CLINICAL CASE 6. Prevention of postthrombotic syndrome after proximal DVT
Zoubida Tazi Mezalek, MD, PhD
Department of Clinical
Hematology, Internal Medicine,
Mohammed V University, Ibn Sina
Hospital, Rabat, Morocco
A38-year-old female patient, a nurse in a hospital ward, presented 6 months earlier with extensive iliofemoral deep venous thrombosis (DVT) of the right lower limb.
She was treated with rivaroxaban 15 mg twice daily for 21 days, followed by 20 mg once daily. The DVT remained unexplained by a classical risk factor. She has not had any surgery or hospitalization and has not traveled recently. She has 2 children aged 9 and 4 years. She has been on oral hormonal contraception for about 10 years and is currently wearing an intrauterine device since the birth of her last child. She reports no notable personal history other than some heaviness in her legs at the end of hard workdays. Her family history includes a mother and an aunt who were treated for varicose veins in the lower extremities. At the time of her current visit, she had mild diameter asymmetry in both legs, with some superficial varicosities in the right leg. The internist decided to maintain the anticoagulant treatment with rivaroxaban 10 mg once daily for an indefinite period, given the unprovoked nature of the DVT and the diagnosis of an obvious postthrombotic syndrome, especially since the patient tolerates rivaroxaban well (some increase in menstrual bleeding without consequences). He also advised her to continue wearing compression stockings and prescribed a micronized purified flavonoid fraction course.
Discussion
Dr Geroulakos. The transatlantic interdisciplinary consensus document defines postthrombotic syndrome (PTS) as “chronic venous symptoms and/or signs secondary to deep venous thrombosis (DVT) and its sequelae.”1 The incidence depends on the location and extension of DVT. The most common instrument for assessing the severity of PTS is the Villalta scale, which combines general symptoms and signs of chronic venous disease (CVD). My group has shown that, surprisingly, there is no relationship between the symptom and the sign part of the Villalta scale. There was an expectation that legs that were severely affected would have more symptoms, but this was not the case.2
Dr Josnin. PTS corresponds to chronic manifestations of secondary chronic venous insufficiency (CVI) following DVT, and PTS is the most frequent complication of DVT. Severe forms affect about 5% to 10% of patients, whereas 20% to 50% of patients are affected after a DVT, despite adapted and well-monitored anticoagulation.3
Dr Kan. PTS, a common and sometimes disabling complication of DVT, reduces the quality of life (QOL) and is costly, burdensome, and potentially debilitating. The manifestations of PTS range from mild clinical symptoms or signs to more severe manifestations such as chronic leg pain, intractable edema, and venous leg ulcer (VLU) that limit activity and work capacity.4
Dr Tazi Mezalek. PTS is the most common complication of DVT. Despite conventional anticoagulation therapy and even after the resolution of DVT, around 60% to 80% of the vein will be recanalized over months, and residual thrombus may persist.5-7 Indeed, DVT can cause direct damage to the venous wall and associated valves. Because the lysis may not be complete in some cases, the thrombus is replaced by fibrous tissue, which may lead to functional obstruction, permanent valve alterations, and venous reflux.8,9 These phenomena are accompanied by local inflammation that aggravates the valve lesions, but also systemic inflammation that may explain the valvular lesions also observed at a distance from the DVT in unaffected venous sites.10,11
PTS is therefore considered a secondary CVI. It refers to chronic clinical manifestations of venous insufficiency, ranging from mild symptoms such as mild pain, swelling, and hyperpigmentation, to more severe manifestations such as intractable pain, venous claudication, and leg ulceration. Symptoms of PTS usually occur within 3 to 6 months after DVT but can occur up to 2 years.5-7
The reported prevalence of PTS differs considerably among studies because of differences in the study populations, the tools used to assess PTS, and the time interval after the index DVT. Standardizing PTS assessment tools and developing patient self-assessment scales were important in researching the epidemiology of PTS, allowing comparison between studies, performing meta-analyses, and increasing the feasibility of longer follow-ups of patients with DVT. Therefore, recommendations for standardization of the definition of PTS for clinical studies have been published.12 The International Society on Thrombosis and Haemostasis (ISTH) has adopted the Villalta scale as a standard to diagnose and grade the severity of PTS in clinical studies.13 It has been shown to be valid, reproducible, and easy to administer.14 Venous thromboembolism (VTE) is a growing public health problem due to increased life expectancy, an increasing proportion of elderly individuals, and an expected increase in the prevalence of PTS. Therefore, improved prevention and treatment of DVT are critical in decreasing the incidence of PTS.3,15
PTS is the primary determinant of patient QOL after DVT. Studies have shown that PTS harms patient QOL compared with DVT patients without PTS, either using generic measures (36-item Short Form Survey [SF-36]) or disease-specific scales (Venous Insufficiency Epidemiological and Economic Study-QOL (VEINES-QOL).16,17 Also, PTS is a costly condition with a total cost over a 2-year period that is 2-fold higher than for DVT patients without PTS.18 This is attributable to the greater use of health care visits and medications and the high cost of treating venous ulcers.
