pulmonary Embolism in Out-Patients (TULIPA) PLUS Registry.

BACKGROUND: Reported post-thrombotic syndrome (PTS) rates may be confounded by including patients with a history of deep venous thrombosis (DVT) before the index event, varicose veins, or chronic venous insufficiency independent of PTS. We were interested in assessing PTS incidence rates of patients without these pre-existing disease conditions. METHODS: A prospective registry with a 3-year follow-up after an initial DVT was assessed. Available for analysis were 135 ambulatory patients without a history of DVT (before the index DVT), signs of varicose veins, or chronic venous insufficiency affecting the ipsilateral or contralateral leg, and Villalta score. RESULTS: PTS was detected in 24.5% of patients, with 17.0% having mild (Villalta score, 5-9), 6.0% moderate (score, 10-14), and 1.5% severe PTS (score ≥15) after a first DVT. Of these, 52.6% had proximal and 47.4% distal DVT; 63.7% were provoked and 35.6% unprovoked (one patient missing). Patients with proximal DVT (32.4%) significantly more often developed any PTS compared with patients with distal DVT (15.6%; P = .024); however, groups were similar with regard to severity of PTS by the four-level Villalta score (P = .109). In univariate analysis, PTS was more frequent (odds ratio, 95% confidence interval) with higher age (1.06 per year; 1.02-1.09), a body mass index of 25 to 30 kg/m(2) (2.38; 0.71-7.97) and ≥30 kg/m(2) (6.08; 1.75-21.14), proximal vs distal DVT (2.59; 1.12-5.98), and calf swelling ≥3 cm larger than the asymptomatic leg (3.77; 1.66-8.55). In a multivariate analysis, age (1.05; 1.01-1.09) and calf swelling ≥3 cm larger than the asymptomatic leg (2.94; 1.20-7.20) remained predictive for PTS. Compression therapy was used by 78.5% of patients at the 1-year follow-up and by 46.7% at the 3-year follow-up. Both rates were higher in patients with PTS (93.9%) vs no PTS (66.7%). CONCLUSIONS: This prospective survey demonstrates a low rate of PTS in patients with a first DVT and no pre-existing DVT, varicose veins, or chronic venous insufficiency, and a high adherence rate to compression therapy, within the first 3 years of follow-up. Age and marked calf swelling were independent predictors of PTS.

Heparin based prophylaxis to prevent venous thromboembolic events and death in patients with cancer - a subgroup analysis of CERTIFY.

BACKGROUND: Patients with cancer have an increased risk of VTE. We compared VTE rates and bleeding complications in 1) cancer patients receiving LMWH or UFH and 2) patients with or without cancer. METHODS: Acutely-ill, non-surgical patients ≥ 70 years with (n = 274) or without cancer (n = 2,965) received certoparin 3,000 UaXa o.d. or UFH 5,000 IU t.i.d. for 8-20 days. RESULTS: 1) Thromboembolic events in cancer patients (proximal DVT, symptomatic non-fatal PE and VTE-related death) occurred at 4.50% with certoparin and 6.03% with UFH (OR 0.73; 95% CI 0.23-2.39). Major bleeding was comparable and minor bleedings (0.75 vs. 5.67%) were nominally less frequent. 7.5% of certoparin and 12.8% of UFH treated patients experienced serious adverse events. 2) Thromboembolic event rates were comparable in patients with or without cancer (5.29 vs. 4.13%) as were bleeding complications. All cause death was increased in cancer (OR 2.68; 95%CI 1.22-5.86). 10.2% of patients with and 5.81% of those without cancer experienced serious adverse events (OR 1.85; 95% CI 1.21-2.81). CONCLUSIONS: Certoparin 3,000 UaXa o.d. and 5,000 IU UFH t.i.d. were equally effective and safe with respect to bleeding complications in patients with cancer. There were no statistically significant differences in the risk of thromboembolic events in patients with or without cancer receiving adequate anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov, NCT00451412.

Certoparin versus unfractionated heparin to prevent venous thromboembolic events in patients hospitalized because of heart failure: a subgroup analysis of the randomized, controlled CERTIFY study.

