III. Secondary chronic venous disease
Plenary lecture: Contemporary management of acute and chronic iliofemoral venous obstruction
Anthony Comerota, USA
Since acute deep vein thrombosis is the leading cause of severe chronic venous disease and postthrombotic syndrome, the 2008 guidelines by the American College of Chest Physicians (ACCP) recommend a strategy for thrombus removal, correction of the underlying lesion, compression and ambulation with extension of the duration of anticoagulation to prevent recurrence. Thrombus removal can be achieved by operative thrombectomy or catheter-directed thrombolysis. A randomized controlled trial conducted in Sweden by Plate et al, with a 5- and 10-year follow-up, compared standard anticoagulation with thrombectomy.1,2 They reported an improvement in patency, a reduction in ambulatory venous pressures and leg swelling, and fewer patients with postthrombotic syndrome (P0.05) in the thrombectomy group. By combining 10 series, involving 605 patients who had a thrombectomy and a mean follow-up of 41 months, the reported iliac vein patency was 76%. Based on the available data, the 2008 ACCP guidelines recommended “in patients with extensive deep vein thrombosis, operative venous thrombectomy may be used to reduce acute symptoms and postthrombotic morbidity (Grade 2B).” In addition, “following thrombectomy we recommend the same intensity of anticoagulant therapy as those who did not undergo venous thrombectomy (Grade 1C).”
Subsequently, in the CaVenT study (Catheter-directed Venous thrombolysis in acute iliofemoral vein Thrombosis) performed in Norway by Enden et al, 209 patients were randomly assigned to conventional anticoagulation or catheter-directed thrombolysis followed by anticoagulation.3 At completion of the 24-month follow-up, 37 patients (41.1%; 95% CI, 31.5-51.4) allocated to additional catheter-directed thrombolysis presented with postthrombotic syndrome compared with 55 patients in the control group (55.6%; 95% CI, 45.7-65.0; P=0.047). The difference in postthrombotic syndrome corresponded to an absolute risk reduction of 14.4% (95% CI, 0.2-27.9) and the number needed to treat was 7 (95% CI, 4-502).4 Iliofemoral patency after 6 months was reported in 58 patients (65.9%; 95% CI, 55.5-75.0) with catheter-directed thrombolysis vs 45 (47.4%; 95% CI, 37.6-57.3) with the control treatment (P=0.012).4 There were 20 bleeding complications related to catheter-directed thrombolysis (3 were major and 5 were clinically relevant).
At least 50% of the patients in the CaVenT study did not have thrombosis in the iliofemoral segment and no pharmacomechanical techniques were used. In patients with true iliofemoral deep vein thrombosis, who applied contemporary pharmacomechanical techniques, there will be substantially more benefit vs anticoagulation alone, and the number needed to treat to prevent severe postthrombotic syndrome should be no more than 2 or 3. Following acute deep vein thrombosis, wearing compression stockings (30 to 40 mm Hg at the ankle) for 2 years reduces postthrombotic syndrome by 50%, which has a Grade A recommendation in the 2008 ACCP guidelines.
Once patients develop chronic postthrombotic iliofemoral venous obstruction, plasminogen activators are no longer effective since the tissue causing luminalobstruction is no longer the thrombus, but collagen type I and III. Such patients improve significantly, if unobstructed venous drainage from the profunda femoris vein to the iliofemoral vein can be restored. Operative endovenectomy of the common femoral vein with endoluminal recanalization of the iliocaval segment is a procedure designed to restore proximal venous drainage and reduce the severity of the postthrombotic syndrome.
References:
1. Plate G, Akesson H, Einarsson E, Ohlin P, Eklöf B. Long-term results of venous thrombectomy combined with a temporary arterio-venous fistula.
2. Plate G, Eklöf B, Norgren L, Ohlin P, Dahlström JA. Venous thrombectomy for iliofemoral vein thrombosis–10-year results of a prospective randomised study. Eur J Vasc Endovasc Surg. 1997;14(5):367-374.
3. Enden T, Sandvik L, Kløw NE, et al. Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis–the CaVenT study: rationale and design of a multicenter, randomized, controlled, clinical trial (NCT00251771). Am Heart J. 2007;154(5):808-814.