Dr Lobastov. Although the Villalta scale is generally validated and approved for PTS verification and severity assessment, it has a very low specificity.19,20 It contains nonspecific symptoms and signs, which could be attributed to either primary or secondary CVD. So, if a patient had primary venous disease with a Villalta scale score ≥5 before DVT, then at 3 to 6 months after thrombosis, he must be classified as having PTS, even without exacerbation of primary CVD. The Villalta scale does not allow differentiation between preexisting symptoms of primary CVD and new symptoms of PTS. Several approaches were introduced to improve the specificity of Villalta scale, particularly adjusting on contralateral CVD, but all failed.21 It has also been shown that Villalta scale does not capture the typical PTS complaints or their importance to patients, which is why it poorly correlates with QOL.22 A patient-reported Villalta scale was developed and externally validated but demonstrated only moderate agreement with the original instrument.23,24 As an alternative to the Villalta scale, the criteria of Ginsberg and Brandjes were introduced but not widely adopted.3
The prevalence of PTS in the population is not studied well. One epidemiological study from Russia reported PTS in 1.4% of 703 rural community residents.25
Dr Geroulakos. According to a recent retrospective study, when DVT is treated using interventional methods, lower Villalta scores are detected after 1 year of follow-up. The development of PTS is reduced substantially. According to VEINES-QOL/Symptoms scale, QOL is higher in patients who underwent interventional procedures. In short and medium terms, the interventional treatment provides persistent benefits, especially in DVT with proximal involvement.26
Dr Josnin. The main risk factors are the location of the venous thrombosis (the more proximal, the more severe the PTS) and a history of ipsilateral recurrent DVT. In the REVERSE study (REcurrent VEnous thromboembolism Risk Stratification Evaluation), which investigated risk factors for PTS in patients with a first episode of unprovoked proximal DVT without primary venous insufficiency, other risk factors were highlighted—obesity, poor quality of anticoagulant therapy, and residual venous obstruction.27
Dr Kan. The main risk factors for PTS were anatomically widespread DVT, recurrent ipsilateral DVT, persistent leg symptoms 1 month after acute DVT, obesity, and older age. PTS is thought to develop after DVT due to venous hypertension (ie, increased pressure in the veins). Venous hypertension reduces calf muscle perfusion, increases tissue permeability, and promotes the associated clinical manifestations of PTS. Two pathological mechanisms lead to venous hypertension: persistent (acute, then residual) venous obstruction and valvular incompetence due to venous valve damage.28
Dr Nikolov. Risk factors are proximal DVT, preexisting venous insufficiency, obesity, age, the severity of symptoms, residual venous obstruction, popliteal valve reflux, and most important, ipsilateral recurrent DVT.15
Dr Tazi Mezalek. The risk and severity of PTS depend on the characteristics of the triggering DVT at baseline and the resolution or persistence of the thrombus during follow-up.5-7,29-31 Other factors increase the risk of PTS, like elevated body mass index, advanced age, and the severity of symptoms at the onset of DVT.30-32 Preexisting primary CVD and varicose veins appear to be associated with an increased risk of VTE and, consequently, PTS.30 However, some authors have expressed concern that some of those patients with CVI may have had prior undiagnosed episodes of VTE. The extensive proximal nature of the DVT is an important parameter. The more proximal and extensive DVT provides a higher risk of PTS.30,31 The risk of PTS is 2- to 3-fold higher after iliac or iliofemoral thrombosis than more distal DVT.30-32
During follow-up, persistent venous symptoms 1 month after acute DVT appear to increase the risk of subsequent PTS.6,33 Moreover, ultrasound parameters measured 1 or 2 months after a proximal DVT proved to be predictive of PTS: residual thrombosis (odds ratio, 2.17) and popliteal reflux (odds ratio, 1.34).34
Finally, recurrent ipsilateral DVT is one of the most important risk factors, increasing the PTS risk by 4- to 6-fold.29,30,34 Therefore, prevention of recurrent thrombotic events is the cornerstone of PTS prevention and raises the question of the duration of anticoagulation.
Dr Lobastov. Risk factors for PTS are well established with calculated risk ratios or odds ratios.3 In descending order of their impact, they are as follows: ipsilateral DVT recurrence (risk of 1.6-9.6), elevated levels of inflammatory biomarkers (risk of 1.4-8.0), proximal DVT localization (risk of 1.5-6.3), older age (risk of 0.6-3.9), obesity (risk of 1.1-3.5), varicose veins at baseline (risk of 1.5-3.2), inadequate anticoagulation (risk of 1.8-2.7), and residual venous obstruction (RVO; risk of 1.6-2.1).
Dr Geroulakos. If the quality of initial anticoagulation is inadequate, this could lead to the recurrence of the DVT and more extensive venous damage resulting in a higher probability of PTS.
Dr Josnin. Studies published today show that poor anticoagulation is a risk factor for PTS.35 However, more studies are needed to understand better which type of anticoagulation is the most appropriate and to discuss the sequence of this treatment.
Dr Kan. In answer to the question whether the quality of initial anticoagulation for DVT reduces the incidence of PTS, I think it’s related. There is a 3-fold increased risk of PTS if anticoagulant levels are insufficient (eg, international normalized ratio [INR] >50% below therapeutic levels) during the first 3 months of vitamin K antagonist (VKA) therapy. Whether treatment of DVT with dual oral anticoagulants (DOACs) affects the risk of PTS compared with treatment with low molecular weight heparin (LMWH) or VKA is unknown. A meta-analysis of available data suggests that treatment of DVT with prolonged LMWH monotherapy may reduce the incidence of PTS compared with a short-term LMWH treatment for 5 to 7 days, followed by VKA. Large multicenter trials using validated diagnostic criteria for PTS are needed to confirm the effectiveness of prolonged LMWH in patients at high risk of PTS and to assess the efficacy of DOACs in preventing PTS.28 The best way to prevent PTS is to prevent DVT with pharmacologic or mechanical thromboprophylaxis in high-risk patients and settings.
Dr Tazi Mezalek. During the first 3 months of treatment with VKA, inadequate control of the INR increases the risk of PTS 2-fold.35 Some data suggest that long-term treatment with LMWH may lead to lower rates of PTS in comparison with VKA.36 Otherwise, DOACs for the initial treatment of DVT are associated with a lower incidence of residual vein thrombosis than VKA.37 In a recent publication, rivaroxaban significantly reduced PTS risk compared with warfarin.38 After adjusting for baseline characteristics, the risk of PTS in the DOAC-treated group was reduced by 54%.37,38 A recent meta-analysis of all available studies addressing this issue confirmed that rivaroxaban was found to significantly reduce the incidence of PTS compared with VKA and also was likely to prevent severe forms of PTS.39
Dr Lobastov. Adequate anticoagulation in terms of preventing thrombus extension and protection of the venous wall in the acute phase of thrombosis, as well as prophylaxis of DVT recurrence and improving recanalization, is a cornerstone for PTS prevention. Emerging evidence suggests that treatment with rivaroxaban, compared with VKA, significantly reduces PTS risk by 46% to 48% and severe PTS by 45% to 51%.40,41 However, this is not a common effect for all DOACs. No evidence is available for apixaban, but edoxaban and dabigatran do not affect PTS risk.42,43 Notable, in the ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis), early start of rivaroxaban within the first 10 days was associated with a 47% reduction in risk of PTS.44 So, it seems to be crucial to give adequate anticoagulation during the acute phase of DVT.