BACKGROUND: Despite the elevated risk for developing venous thromboembolic events in patients with heart failure, there are no randomized, double-blind, controlled trial data on the comparison of low-molecular-weight heparin with unfractionated heparin (UFH) in this patient population. METHODS: This was a subgroup analysis of the CERTIFY trial, which included 3,239 nonsurgical, acutely ill medical patients 70 years or older. Patients were randomized to receive 3,000-U anti-Xa certoparin once daily or 5,000-IU UFH 3 times a day. The analysis was performed on a subgroup of 542 patients diagnosed with heart failure at hospital admission. RESULTS: Patients with heart failure differed from patients without heart failure in that they were more likely using antiplatelets (67.2% vs 48.9%; P < .0001) and had a lower glomerular filtration rate (8.0% vs 5.5%; ≤ 30 mL/min per 1.73 m²; P = .0232). Thromboembolic risk was comparable except for a higher incidence of distal deep venous thrombosis (DVT) in patients with heart failure (10.80% vs 7.26%; P = .0144). Within the heart failure population, patient characteristics were comparable between randomized treatment groups. The incidence of the primary end point (proximal DVT, symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death combined) was numerically, slightly smaller with certoparin (3.78% vs 4.74% with UFH; odds ratio 0.79, 95% CI 0.32-1.94), and the incidence of major bleeding was 0.72% with certoparin versus 0.38% with UFH. CONCLUSIONS: Patients hospitalized for heart failure are at high risk for developing distal DVT and bleeding complications compared with acutely ill medical patients without heart failure. Within the heart failure population, the observed differences in prophylactic efficacy between 3,000-U anti-Xa certoparin once daily and 5,000-IU UFH 3 times a day were similar to those observed in the overall study population; this suggests that certoparin might be at least as effective as UFH also in this subgroup. There were no relevant differences in bleeding risk or frequency of adverse events.

Impact of gender on the clinical presentation and diagnosis of deep-vein thrombosis.

It is uncertain whether gender influences the clinical presentation of deep-vein thrombosis (DVT) and the discriminative value of the Wells diagnostic pretest probability score. The aim of the study was to determine whether gender impacts the clinical presentation and diagnosis of DVT. The study analysed a cohort of 4,976 outpatients with clinically suspected DVT of the leg prospectively recruited by 326 vascular medicine physicians in the German ambulatory care sector between October and December 2005. The diagnosis of DVT was based on compression ultrasonography in 96% of patients. Among 4,777 patients who had a diagnostic work-up for DVT there were more women (n=2,998) than men (n=1,779). However, the prevalence of confirmed DVT was 37.0% (658/1779) in men vs. 24.3% (730/2,998) in women (p<0.001). Among patients with confirmed DVT, proximal DVT was more common in men (59.6% vs. 44.5% in women, p<0.001). Swelling of the leg, pitting oedema and dilated superficial veins were more frequently reported by men (p<0.001). The percentage of patients with a high probability Wells clinical pretest score was higher in men than in women (67.0% vs. 57.0%, p<0.001). However, overall, the score equally discriminated risk groups for DVT in both sexes. In conclusion, women were more frequently referred for a diagnostic work-up for DVT than men, but the prevalence of DVT was higher in men and their thrombotic events were more severe. Nevertheless, the Wells clinical pretest probability score correctly identified low- and high-risk groups in both genders.

Diagnosis of deep-vein thrombosis: adherence to guidelines and outcomes in real-world health care.

Current guidelines recommend optimised algorithms for diagnosis of suspected deep-vein thrombosis (DVT). There is little data to determine to what extent real-world health care adheres to guidelines, and which outcome in terms of diagnostic efficiency and safety is achieved. This registry involved patients with clinically suspected DVT of the leg recruited in German ambulatory care between October and December 2005. Registry items were: diagnostic methods applied, diagnostic categories at day 1, and venous thromboembolic events up to 90 days in patients without firmly established DVT. A total of 4,976 patients were recruited in 326 centres. Venous ultrasonography was performed in 4,770 patients (96%), D-dimer assay in 1,773 patients (36%) and venography in 288 patients (6%). At day 1, DVT was confirmed in 1,388 patients (28%), and ruled out in 3,389 patients (68%), and work-up was inconclusive in 199 patients (4%). The rate of venous thromboembolism at 90 days was 0.34% (95% confidence interval [CI]: 0.09 to 0.88) in patients in whom the diagnosis of DVT had been ruled out, and 2.50% (95% CI: 0.69 to 6.28) in patients with inconclusive diagnostic workup. This nationwide evaluation in German ambulatory care revealed that the diagnostic work-up for suspected DVT did not adhere to current guidelines. However, the overall diagnostic safety was excellent, although there is potential for improvement in a well defined minority of patients.

[Diagnosing deep vein thrombosis in the leg]. / Thrombose-check mit Risiko-Score und D-Dimer-Test.

As a consequence of changes in lifestyle, an ageing population sometimes overdoing things in terms of sports activities, long-haul travel and an increasing incidence of malignomas, deep vein thrombosis (DVT) is increasingly being seen in ambulatory patients. The incidence of DVT is some 0.1-0.3%, and increases with age. With ultrasound and phlebography the exclusion of a thrombosis is almost always possible in an ambulatory setting. Diagnostic algorithms involving the standardized determination of clinical probability (CP) and measurement of D-dimers can help to reduce diagnostic problems in the doctor's office. A low CP in combination with a negative D-dimer excludes a DVT with virtual certainty.