4. Enden T, Haig Y, Kløw NE, et al; CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012;379(9810):31-38.
Venous thromboembolism
The prevalence of venous thromboembolism in patients with malignant tumors is considered much higher than in other patients, which was confirmed in the data from the French national database and presented by François-André Allaert (France). Venous thromboembolisms occurring in patients hospitalized for cancer was 4.95% vs 1.09% in patients with no malignancy, emphasizing the need for quality and effective prevention of venous thromboembolism in this patient population.
The risks of distal deep vein thrombosis and the desirability of its treatment are now being debated. Kazuhiko Hanzawa (Japan) discussed the role of distal deep vein thrombosis as a possible source of pulmonary embolism in residents in earthquake-prone areas. A total of 21 isolated deep vein thromboses of the calf were identified in 67 residents who had slept in their small cars every day after the earthquake in the Niigata prefecture. More than 1400 people were examined 8 years after the earthquake and pulmonary embolism developed in 2.7% of the people affected by distal deep vein thrombosis vs 0.09% in those without. Surprisingly, multivariate analysis confirmed that distal deep vein thrombosis was a risk factor for other vascular events, such as ischemic stroke and ischemic heart disease, long after the earthquake.
Fausto Passariello (Italy) presented a novel score to assess thrombus extension after thermal ablation of the great saphenous vein. His classification, called X-PASTE (postablation superficial thrombus extension), is wider than the EHIT score (endovenous heat-induced thrombosis) that is usually used in practice and research. In addition, the X-PASTE score is able to include postablation thrombosis and spontaneous superficial vein thrombosis.
Three presentations were devoted to the review of the efficacy of retrievable inferior vena cava filters in preventing pulmonary embolism and the assessment of the complication rate and success of their retrieval. Jinisha Pankaj Bhanushali (India) reported a successful 73% retrieval of the inferior vena cava filters and Yu Jae Seung (Korea) reported a 68% retrieval rate, whereas Mari Chiyoya (Japan) reported only a 15.9% to 26.3% retrieval rate. These data demonstrate the controversial role of inferior vena cava filters, plus their ability to prevent pulmonary embolisms is not well evidenced. While many are theoretically retrievable, they often become practically permanent, which increases the possible risk of complications and venous thromboembolism recurrence.
Benchet’s disease, a rare multisystem vasculitis, is characterized by skin-mucosa lesions, multiorgan damage, and major vessel involvement; however, data on venous disease in these patients are lacking. Hasan Tuzun (Turkey) presented data on venous claudication in Benchet’s disease. A total of 101 patients with Benchet’s disease were examined and 61 patients had a history of venous thrombosis of the lower limbs, which developed a median of 3.6 years after the onset of Benchet’s disease and affected both limbs in 66% of patients and recurred in 38% of cases at 5 years. Using the treadmill, venous claudication was found in 34% of patients, while in 10% of cases, there was a limited walking capacity.
Mark Meissner (USA) focused on early thrombus removal to avoid the development of postthrombotic syndrome (from 20% to 50%). Evidence for the strategies to prevent postthrombotic syndrome were obtained from natural history records, observational studies, and clinical trials (eg, CaVenT study [Catheter-directed Venous thrombolysis in acute iliofemoral vein Thrombosis], ATTRACT trial [Acute venous Thrombosis: Thrombus Removal with Adjunctive Catheter-directed Thrombolysis], etc). According to all of these sources, thrombus removal (rapid recanalization) potentially prevents reflux and relieves obstruction. Patients with a short duration of symptoms of the first episode of iliofemoral deep vein thrombosis are the most likely to benefit.
Jang Yong Kim (Korea) presented different types and devices for catheterdirected thrombolysis of acute deep vein thrombosis and promoted catheterdirected thrombolysis as a first-line therapy. In some cases, pharmacomechanical thrombectomy could be considered over catheter-directed thrombolysis alone. Pharmacomechanical thrombectomy is a short-duration procedure that has a low consumption of the thrombolytic agent and it is potentially safer than catheterdirected thrombolysis. More pharmacomechanical thrombectomies will be available for extended treatment indications in the near future.
Neil Khilnani (USA) provided an overview on the management of occlusions of the chronic iliac vein and inferior vena cava. Stenting has become the procedure of choice with percutaneous access, good clinical improvement, and good patency rates, but the technique is not standardized (stent choices, patient selection) and reintervention rates are still high (25% overall). Procedural success is higher with stenotic vs occluded veins.