Dr Geroulakos. The ATTRACT trial has shown that early catheter-directed thrombolysis (CDT) reduces the incidence of severe PTS.45
Dr Josnin. Thrombolysis remains a treatment that is decided on a case-by-case basis according to precise criteria, but it has proven its effectiveness.
Dr Kan. Upfront thrombolytic therapy combined with heparin for acute DVT resulted in higher venous patency rates and better valvular function preservation than using heparin alone. CDT or pharmacomechanical CDT (PCDT) may be safer and more effective than systemic thrombolysis. It may prove to be a promising technique for preventing PTS after proximal DVT.
According to the trial results by Enden T et al, the use of additional CDT in anticoagulated patients with acute DVT involving the iliac and/or common femoral veins showed a statistically significant 2-year PTS risk reduction at the expense of a 3% increase in major bleeding.4 However, 41% of patients with CDT still developed PTS, suggesting that it did not eliminate the risk of PTS and did not improve QOL at 2 to 5 years of follow-up. The CAVA trial (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-Thrombotic Syndrome) did not show a reduction in PTS after additional ultrasound-accelerated CDT in patients with acute iliofemoral DVT at 1-year follow-up.46 Susan Kahn recommends these techniques in patients on a case-by-case basis: those with extensive (eg, iliofemoral) thrombosis and who are recently (ie, ≤14 days) symptomatic, with low bleeding risk, and life expectancy of at least 1 year.28
Dr Nikolov. Unfortunately, there is no clear evidence. However, in 2019, the NICE guidelines acknowledged that percutaneous mechanical thrombectomy (PMT) could be used for patients with acute iliofemoral DVT with special arrangements for informed consent, local governance, and quality improvement, though it remains investigational for femoropopliteal DVT.47 The 2020 American Society of Hematology guidelines state that thrombolysis is reasonable to consider for patients with limb-threatening DVT (phlegmasia cerulea dolens) and for selected younger patients at low risk for bleeding with symptomatic DVT involving the iliac vein and common femoral vein, but that its use should be rare for femoropopliteal DVT.48 In 2021, the European Society of Vascular Surgery issued guidelines recommending early thrombus removal strategies for selected patients with acute iliofemoral DVT but not for less extensive DVT.49 Nowadays, CDT is indicated mostly for patients with acute iliofemoral DVT, severe symptoms, low bleeding risk, and good functional status.50
Dr Tazi Mezalek. Early thrombus removal by surgical or instrumental thrombectomy was popularized many years ago. Because iliofemoral DVT is associated with severe forms of PTS, it has been suggested that early surgical removal of thrombus may be beneficial in certain conditions.51 Meanwhile, the demonstration that surgical thrombectomy prevents PTS is not yet validated.
The association of upfront heparin and systemic thrombolytic therapy to treat DVT leads to higher rates of vein patency and better preservation of valve function than using heparin alone.52 CDT is likely to be safer, is also associated with improved venous patency and valve preservation, and may reduce the incidence of PTS compared with conventional anticoagulation alone.53 Three randomized controlled clinical trials (RCTs) on this topic have been published, with conflicting results.45,46,54 Globally, the additional use of CDT had no benefit over anticoagulation alone in preventing PTS, with a higher major rate of bleeding. However, subgroup analysis showed a benefit in reducing severe PTS, limited to patients with iliofemoral DVT.55
Dr Lobastov. Despite discouraging results of ATTRACT and CAVA trials, the meta-analysis considering their data demonstrates a significant PTS risk reduction by 22% after thrombolysis.56 Of course, there is a lot of criticism of the last RCTs due to low technical success (76% in ATTRACT and 53% in CAVA), low rate of venous stenting for residual obstruction (28% in ATTRACT and 45% in CAVA), enrolment of patients with femoropopliteal DVT, and nonoptimal anticoagulation with a high rate of recurrent DVT (10% in ATTRACT and 5.5% in CAVA).45,46 So, selecting patients that would receive maximal technical success and clinical benefits from CDT remains a crucial question. Post hoc analysis of the CAVA trial showed that patients with acute and subacute thrombosis assessed by results of magnetic resonance venography (MRV) and clinical presentation had an 11 times higher success rate after ultrasound-accelerated thrombolysis.57 The recent consensus by the Society of Interventional Radiology stated that CDT/ PCDT is suggested for the following: (i) patients with iliofemoral DVT and acute limb-threatening circulatory compromise (eg, phlegmasia cerulea dolens); ii) nonelderly patients at low bleeding risk with acute iliofemoral DVT and nonthreatening limb and who have moderate-to-severe symptoms; and iii) patients with acute iliofemoral DVT who continue to have moderate-to-severe symptoms or impaired ambulation despite initial anticoagulation, who are at low risk of bleeding, and whose thrombus is believed to have formed within the past 14 days.58 So, interventional treatment is considered for acute presentation of proximal DVT and patients with poor response to standard anticoagulation. It is probable that those patients with poor response to standard anticoagulation may receive additional benefits from CDT/PCDT.
Dr Geroulakos. We and others have shown that elastic compression stockings (ECS) can significantly reduce the incidence of PTS after DVT, and therefore these should be routinely prescribed.59
Dr Josnin. The SOX study (Compression Stockings to Prevent the Post-Thrombotic Syndrome After Symptomatic Proximal Deep Venous Thrombosis) has profoundly changed our habits, and until now, we’ve recommended wearing ECS for 2 years after a venous thrombosis. However, the SOX study showed an apparent decrease in treatment adherence with ECS compared with other studies.60 This finding has generated doubts about the benefits of prolonged compression treatment after DVT. So current guidelines recommend wearing compression to relieve symptoms in the acute phase, and further studies are needed to make progress on this subject. In my practice, prescribing compression remains systematic.
