Servier – Phlebolymphology

XXI. Post-thrombotic syndrome: towards
consensus on definition, scoring and
effective prevention

What is PTS and how we measure this?
Mark Meissner (US)
The clinical definition of the syndrome is the presence of pain (often described as aching, heaviness, or, in some cases, as venous claudication) with associated swelling and skin changes, which eventually leads to ulceration. In addition, there is evidence of reflux and/or obstruction due to a previous deep vein thrombosis. It has been demonstrated that, after deep vein thrombosis, thrombus organization and recanalization occurs over a period of 6 months with increasing prevalence of reflux reaching 70%. Thus, the measurement of postthrombotic syndrome before 6 months is meaningless. In assessing postthrombotic syndrome, one should first consider the method of treatment of deep vein thrombosis and categorize patients in groups of similar categories according to treatment, extent of thrombosis, etc. In addition, we need a method of evaluating change in response to natural history or intervention. The CEAP classification is considered the gold-standard discriminative instrument that categorizes patients according to different stages of the disease. However, it is based on signs and it ignores symptoms. The Villalta scale is a mixture of patient-reported symptoms and clinician-rated signs. It is overly sensitive to mild postthrombotic syndrome. The venous clinical severity score is clinician-rated because, with the exception of pain, it is based on signs. It is associated with a high interobserver variability. It has been suggested that mild postthrombotic syndrome can be defined by a Villalta score of 5 to 14 with a venous clinical severity score a 4 to 7 and severe postthrombotic syndrome by a Villalta score ≥15 or ulcer with venous clinical severity score ≥8. However, in the CaVenT study, where there was a 28% risk reduction in postthrombotic syndrome (Villalta score >4) (P<0.001) in the catheter-directed thrombolysis group, there was no corresponding significant improvement in quality of life. It was concluded that we need better evaluation instruments for postthrombotic syndrome.

Post-thrombotic syndrome: need for a new instrument
Mark Meissner (US)
Although direct oral anticoagulants and extended therapy for unprovoked deep vein thrombosis have been proven very effective in reducing the incidence of recurrent deep vein thrombosis, recent randomized controlled studies have shown that graduated elastic stockings (SOX trial) and thrombolytic therapy for acute deep vein thrombosis (ATTRACT trial) are not effective in reducing the incidence of postthrombotic syndrome. In the SOX trial, which involved 806 patients, the primary outcome was based on the Ginsberg scale and the secondary outcome on the Villalta score. At 2 years, there was no difference between those with 30 to 40 mm Hg graduated elastic stockings and placebo (5 mm Hgstockings). In the ATTRACT trial, which involved 692 patients with proximal deep vein thrombosis, the primary outcome was also based on the Villalta score. Postthrombotic syndrome was defined as a Villalta score ≥5. At 1 year, there was no difference in the incidence of postthrombotic syndrome between the percutaneous catheter-directed thrombolysis group and the standard care group (P=0.56). However, in a subgroup analysis, it was found that, in patients with iliofemoral deep vein thrombosis, the incidence of moderate or severe postthrombotic syndrome (Villalta score >9) was lower in the pharmacomechanical catheter-directed thrombolysis group (17.9% vs 23.7%; P=0.035).

Were the failures in the above studies, a result of inappropriate study design or the use of inappropriate primary outcome measures? Postthrombotic syndrome is defined as the presence of chronic pain, edema, skin changes, and ulcerations occurring after an episode of deep vein thrombosis. The Ginsberg scale, which is based on pain and swelling is insensitive to mild postthrombotic syndrome. The Villalta score is based on (i) pain, cramps, heaviness, paresthesia, pruritus (patient-reported symptoms) and (ii) edema, induration, pigmentation, redness, ectasia, and calf tenderness (clinician-rated). It is overly sensitive to mild postthrombotic syndrome. In contrast, with the exception of pain, the venous clinical severity score is entirely based on signs (pain, varicose veins, pigmentation, inflammation, induration, ulcer number, size, and duration). These instruments have not been validated for prospective studies and they do not capture typical postthrombotic syndrome complaints or their importance to patients. A direct comparison between the Villalta scale and the venous clinical severity score demonstrated that the Villalta scale overidentifies mild-to-moderate postthrombotic syndrome and under identifies severe postthrombotic syndrome.