Symposium on venous thromboembolism
Antony Comerota (USA) opened the symposium with a presentation on iliofemoral deep vein thrombosis during pregnancy, which is a problem of great importance as there are no high-grade guidelines on this aspect and pulmonary embolism remains one of the most frequent causes of maternal mortality in many countries. The approach to treating pregnant women with deep vein thrombosis should be the same as for other patients. Therefore, catheter-directed thrombolysis was suggested as a safe option for both the woman and the fetus. If ineffective, open thrombectomy may be an alternative. Incredible results were obtained with catheter-directed thrombolysis in 15 women, leading to 14 successful deliveries and no cases of postthrombotic syndrome in 10 women.
Current trends in the management of deep vein thrombosis in Japan were discussed by Toshiyuki Miyata (Japan). He stressed the growing incidence of venous thromboembolism in Asia, which has been confirmed in several recent studies, and it is due to stated that both the changing lifestyle of Asians and the increasing awareness of the problem by specialists and patients. In Japan, very aggressive strategies are used in the acute phase of the disease; 20% of patients underwent thrombolysis and inferior vena cava filters were implanted in 40% of patients. In the past, the most commonly used anticoagulant for extended therapy was warfarin. The targeted international normalized ratio (1.5 to 2.5 in Japan), is successfully maintained in about 90% of patients. Nevertheless, the recurrence rate is 4.0% per patient-year and that seems too high.
The final presentation by Fedor Lurie (USA) on the changing paradigm of deep vein thrombosis management discussed future changes in diagnostic strategy, initial treatment, and its duration. There are some data confirming poor adherence to evidence-based venous thromboembolism guidelines in real-world practice. Many people with suspected deep vein thrombosis underwent duplex ultrasound, which provides a false positive in 5.8% of cases. Thus, many patients without deep vein thrombosis receive potentially harmful treatments. Using a clinical score, such as the Wells score system, and measuring the levels of D-dimer are recommended by current guidelines, which might make duplex investigation unnecessary for patients with a low clinical probability of deep vein thrombosis. The main goal of the initial treatment is not to prevent pulmonary embolisms because at least two-thirds are not fatal, but to prevent mortality because 65% of patients with a pulmonary embolism die within 1 hour and 80% within 2.5 hours. Thus, anticoagulation has to be administered as soon as deep vein thrombosis is confirmed. Duration of treatment is also very important because the majority of patients die from recurrent venous thromboembolism.
The postthrombotic syndrome: factors associated with the development of postthrombotic syndrome in
patients with deep vein thrombosis
Takashi Yamaki, Japan
The initial treatment of deep vein thrombosis includes preventing thrombus propagation and pulmonary embolism development. Meanwhile, the relevance of preventing the development of a postthrombotic syndrome and the late complications of deep vein thrombosis was emphasized. Postthrombotic syndrome has been reported in 20% to 40% of patients who have deep vein thrombosis, with severe cases in 5% to 10% of the patients. Recent studies have identified ipsilateral recurrent deep vein thrombosis as a risk factor for postthrombotic syndrome. However, most patients with no apparent history of recurrent deep vein thrombosis may also develop severe symptoms of postthrombotic syndrome over time. For this reason, it is difficult to reliably predict which patients are likely to develop postthrombotic syndrome in the acute phase of deep vein thrombosis.
While objective evidence of venous incompetence by duplex ultrasound helps to confirm the diagnosis, postthrombotic syndrome should not be diagnosed if clinical symptoms are absent. At this moment, the Villalta scale has been validated in several studies, showing a good correlation with disease-specific quality of life. It has been demonstrated that iliofemoral deep vein thrombosis (odds ratio [OR], 3.4; 95% CI, 1.4-8.6) was highly associated with the development of a postthrombotic syndrome. Moreover, venous occlusion combined with reflux (OR, 4.4; 95% CI, 2.9- 20.7), peak reflux velocity >29.7 cm/s (OR, 13.7; 95% CI, 4.1-45.7), and mean reflux velocity >8.6 cm/s (OR, 4.4; 95% CI, 1.5-12.9) in the popliteal vein detected by duplex scanning at 6 months after deep vein thrombosis were strong predictors of postthrombotic syndrome. Recently, changes in calf-muscle oxygenation during standing and exercise, which were measured by near-infrared spectroscopy, were significantly different between patients with and without postthrombotic syndrome.