Dr Kan. ECS can prevent PTS by reducing leg swelling and venous hypertension. However, there is conflicting evidence regarding the long-term effectiveness of ECS in preventing PTS. Evidence-based consensus guidelines recommend using ECS for at least 2 years after DVT to prevent PTS, a recommendation based on the results of small open-label trials.28
However, the SOX trial showed no evidence that active compression stockings help prevent PTS, reduce the risk of recurrent VTE, or improve QOL.60 A meta-analysis including data from the SOX trial reported a combined hazard ratio of 0.69 (95% CI, 0.47-1.02) for developing PTS with ECS.61 However, the authors caution that confidence in this pooled estimate is very low due to heterogeneity and inclusion of unblinded studies at high risk of bias and that the highest quality evidence recently available shows no effect of ECS on PTS. Based on these data, recent guidelines recommend against the routine use of ECS for prevention of PTS.28
Although unlikely to cause harm, ESC can be difficult to apply, uncomfortable, expensive, and must be replaced every few months. Given current evidence, not all patients with DVT require routine use of ECS that must continue until symptoms improve.28
Dr Nikolov. All current evidence suggests that ECS are beneficial in preventing PTS after DVT.15
Dr Tazi Mezalek. Effective compression has been shown to reduce venous hypertension, edema, to minimize microcirculatory changes, and to plausibly play a role in preventing PTS.62 A 2017 Cochrane systematic review concluded that there was a trend favoring the use of ECS after DVT (RR, 0.62; 95% CI, 0.38-1.01); however, there were methodological limitations in the included trials.
Dr Lobastov. Many discussions were raised around the SOX trial.60 It was criticized for placebo stockings, delayed start of compression, low compliance, and many other issues. Further trials showed that the early start of elastic compression in the acute phase of DVT prevents PTS signs such as skin induration, hyperpigmentation, venous ectasia, and pain with calf compression.64 So, removing acute edema in DVT to protect lymphatic outflow is crucial because damage to lymphatic vessels seems to play a pivotal role in PTS development.65-67 Considering placebo stockings with a pressure of 5 mm Hg, a previous trial showed that such pressure is enough to prevent occupational edema.68 Moreover, progressive ECS with increased pressure at the wide part of the calf may be more effective than classical graduated ECS.69,70 So, the results of the SOX trial could be interpreted as evidence that low-pressure compression stockings are noninferior to high-pressure ones in terms of PTS development. This idea could be partially confirmed by the results of the recent CELEST trial (Compression Elastique Evaluation du Syndrome post Thrombotique), which found stockings of 25 mm Hg noninferior to 35 mm Hg for PTS occurrence within 2 years after DVT.71 At the same time, 2 studies (OCTAVIA [Optimal duration of Compression Therapy As prevention of chronic Venous Insufficiency After deep venous thrombosis] and IDEAL DVT [Individually Tailored Elastic Compression Therapy After Deep Venous Thrombosis in Relation to the Incidence of Post Thrombotic Syndrome]) showed no need for permanent use of ECS for 2 years in persons with no PTS symptoms at 6 to 12 months after DVT.72,73 Considering all these findings, the latest guidelines still recommend using ECS for at least 12 months to prevent PTS after proximal DVT.49
Dr Josnin. The importance of anticoagulant therapy in preventing PTS is undeniable, with the American Heart Association recommendations clearly emphasizing this.3 However, the type of treatment is not as clearly defined. Studies tend to show that LMWH are better at preventing PTS than VKA and DOAC as well. Some investigators consider that the anti-inflammatory role of LMWH would indicate its use in the initial phase of treatment.
Dr Kan. Timely and effective anticoagulant therapy is the best way to prevent PTS after acute DVT. Data suggest that LMWH and DOACs may be superior to VKA in preventing PTS, and the anti-inflammatory properties of LMWH and DOAC may drive this improved efficacy. LMWH appear to have stronger anti-inflammatory properties than DOACs, but direct comparisons in PTS prevention are still lacking.74
Thrombus regression in acute DVT has been shown to be rapid during the first 2 to 3 months after initiation of anticoagulant therapy and to slow gradually after 3 months. After 2 years, no additional thrombus is expected to resolve, and the extent of residual venous obstruction (RVO) is fixed. From a hemodynamic point of view, better and earlier thrombolytic conditions lead to better valve protection and reduced venous valve regurgitation. In addition, the smaller the clot burden, the lower the risk of developing RVO, venous reflux, and ultimately PTS. This is the rationale for using CDT in extensive DVT, but any treatment that reduces the initial clot burden should reduce the risk of PTS. This may be why all anticoagulant treatments are effective in preventing PTS.74
Dr Tazi Mezalek. Given the parietal alteration, venous reflux, and obstruction attributed to PTS, it has been suggested that patients with PTS may be at increased risk for VTE recurrence, independent of other risk factors. The data in the literature are conflicting. In one study, RVO was accompanied by a 2-fold increased risk of VTE recurrence after 3 months of conventional anticoagulant therapy.
Dr Lobastov. PTS and VTE recurrence have a close relationship. New DVT is associated with an approximately 10-fold increase in the risk of PTS development, whereas PTS increases the risk of recurrent VTE by 2.5- to 3-fold.3,77 Moreover, such factors as RVO, elevated D-dimer, and obesity affect both risks.
According to the current guidelines, any VTE event should be treated with anticoagulation for at least 3 months.49,78,79 The further decision for indefinite anticoagulation should be based on the individual assessment of risks (major bleeding) and benefits (prevention of VTE recurrence). DOACs appeared to be very safe during prolonged anticoagulation. Compared with placebo, they reduce overall mortality by 61% by decreasing the risk of VTE recurrence, including fatal pulmonary embolism, without increasing the risk of major bleeding, including fatal hemorrhage.80 That’s why current guidelines tend to prolong anticoagulation with DOACs in most patients at risk of recurrent VTE.
Individual risk of recurrence is determined by different factors, of which the most important is a clinical provocation of the index VTE. Suppose DVT is provoked by a major transient risk factor (major surgery, trauma with fractures, confined to bed in the hospital for ≥3 days). In that case, the risk of recurrence is the lowest, and anticoagulation may be stopped after 3 months. Also, in VTE provoked by pregnancy and oral contraceptives (formally, minor transient risk factor), the risk of recurrence is low (8% per year) such as the following: repeated VTE in the absence of major transient risk factors, active cancer, and antiphospholipid syndrome.