Mark Meissner concluded that recent large, randomized trials addressing the prevention of postthrombotic syndrome have largely been negative. It is possible that these interventions (elastic compression and thrombolysis) are truly ineffective. However, it is more likely that the trials are flawed by inappropriate patient selection, inappropriate interventions, or by using inappropriate outcome measures. What is urgently needed is the development of a validated, patient-important, and widely accepted outcome measure for postthrombotic syndrome. A moratorium on research addressing postthrombotic syndrome prevention should be considered until valid measures can be developed.

Management of the post-thrombotic syndrome – lessons learned
Paolo Prandoni (Italy)
There are four independent predictors of postthrombotic syndrome: excess body weight, residual vein thrombosis with development of popliteal valve incompetence, inadequate anticoagulation therapy, and development of ipsilateral recurrent deep vein thrombosis. A systematic review and meta-analysis of 8 studies involving 1577 patients demonstrated that the development of reflux increased the risk of postthrombotic syndrome by 34%. Three randomized control trials, involving 194, 100, and 518 patients, demonstrated that elastic compression following deep vein thrombosis reduced the development of the postthrombotic syndrome by 35% to 58%. However, a fourth randomized control trial, involving 873 patients, failed to confirm the benefit of elastic stockings. Methodological problems (self-reporting, wearing the stockings only 3 days per week) have brought the validity of the last study into question. More studies are needed. In patients in whom the international normalized ratio is <2 more than 50% of the time during the first 3 months after deep vein thrombosis, the incidence of deep vein thrombosis and postthrombotic syndrome recurrence is 9 and 3 times higher, respectively, compared with patients with an international normalized ratio <2.0 less than 50% of the time.

PTS predictive factors – what do we know about?
Tomasz Urbanek (Poland)
Risk factors related to the patient’s initial state include sex, age, obesity, and preexisting primary chronic venous disease. The latter is associated with a 2-fold increase in postthrombotic syndrome. High rates of postthrombotic syndrome have been reported after surgery, eg, 5.8% following abdominal surgery and 24% to 88% following knee replacement surgery). In a series of 376 patients followed-up after a single deep vein thrombosis episode, there was a strong association between the Villalta score in the leg after deep vein thrombosis leg and the Villalta score in the contralateral leg. Ipsilateral postthrombotic syndrome, defined as a Villalta score >4, developed in 116 (31.6%) patients, and, in 40% of these patients, the Villalta score in the contralateral leg was also >4.

Risk factors related to the initial characteristics of deep vein thrombosis can be symptomatic vs asymptomatic, massive proximal vs distal deep vein thrombosis, poor international normalized ratio control in the treatment phase, residual thrombus, and incomplete resolution of the symptoms at 1 month. The presence of proximal deep vein thrombosis increases the risk of postthrombotic syndrome by 2 to 3 fold. Treatment with low-molecular-weight heparin for 3 to 6 months is associated with a reduced incidence of postthrombotic syndrome compared with vitamin K antagonist therapy.

In conclusion, postthrombotic syndrome is still a challenging condition, a better method of scoring is needed, and it is still difficult to predict its occurrence, despite knowing some of the risk factors.