The relationship between changes in oxygenated and deoxygenated hemoglobin levels during calf-muscle exercise might become an important indicative parameter reflecting the progression of postthrombotic syndrome; thereby, introducing new insights into calf-muscle hemodynamics at the microcirculation level.
Pulmonary embolism probability based on the location of thrombi in legs
Sang Jun Park, Korea
A study analyzing the relationship between the location of leg thrombi and pulmonary embolism was presented. All patients who were diagnosed with deep vein thrombosis in the author’s center during 2006 were enrolled in the study. Pulmonary embolisms were classified and scored according to the affected arteries: main (4), lobar (3), segmental (2), and subsegmental (1) arteries. The deep vein thromboses were grouped according to their laterality (right/left/bilateral) and level of thrombi (iliac/ femoral/popliteal/calf).
Overall, 388 patients were enrolled, 52% were female, with a mean age of 64. Pulmonary embolism was detected in 57.1% of the deep vein thrombosis patients. Pulmonary embolism from a right, left, or bilateral deep vein thrombosis was 62.9%, 52.2%, and 79.0% (P=0.050), respectively, and the mean pulmonary embolism severity score was 1.750, 1.293, and 2.474 (P=0.004), respectively. Pulmonary embolism from an iliac, femoral, popliteal, or calf vein was 48.5%, 66.4%, 60%, and 57.6% (P=0.039), respectively, and the mean pulmonary embolism severity score was 1.170, 1.942, 1.600, and 1.242 (P=0.001), respectively. Pulmonary embolisms were more frequent when the deep vein thrombosis occurred in the femoral vein. The main pulmonary artery embolism was also more frequent after femoral vein deep vein thrombosis (30.7%; P=0.001).
Deep vein thrombosis on the left side was more frequent than on the right side, but the probability of a pulmonary embolism was higher with deep vein thrombosis on the right side. The probability and severity of pulmonary embolisms were highest in the presence of deep vein thrombosis in the femoral vein among the leg thrombi.
Exercise versus immobilization in the treatment of acute deep vein thrombosis during different clot-organized
stages: an animal experiment
Fuxian Zhang, China
An animal study to evaluate the corresponding influence on the incidence of pulmonary embolisms between immobilization and exercise in different stages of thrombus after acute deep vein thrombosis was presented. New Zealand rabbits (n=48) were randomly divided into 3 groups depending on the different organized stage of the thrombus: early, middle, and late stage. Each group was subdivided into 2 subgroups: immobile and mobile. Rabbit modeling of deep vein thrombosis was completed by ligating the right femoral vein. In the early stages, the rabbits were either allowed to move or not for 3 days; in the middle stages, the rabbits were either not allowed to move for 7 days or allowed to move for 3 days after being immobile for 4 days; and in the late stages, the rabbits were either not allowed to move for 14 days or allowed to move for 7 days after being immobile for 7 days. After the treatment phase, the rabbits were euthanized and the lungs were extracted to examine them for pulmonary embolisms. The incidence of pulmonary embolisms among the immobile rabbits in the early, middle, and late stages was 37.5%, 25%, and 37.5%, respectively, and the incidence among the mobile rabbits in the early, middle, and late stages was 50%, 37.5%, and 35.7%, respectively. There were no statistical differences between the mobile/immobile subgroups at the different stages. In conclusion, early ambulation does not increase the incidence of pulmonary embolisms after acute deep vein thrombosis in the lower extremities of rabbits.
Management of superficial vein thrombosis of the legs: update and current recommendations (French Society
of Phlebology)
Jean-Luc Gillet, France
For a long time, superficial vein thrombosis was considered a benign disease; however, recent studies have shown their potential seriousness. In fact, in the studies POST (Prospective Observational Superficial Thrombophlebitis) and OPTIMEV (OPTimisation de l’Interrogatoire pour la Maladie thromboEmbolique Veineuse), a concomitant deep vein thrombosis was identified in 23% to 26% of patients at presentation, and a pulmonary embolism in 4% of patients, leaving isolated superficial vein thrombosis at a 74% frequency. Subsequent venous thromboembolisms (eg, superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism) were reported in 3% to 20% of superficial vein thrombosis patients.1,2,3 The author argued that superficial vein thrombosis cannot be considered a benign condition anymore and that an ultrasound should be performed every time to rule out concomitant deep vein thrombosis (present in 25% of the cases) and to determine the precise location and extent of the superficial vein thrombosis (high level of evidence).