Thus, in the current case of unprovoked DVT with good treatment tolerability, indefinite anticoagulation with a reduced dose of DOAC is indicated.
Dr Geroulakos. This would be treatment with micronized purified flavonoid fraction (MPFF), ECS, analgesia, and iliac stenting, if appropriate.
Dr Josnin. Physical exercises are indicated, although studies with larger cohorts are still needed.83 ECS is indicated, but the strength of this compression must be adapted to the patient’s clinical response and improvement in QOL. Concerning MPFF, a study is underway, the MUFFIN-PTS trial (Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome), with results pending.84
Dr Kan. The management cornerstones for patients with established PTS are ECS, exercise, and lifestyle changes.85 Every day, wearing a knee-length ECS of 20 to 30 mm Hg is recommended for patients with established PTS. For patients with moderate-to-severe PTS whose symptoms are not adequately controlled with ECS alone, it is also recommended to try intermittent compression devices. A supervised exercise training program of 6 months or longer is reasonable for patients with PTS who can tolerate it. A multidisciplinary approach is recommended for the management of postthrombotic ulcers.86 In refractory cases, surgery or endovascular intervention may be considered. However, due to the lack of effective treatments, new approaches are needed to prevent and treat PTS.
Dr Nikolov. The first line of treatment is lifestyle modification, exercises, ECS, and venoactive drugs (VADs). The second line is invasive endovenous techniques, such as different ablation modalities for superficial reflux and venous stenting for chronic iliac vein occlusions.
Dr Tazi Mezalek. Support options for PTS are limited. Recently, evidence-based guidelines focused on PTS were published.3,15,86,87 The recommendations are based on a few controlled studies with a limited number of patients and limited follow-up time.
In contrast to the uncertainty surrounding ECS use for PTS prevention, they are the cornerstone of treatment in PTS to reduce symptoms. However, their use is based primarily on extrapolation of results from patients with primary CVD and a low risk of harm.88,89 The optimal degree of compression is unknown, and guidelines suggest prescribing knee-length 20-30-mm-Hg ESC to patients with PTS-related leg heaviness or swelling. If 20-30-mm-Hg ECS is not effective enough, a stronger pressure stocking (30-40 mm Hg; or ≥40 mm Hg) can be tried. Intermittent pneumatic compression can also be used with severe symptoms and edema in PTS.90 Walking exercise implemented early after DVT diagnosis, associated with early compression, reduces DVT-related symptoms. A 6-month walking exercise program should be encouraged to enhance calf muscle contractions and plantar loading to enhance venous drainage and then improve PTS severity, and QOL, with no adverse events.91
Several reports have demonstrated promising clinical response and durability of recanalization and venous stenting for chronic iliocaval obstructions in selected PTS patients.92 Experience with these procedures varies substantially. Complications and failure rates are uncertain, and it remains difficult to identify which patients would benefit most.
One treatment option to explore is the use of VADs. Four randomized trials have been performed to evaluate the effectiveness of VADs for PTS (rutosides, defibrotide, and hidrosmine). Overall, low-quality evidence supports the use of VADs to treat PTS.93 Among the VADs that could be tested, MPFF seems to have a favorable profile. It acts to improve venous obstruction, valvular reflux, and inflammatory venous lesions, which are vital contributors to the pathogenesis of PTS. This molecule appears promising, especially since it improves clinical manifestations, QOL, and objective venous parameters of CVD.94 Observational studies have reported that MPFF improved clinical manifestations or objective venous measures in patients with PTS.95 When combined with rivaroxaban in femoropopliteal DVT, MPFF improved the Villalta score and the venous clinical severity score and decreased the incidence of PTS in DVT patients compared with rivaroxaban alone.96 However, there is a lack of high-quality confirmatory studies to strengthen the evidence for using venotonic drugs to treat PTS.
Dr Lobastov. Today, there is a lack of direct evidence on the efficacy and safety of different treatment approaches in PTS. Exercises, ECS, VADs, and intermittent pneumatic compression are traditionally recommended to improve symptoms and signs of PTS.3,28,85,97,98 However, the majority of these recommendations are driven by nonspecific studies in CVD patients, which may include unselected populations with postthrombotic reflux and obstruction. MPFF has a high potential to be beneficial in PTS because it controls symptoms and signs of CVD and improves deep vein recanalization due to topical anti-inflammatory activity in the vein wall.94,96,99,100 In addition, electrical calf muscle stimulation may be recommended at the top of standard therapy for further improvement of symptoms, recanalization, and prevention of VTE recurrence.101
Conclusion
• The best way to prevent PTS is to prevent DVT occurrence and ipsilateral recurrence with pharmacologic primary and secondary prophylaxis in high-risk patients.
• Clinical scales may help predict the development of PTS after proximal DVT.
• Anticoagulation with DOACs rather than VKA may reduce the development of PTS.
• Careful consideration for CDT/PCDT in patients with iliofemoral DVT, moderate-to-severe symptoms, and low risk of bleeding may help to prevent PTS.
• Using ECS after DVT can prevent PTS, but the evidence is conflicting. Individual adjustment of treatment duration according to the symptoms of PTS is recommended. Early compression starting in the acute phase of DVT, and maintenance of high adherence to ECS use is essential for PTS prevention.
• The nature of index DVT should drive the duration of anticoagulation treatment. In the absence of a major transient risk factor, indefinite anticoagulation with DOACs is indicated in most patients.
• MPFF has a high potential in PTS prevention and treatment, but direct evidence is still neeed.
CORRESPONDING AUTHOR
Zoubida Tazi Mezalek
Department of Clinical Hematology,
Internal Medicine, Mohammed V
University, Ibn Sina Hospital,
Rabat, Morocco
email: z.tazimezalek@gmail.com
References
1. Eklof B, Perrin M, Delis KT, Rutherford RB, Gloviczki P. Updated terminology of chronic venous disorders: the VEIN-TERM transatlantic interdisciplinary consensus document. J Vasc Surg. 2009;49(2):498- 501.
2. Lattimer CR, Kalodiki E, Azzam M, Geroulakos G. Validation of the Villalta scale in assessing post-thrombotic syndrome using clinical, duplex, and hemodynamic comparators. J Vasc Surg Venous Lymphat Disord. 2014;2(1):8-14.