Does thrombolysis work in PTS prevention? Recent RCT results—ATTRACT trial data
Antonios Gasparis (US)
The CaVenT randomized control trial, which was published in 2012, involved 189 patients with iliofemoral deep vein thrombosis. Of these patients, 99 had anticoagulant therapy only and 90 had catheter-directed thrombolysis plus anticoagulant therapy (combination therapy). At 24 months, postthrombotic syndrome was present in 41% of patients in the combination therapy group and 56% in the anticoagulant therapy group (P=0.047). At 5 years, these figures were 43% vs 71% (P<0.0001) and the number needed to treat to prevent a postthrombotic syndrome in 1 patient was 4. The ATTRACT trial, which was published in 2017, involved 691 patients with iliofemoral or femoropopliteal deep vein thrombosis. They were randomized to anticoagulant therapy or catheter-directed thrombolysis plus anticoagulant therapy (combination therapy). The primary outcome was defined as a Villalta score >4 or development of a venous ulcer or for unplanned endovenous procedure to treat symptoms 6 months after randomization. The secondary endpoints were the changes from baseline to 24 months in leg pain (Likert scale of 7 points), calf circumference, and health-related quality of life (SF36 and VEINES-QOL). At 24 months, the primary outcome was 47% in the combination therapy group and 48% in the anticoagulant therapy group (P=0.56).

A subgroup analysis of the 311 patients with iliofemoral deep vein thrombosis in the ATTRACT study showed the presence of postthrombotic syndrome (Villalta score >4) in 49% in the combination therapy group and 51% in the anticoagulant therapy group (P=0.59). However, moderate and severe postthrombotic syndrome (Villalta score >9) was present in 18% of patients in the combination therapy group and 28% in the anticoagulant therapy group (P=0.021). Severe postthrombotic syndrome (Villalta score >14) was present in 8.7% in the combination therapy group and 15% in the anticoagulant therapy group (P=0.048). In these subgroups, the mean Villalta score was 3.82 in the combination therapy group and 5.43 in the anticoagulant therapy group (P<0.001). At 30 days posttreatment, the mean reduction in pain score from baseline was -2.36 in the combination therapy group and -1.80 in the anticoagulant therapy group (P=0.0082). Mean quality of life scores at 24 months was 21.5 in the combination group and 16.2 in the anticoagulant therapy group (P=0.043) (Comerota AJ et al. Circulation. In Press)

Although the primary endpoint was not reached in patients with iliofemoral deep vein thrombosis compared with anticoagulant therapy, combination therapy resulted in: (i) a reduction in postthrombotic syndrome of any severity using the venous clinical severity score; (ii) a reduction in moderate/severe postthrombotic syndrome using the Villalta score; (iii) a reduction in severe postthrombotic syndrome using the Villalta score; (iv) a reduction in pain and swelling; and (v) an improved disease-specific quality of life. Thus, for those offering catheter-directed thrombolysis to patients with moderate/severe symptoms of iliofemoral deep vein thrombosis, the ATTRACT trial confirms the approach. Those who do not offer catheter-directed thrombolysis to their patients with moderate/ severe symptoms, they should study the focused results of ATTRACT and seriously consider catheter-based thrombolysis.

Does anticoagulation work in PTS prevention?
Zbigniew Krasinski (Poland)
A recent publication used USA MarketScan claims from 2012 to 2015 to identify adults with the diagnosis of venous thromboembolism who were treated with rivaroxaban or warfarin. A total of 1463 patients treated with rivaroxaban and 26 494 with warfarin were followed for a mean of 16}9 months (range, 4 to 39 months). The duration of anticoagulation was similar between the groups. Rivaroxaban was associated with a 23% (95% CI, 16 to 30) reduced-hazard of postthrombotic syndrome compared with warfarin. In addition, rivaroxaban was associated with a significant risk reduction in calf pain and swelling compared with warfarin.

A 5-year follow-up analysis for the development of postthrombotic syndrome was performed in a registry of patients with deep vein thrombosis. Patients were admitted to the registry after completion of an anticoagulation period. A group of 167 patients received standard therapy of elastic compression, a second group of 124 patients received sulodexide and a third group of 48 received aspirin. The incidence of postthrombotic syndrome was 14.9% at 1 year and 19.5% at 5 years in the standard therapy group. It was 8.8% at 1 year and 12.2% at 5 years in the sulodexide group. It was 23.5% at 54 months in the aspirin group compared with 12.2% in the sulodexide and 18.2% in the standard therapy groups. Randomized controlled trials are needed to validate these results.