Until recently, although numerous anticoagulation strategies have been tested, none of them have clearly demonstrated a clinical benefit. Recently, the Calisto study validated a protocol based on fondaparinux 2.5 mg daily for 45 days, leading to an update in the recommendations. On the basis of the data in the literature and in agreement with both the latest American College of Chest Physicians recommendations and the conclusions of the last Cochrane review, it is prudent to recommend, in patients with symptomatic superficial vein thrombosis of at least 5 cm, the use of a prophylactic dose of fondaparinux or low-molecular-weight heparin for 45 days vs no anticoagulation (Grade 2B). Wherever the cost of treatment with fondaparinux is acceptable, we suggest fondaparinux 2.5 mg daily over a prophylactic dose of low molecular- weight heparin (Grade 2C).
The recommendations and guidelines are still based on low-grade evidence. Some questions remain concerning the management of superficial vein thrombosis. Some risk factors for subsequent development of venous thromboembolisms have been identified, but further research is needed to clearly define subgroups of patients with a higher incidence of venous thromboembolism after superficial vein thrombosis.
References
1. Decousus H, Quéré I, Presles E, et al; POST Study Group. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152:218-224.
2. Dewar C, Panpher S. Incidence of deep vein thrombosis in patients diagnosed with superficial thrombophlebitis after presenting to an emergency department outpatient deep vein thrombosis service. Emerg Med J. 2010;27:758-761.
3. Galanaud JP, Genty C, Sevestre MA, et al; OPTIMEV-SFMV Investigators. Predictive factors for concurrent deep-vein thrombosis and symptomatic venous thromboembolic recurrence in case of superficial venous thrombosis. The OPTIMEV study. Thromb Haemost. 2011;105:31-39.
Rivaroxaban: simplifying effective treatment for venous thromboembolism
Sang Hoon Na, Korea
Venous thromboembolism is a clinical condition with significant levels of mortality and morbidity. Until recently, anticoagulant therapy was centered on vitamin K antagonists and low-molecular-weight heparins. Despite proven efficacy of the conventional therapeutic approach, the narrow and unpredictable therapeutic index, the need for frequent monitoring of the international normalized ratio, genetic heterogeneity in pharmacokinetic response, the risk of multiple interactions (drugs and food), and the need for initial parenteral administration entails real difficulties in implementing adequate treatment over time. A new option has emerged with the development of direct oral anticoagulants, such as rivaroxaban. These new drugs allow comparable efficacy with increased convenience and safety. As a result, direct oral anticoagulants offer greater compliance and increased treatment efficacy, and at the same time, facilitate the therapeutic approach, which may possibly change the approach for the secondary prevention of thromboembolisms.
These drugs act as direct inhibitors of a specific coagulation factor (thrombin inhibition with dabigatran or factor Xa inhibition with rivaroxaban, apixaban, and edoxaban).