3. Kahn SR, Comerota AJ, Cushman M, et al. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130(18):1636-1661.
4. Enden T, Haig Y, Kløw NE, et al. 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.
5. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149(10):698-707.
6. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1-7.
7. Roumen-Klappe EM, den Heijer M, Janssen MC, van der Vleuten C, Thien T, Wollersheim H. The post-thrombotic syndrome: incidence and prognostic value of non-invasive venous examinations in a six-year follow-up study. Thromb Haemost. 2005;94(4):825-830.
8. Deatrick KB, Elfline M, Baker N, et al. Postthrombotic vein wall remodeling: preliminary observations. J Vasc Surg. 2011;53(1):139-146.
9. Vedantham S. Valvular dysfunction and venous obstruction in the post-thrombotic syndrome. Thromb Res. 2009;123(suppl 4):S62-S65.
10. Audu CO, Gordon AE, Obi AT, Wakefield TW, Henke PK. Inflammatory biomarkers in deep venous thrombosis organization, resolution, and post-thrombotic syndrome. J Vasc Surg Venous Lymphat Disord. 2020;8(2):299-305.
11. Caps MT, Manzo RA, Bergelin RO, Meissner MH, Strandness DE. Venous valvular reflux in veins not involved at the time of acute deep vein thrombosis. J Vasc Surg. 1995;22(5):524-531.
12. Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C. Definition of post thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost. 2009;7(5):879-883.
13. Villalta S BP, Piccioli A, Lensing A, Prins M, Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome [abstract]. Haemostasis. 1994(24 suppl 1):158a.
14. Kahn SR. Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome. J Thromb Haemost. 2009;7(5):884-848.
15. Visonà A, Quere I, Mazzolai L, et al. Post-thrombotic syndrome. Vasa. 2021;50(5):331-340.
16. van Korlaar I, Vossen C, Rosendaal F, Cameron L, Bovill E, Kaptein A. Quality of life in venous disease. Thromb Haemost. 2003;90(1):27-35.
17. Kahn SR, Ducruet T, Lamping DL, et al. Prospective evaluation of health-related quality of life in patients with deep venous thrombosis. Arch Intern Med. 2005;165(10):1173-1178.
18. Guanella R, Ducruet T, Johri M, et al. Economic burden and cost determinants of deep vein thrombosis during 2 years following diagnosis: a prospective evaluation. J Thromb Haemost. 2011;9(12):2397-2405.
19. Ning J, Ma W, Fish J, Trihn F, Lurie F. Biases of Villalta scale in classifying post thrombotic syndrome in patients with pre-existing chronic venous disease. J Vasc Surg Venous Lymphat Disord. 2020;8(6):1025-1030.
20. Engeseth M, Enden T, Sandset PM, Wik HS. Limitations of the Villalta scale in diagnosing post-thrombotic syndrome. Thromb Res. 2019;184:62-66.
21. Pop CT, Gu CS, Vedantham S, Galanaud JP, Kahn SR. Exploring the Villalta scale to capture postthrombotic syndrome using alternative approaches: a subanalysis of the ATTRACT trial. Res Pract Thromb Haemost. 2023;7(1):100032.
22. Engeseth M, Enden T, Andersen MH, Sandset PM, Wik HS. Does the Villalta scale capture the essence of postthrombotic syndrome? A qualitative study of patient experience and expert opinion. J Thromb Haemost. 2019;17(10):1707-1714.
23. Utne KK, Ghanima W, Foyn S, Kahn S, Sandset PM, Wik HS. Development and validation of a tool for patient reporting of symptoms and signs of the post thrombotic syndrome. Thromb Haemost. 2016;115(2):361-367.
24. Ng S, Rodger MA, Ghanima W, et al. External validation of the patient reported villalta scale for the diagnosis of postthrombotic syndrome. Thromb Haemost. 2022;122(8):1379-1383.
25. Zolotukhin IA, Seliverstov EI, Shevtsov YN, et al. Prevalence and risk factors for chronic venous disease in the general Russian population. Eur J Vasc Endovasc Surg. 2017;54(6):752-758.
26. Donbaloğlu MO, Gürkan S, Gür Ö. Do treatment methods for deep vein thrombosis have different effects on post-thrombotic syndrome and the quality of life? Vascular. 2023;17085381231158833.
27. Galanaud JP, Holcroft CA, Rodger MA, et al. Comparison of the Villalta post-thrombotic syndrome score in the ipsilateral vs. contralateral leg after a first unprovoked deep vein thrombosis. J Thromb Haemost. 2012;10(6):1036-1042.
28. Kahn SR. The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Program. 2016;2016(1):413-418.
29. Galanaud JP, Monreal M, Kahn SR. Epidemiology of the post-thrombotic syndrome. Thromb Res. 2018;164:100- 109.
30. Galanaud JP, Holcroft CA, Rodger MA, et al. Predictors of post-thrombotic syndrome in a population with a first deep vein thrombosis and no primary venous insufficiency. J Thromb Haemost. 2013;11(3):474-480.
31. Rabinovich A, Kahn SR. How to predict and diagnose postthrombotic syndrome. Pol Arch Med Wewn. 2014;124(7- 8):410-416.
32. Cucuruz B, Kopp R, Pfister K, et al. Risk and protective factors for post-thrombotic syndrome after deep venous thrombosis. Vasc Surg Venous Lymphat Disord. 2020;8(3):390-395.
33. Schulman S, Lindmarker P, Holmström M, et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost. 2006;4(4):734-742.
34. Dronkers CEA, Mol GC, Maraziti G, et al. Predicting post-thrombotic syndrome with ultrasonographic follow-up after deep vein thrombosis: a systematic review and meta-analysis. Thromb Haemost. 2018;118(8):1428-1438.
35. Chitsike RS, Rodger MA, Kovacs MJ, et al. Risk of post-thrombotic syndrome after subtherapeutic warfarin anticoagulation for a first unprovoked deep vein thrombosis: results from the REVERSE study. J Thromb Haemost. 2012;10(10):2039-2044.
36. Hull RD, Liang J, Townshend G. Long-term low-molecular-weight heparin and the post-thrombotic syndrome: a systematic review. Am J Med. 2011;124(8):756-765.
37. Prandoni P, Ageno W, Mumoli N, et al. Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants. Thromb Res. 2017;153:97-100.
38. Prandoni P, Ageno W, Ciammaichella M, et al. The risk of post-thrombotic syndrome in patients with proximal deep vein thrombosis treated with the direct oral anticoagulants. Intern Emerg Med. 2020;15(3):447-452.
39. Li R, Yuan M, Cheng J, et al. Risk of post thrombotic syndrome after deep vein thrombosis treated with rivaroxaban versus vitamin-K antagonists: a systematic review and meta-analysis. Thromb Res. 2020;196:340-348.
40. Karathanos C, Nana P, Spanos K, et al. Efficacy of rivaroxaban in prevention of post-thrombotic syndrome: a systematic review and meta-analysis. J Vasc Surg Venous Lymphat Disord. 2021;9(6):1568- 1576.e1.
41. Lobastov KV, Schastlivtsev IV, Bargandzhiya AB. Risk of post-thrombotic syndrome following direct oral anticoagulant intake: a systematic review and meta-analysis [Article in Russian]. Khirurgiia (Mosk). 2022(2):89-99.
42. Bistervels IM, Bavalia R, Beyer-Westendorf J, et al. Postthrombotic syndrome and quality of life after deep vein thrombosis in patients treated with edoxaban versus warfarin. Res Pract Thromb Haemost. 2022;6(5):e12748.
43. Wik HS, Kahn SR, Eriksson H, et al. Post thrombotic syndrome in patients with venous thromboembolism treated with dabigatran or warfarin: a long-term cross-sectional follow-up of RE-COVER study patients. J Thromb Haemost. 2021;19(10):2495-2503.
44. Rinfret F, Gu CS, Vedantham S, Kahn SR. New and known predictors of the postthrombotic syndrome: a subanalysis of the ATTRACT trial. Res Pract Thromb Haemost. 2022;6(6):e12796.
45. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017;377(23):2240-2252.
46. Notten P, de Smet A, Tick LW, et al. CAVA (Ultrasound-Accelerated Catheter Directed Thrombolysis on Preventing Post-Thrombotic Syndrome) trial: long-term follow-up results. J Am Heart Assoc. 2021;10(11):e018973.
47. National Institute for Health and Care Excellence. Percutaneous mechanical thrombectomy for acute deep vein thrombosis of the leg. Interventional procedures guidance [IPG651]. Published June 12, 2019. https://www.nice.org.uk/ guidance/ipg651
48. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738.
49. Kakkos SK, Gohel M, Baekgaard N, et al. Editor’s choice – European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of venous thrombosis. Eur J Vasc Endovasc Surg. 2021;61(1):9-82.
50. Goldhaber SZ, Magnuson EA, Chinnakondepalli KM, Cohen DJ, Vedantham S. Catheter-directed thrombolysis for deep vein thrombosis: 2021 update. Vasc Med. 2021;26(6):662- 669.
51. Lindow C, Mumme A, Asciutto G, Strohmann B, Hummel T, Geier B. Long-term results after transfemoral venous thrombectomy for iliofemoral deep venous thrombosis. Eur J Vasc Endovasc Surg. 2010;40(1):134-138.
52. Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2016;11(11):CD002783.
53. Comerota AJ, Grewal N, Martinez JT, et al. Postthrombotic morbidity correlates with residual thrombus following catheter directed thrombolysis for iliofemoral deep vein thrombosis. J Vasc Surg. 2012;55(3):768-773.
54. Haig Y, Enden T, Grøtta O, et al. Post thrombotic syndrome after catheter directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Haematol. 2016;3(2):e64-e71.
55. Mastoris I, Kokkinidis DG, Bikakis I, et al. Catheter-directed thrombolysis vs. anticoagulation for the prevention and treatment of post-thrombotic syndrome in deep vein thrombosis: an updated systematic review and meta-analysis of randomized trials. Phlebology. 2019;34(10):675-682.
56. Broderick C, Watson L, Armon MP. Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb. Cochrane Database Syst Rev. 2021;1(1):CD002783.
57. Arnoldussen C, Notten P, Brans R, et al. Clinical impact of assessing thrombus age using magnetic resonance venography prior to catheter-directed thrombolysis. Eur Radiol. 2022;32(7):4555-4564.
58. Vedantham S, Desai KR, Weinberg I, et al. Society of Interventional Radiology position statement on the endovascular management of acute iliofemoral deep vein thrombosis. J Vasc Interv Radiol. 2023;34(2):284-299.e7.
59. Kakkos SK, Daskalopoulou SS, Daskalopoulos ME, Nicolaides AN, Geroulakos G. Review on the value of graduated elastic compression stockings after deep vein thrombosis. Thromb Haemost. 2006;96(4):441-445.
60. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383(9920):880-888.
61. Berntsen CF, Kristiansen A, Akl EA, et al. Compression stockings for preventing the postthrombotic syndrome in patients with deep vein thrombosis. Am J Med. 2016;129(4):447.e1-447.e20.
62. Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349(9054):759-762.
63. Appelen D, van Loo E, Prins MH, Neumann MH, Kolbach DN. Compression therapy for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev. 2017;9(9):CD004174.
64. Amin EE, Joore MA, Ten Cate H, et al. Clinical and economic impact of compression in the acute phase of deep vein thrombosis. J Thromb Haemost. 2018 Jun 1. Epub ahead of print. doi:10.1111/ jth.14163
65. Byung-Boong L. Phlebolymphedema: is it a new concept? Phlebolymphology. 2021;28(1):3-13.
66. Rasmussen JC, Aldrich MB, Tan IC, et al. Lymphatic transport in patients with chronic venous insufficiency and venous leg ulcers following sequential pneumatic compression. J Vasc Surg Venous Lymphat Disord. 2016;4(1):9-17.
67. Rasmussen JC, Zhu B, Morrow JR, et al. Degradation of lymphatic anatomy and function in early venous insufficiency. J Vasc Surg Venous Lymphat Disord. 2021;9(3):720-730.e2.
68. Mosti G, Partsch H. Occupational leg oedema is more reduced by antigraduated than by graduated stockings. Eur J Vasc Endovasc Surg. 2013;45(5):523-527.