They are taken orally and have an early pharmacological action and a short half-life (which increases the safety), few predictable drug interactions, no dietary restrictions, and no monitoring requirements. Rivaroxaban was compared with conventional anticoagulant therapy (enoxaparin + vitamin K antagonists) in two randomized, open, noninferiority trials: Einstein-DVT (n=3449 patients with symptomatic deep vein thrombosis with or without asymptomatic pulmonary embolism) and Einstein-PE (n=4832 patients with symptomatic pulmonary embolism with or without deep vein thrombosis). The results were then gathered in a prespecified joint analysis (n=8281 patients). Overall, noninferiority in efficacy of rivaroxaban has been consistently demonstrated, with increased safety compared with conventional therapy, and a significant reduction in major bleeding, which is more pronounced in elderly patients (>75 years old) and patients with a CrCl <50 mL/min. The initial dose of rivaroxaban is 15 mg twice daily for the first 3 weeks (21 days), followed by 20 mg once daily during the prolonged phase of venous thromboembolism treatment. Rivaroxaban is contraindicated when there is active liver disease (with increased international normalized ratio and decreased albumin serum), pregnancy, and breastfeeding. No dosage adjustment is necessary in patients with minor renal impairment (CrCl >50 mL/min), but, in patients with moderate renal impairment (CrCl =30 to 50 mL/min), rivaroxaban should be used with caution and patients kept under close vigilance for any signs or symptoms of blood loss. Rivaroxaban should not be used in patients with severe renal impairment (CrCl <30 mL/min). Additionally, rivaroxaban should be discontinued if acute renal failure develops. The decision to extend the oral anticoagulant therapy beyond the initial 3 months can be difficult and must take into account the probability of a new thromboembolic event (depending on the clinical context of the first occurrence), the bleeding risk, and associated comorbidities. The EINSTEIN-Extension study (n=1197), a randomized, double-blind trial, evaluated the efficacy and safety of prolonged treatment with rivaroxaban (20 mg, once daily) vs placebo in patients who completed at least 6 to 12 months of anticoagulation. The treatment with rivaroxaban caused an 82% relative risk reduction (number needed to treat =15) for preventing a thromboembolic event (primary outcome). Clinically relevant bleeding (5.4% vs 1.2%) and major bleeding (0.7% vs 0%; P>0.05) was more frequent with rivaroxaban. Compared with placebo, rivaroxaban provided a significant improvement in terms of net clinical benefit. A prespecified secondary end point was defined as the composite of the primary efficacy end point and major bleeding, which occurred in 2.0% of patients receiving rivaroxaban and in 7.1% of patients receiving placebo (hazard ratio, 0.28; 95% CI, 0.15-0.53; P<0.001). For the time being, there is still no antidote to reverse the steady-state anticoagulation activity of rivaroxaban. Yet, rivaroxaban appears safer than conventional therapy. Meanwhile, an antibody-based antidote is being developed and will be available soon. In conclusion, rivaroxaban has arrived to simplify the acute therapeutic approach of treating venous thromboembolisms with potentially more consistent and safe results, and may change how the secondary prevention of thromboembolisms is performed.
Anticoagulant and venoactive drugs
Ahmed Kursat Bozkurt (Turkey) presented an overview of new anticoagulants (ie, apixaban, dabigatran, edoxaban, and rivoraxaban) with respect to major bleeding complications. Antony Comerota (USA) discussed the proper duration of anticoagulation for acute venous thromboembolism, focusing on extended therapy. Results from the benefit-risk analysis are awaited. Patients at a high risk of recurrence are those with unprovoked deep vein thrombosis and a residual venous obstruction and/or elevated D-dimer. New oral anticoagulants appear very helpful, especially at reduced doses.
Andrew Nicolaides (Cyprus) presented the talk “Effects of venoactive drugs in chronic venous disease.” Indications for venoactive drugs include treating: (i) symptoms and edema that likely have a venous origin; and (ii) symptoms of pelvic congestion syndrome and adjunctive treatment in venous leg ulcer healing. Venoactive drugs may be used in association with sclerotherapy, endovascular treatment, or surgery. Diosmin/hesperidin (micronized purified flavonoid fraction [MPFF])* was assigned a Grade 1B recommendation in the last international guidelines on the management of chronic venous disorders for its ability to relieve symptoms of chronic venous disorders and accelerate the healing of venous ulcers. In ulcer healing studies, pentoxyfilline and sulodexide are also mentioned.
Doyeun Oh (Korea) mentioned the current guidelines in the management of deep vein thrombosis, and highlighted the present role of thrombolysis and inferior vena cava filters (only in special situations). Most deep vein thrombosis can now be treated in outpatient clinics. Direct oral anticoagulant drugs are preferable over vitamin K antagonists for the secondary prevention of deep vein thrombosis due to a lower rate of bleeding complications. Various models to predict bleeding and recurrence of deep vein thrombosis were introduced. Bleeding associated with direct oral anticoagulant drugs is a new concern with their increasing use. Elastic stockings have now been proven to not be useful in the prevention of a postthrombotic syndrome.
*Also registered as MPFF at a dose of 500 mg, Alvenor, Ardium, Arvenum, Capiven, Detralex,
Variton, Venitol