69. Mosti G, Partsch H. Improvement of venous pumping function by double progressive compression stockings: higher pressure over the calf is more important than a graduated pressure profile. Eur J Vasc Endovasc Surg. 2014;47(5):545-549.
70. Couzan S, Leizorovicz A, Laporte S, et al. A randomized double-blind trial of upward progressive versus degressive compressive stockings in patients with moderate to severe chronic venous insufficiency. J Vasc Surg. 2012;56(5):1344-1350.e1.
71. Galanaud JP, Genty-Vermorel C, Barrellier MT, et al. 25 mm Hg versus 35 mm Hg elastic compression stockings to prevent post-thrombotic syndrome after deep vein thrombosis (CELEST): a randomised, double-blind, non-inferiority trial. Lancet Haematol. 2022;9(12):e886-e896.
72. Mol GC, van de Ree MA, Klok FA, et al. One versus two years of elastic compression stockings for prevention of post-thrombotic syndrome (OCTAVIA study): randomised controlled trial. BMJ. 2016;353:i2691.
73. Ten Cate-Hoek AJ, Amin EE, Bouman AC, et al. Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial. Lancet Haematol. 2018;5(1):e25-e33.
74. Makedonov I, Kahn SR, Abdulrehman J, et al. Prevention of the postthrombotic syndrome with anticoagulation: a narrative review. Thromb Haemost. 2022;122(8):1255-1264.
75. Stain M, Schönauer V, Minar E, et al. The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. J Thromb Haemost. 2005;3(12):2671-2676.
76. Prandoni P, Lensing AW, Prins MH, et al. The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation. Semin Thromb Hemost. 2015;41(2):133-140.
77. Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179(5):417-426.
78. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603.
79. Stevens SM, Woller SC, Baumann Kreuziger L, et al. Executive summary: Antithrombotic therapy for VTE disease: second update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6):2247-2259.
80. Ebraheem M, Alzahrani I, Crowther M, Rochwerg B, Almakadi M. Extended DOAC therapy in patients with VTE and potential risk of recurrence: a systematic review and meta-analysis. J Thromb Haemost. 2020;18(9):2308-2317.
81. Aziz D, Skeith L, Rodger MA, et al. Long-term risk of recurrent venous thromboembolism after a first contraceptive-related event: data from REVERSE cohort study. J Thromb Haemost. 2021;19(6):1526-1532.
82. Prins MH, Lensing AWA, Prandoni P, et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv. 2018;2(7):788-796.
83. Jasionowska S, Turner BRH, Machin M, et al. Systematic review of exercise therapy in the management of post-thrombotic syndrome. Phlebology. 2022;37(10):695- 700.
84. Galanaud JP, Abdulrehman J, Lazo-Langner A, et al. MUFFIN-PTS trial, Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome: protocol of a randomised controlled trial. BMJ Open. 2021;11(9):e049557.
85. Rabinovich A, Kahn SR. How I treat the postthrombotic syndrome. Blood. 2018;131(20):2215-2222.
86. Kahn SR, Galanaud JP, Vedantham S, Ginsberg JS. Guidance for the prevention and treatment of the post-thrombotic syndrome. J Thromb Thrombolysis. 2016;41(1):144-153.
87. Vedantham S, Kahn SR, Goldhaber SZ, et al. Endovascular therapy for advanced post thrombotic syndrome: proceedings from a multidisciplinary consensus panel. Vasc Med. 2016;21(4):400-407.
88. Kahn SR, Shapiro S, Ducruet T, et al. Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial. Thromb Haemost. 2014;112(6):1137-1141.
89. Subbiah R, Aggarwal V, Zhao H, Kolluri R, Chatterjee S, Bashir R. Effect of compression stockings on post thrombotic syndrome in patients with deep vein thrombosis: a meta-analysis of randomised controlled trials. Lancet Haematol. 2016;3(6):e293-e300.
90. Ginsberg JS, Magier D, Mackinnon B, Gent M, Hirsh J. Intermittent compression units for severe post-phlebitic syndrome: a randomized crossover study. CMAJ. 1999;160(9):1303-1306.
91. Kahn SR, Shrier I, Shapiro S, et al. Six month exercise training program to treat post-thrombotic syndrome: a randomized controlled two-centre trial. CMAJ. 2011;183(1):37-44.
92. Razavi MK, Jaff MR, Miller LE. Safety and effectiveness of stent placement for iliofemoral venous outflow obstruction: systematic review and meta-analysis. Circ Cardiovasc Interv. 2015;8(10):e002772.
93. Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012;141(2):308-320.
94. Li KX, Diendéré G, Galanaud JP, Mahjoub N, Kahn SR. Micronized purified flavonoid fraction for the treatment of chronic venous insufficiency, with a focus on postthrombotic syndrome: a narrative review. Res Pract Thromb Haemost. 2021;5(4):e12527.
95. Ignat’ev IM. Open prospective randomized study of the results of using Venarus in postthrombotic disease [Article in Russian]. Angiol Sosud Khir. 2018;24(1):97-101.
96. Lobastov K, Schastlivtsev I, Barinov V. Use of micronized purified flavonoid fraction together with rivaroxaban improves clinical and ultrasound outcomes in femoropopliteal venous thrombosis: results of a pilot clinical trial. Adv Ther. 2019;36(1):72-85.
97. Kahn SR, Ginsberg JS. The post thrombotic syndrome: current knowledge, controversies, and directions for future research. Blood Rev. 2002;16(3):155-165.
98. Kahn SR. How I treat postthrombotic syndrome. Blood. 2009;114(21):4624- 4631.
99. Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon®) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol. 2018;37(2):143-154.
100. Lobastov K, Schastlivtsev I, Barinov V. Micronized purified flavonoid fraction in adjunction to rivaroxaban improves outcomes of popliteal-femoral deep vein thrombosis at 12-month follow-up. Phlebolymphology. 2020;27(3):113-124.
101. Lobastov K, Ryzhkin V, Vorontsova A, et al. Electrical calf muscle stimulation in patients with post-thrombotic syndrome and residual venous obstruction after anticoagulation therapy. Int Angiol. 2018; 37(5):400-410.
