Background
Post-thrombotic syndrome (PTS) is a long-term complication in up to 50% of patients with a previous proximal deep vein thrombosis (DVT) [
1‐
3]. PTS is a chronic syndrome with various intermittent or persistent symptoms and signs of the lower limb; typically skin discoloration, swelling, and heaviness, and in severe cases painful venous ulcers and activity limiting venous claudication [
4‐
8]. PTS is associated with a reduction in quality of life (QoL), high demands on health care costs, and there are few treatment options [
9‐
12].
There is no gold standard objective test for diagnosing PTS [
13]. In clinical practice, patients who present with typical lower limb symptoms and signs later than 3–6 months following an acute DVT, and with no other obvious cause, are considered to have developed PTS [
14,
15]. On the other hand, in clinical trials various scorings systems have been used for the diagnosing, grading, and follow-up of PTS [
13,
16‐
18]. This is problematic when comparing results across studies and when implementing research for improved post-thrombotic care [
19,
20]. In 2009, the International Society on Thrombosis and Hemostasis (ISTH) recommended the Villalta scale [
13,
17] for PTS assessment in clinical research. In the absence of a gold standard test, the Villalta scale has been validated through correlations to generic and disease-specific QoL scores [
10,
21‐
23], and anatomic and physiologic markers [
20,
24,
25].
Despite being the recommended scoring system, limitations in the diagnostic accuracy of the Villalta scale have been recognized [
26‐
29]. The scale is unspecific and includes symptoms and signs that may occur in various other diseases [
26]. Moreover, some patients with severe leg problems that obviously relate to the DVT, i.e., they appeared in the same leg with no other obvious cause(s), may not qualify as PTS by the Villalta score [
13,
28,
30,
31]. This typically applies to patients with activity limitations due to venous claudication [
18,
27]. In a recent qualitative study, we explored the relations between the different items of the Villalta scale and the clinical characteristics and complaints described by patients with moderate and severe PTS. Our findings indicated that the Villalta scale does not capture various typical PTS complaints or reflect on the importance of PTS symptoms and signs [
5]. Thus, an improved diagnostic approach for PTS seems warranted. In the absence of a gold standard diagnostic test, we used four mandatory predefined clinical PTS criteria in line with how we diagnose PTS in clinical practice [
5,
32,
33]. We included any chronic complaint that had developed in the index limb following the objectively verified acute DVT, and an alternative diagnosis for the complaints had to be unlikely; hereunder excluding any preexisting comorbidity of the leg (Table
1).
Table 1
Four mandatory and predefined clinical criteria for PTS
1. Previous objectively verified DVT 2. Development of chronic complaints (> 1 month) in the DVT leg* |
3. The chronic complaints appeared or worsened following the DVT |
4. An alternative diagnosis to the patient’s complaints is not likely |
As there is no curative treatment for PTS [
17], identification of predictors of PTS may help identifying patients at risk of developing PTS, facilitate PTS prevention, and guide in the development toward improved PTS management and care [
34]. Previous studies of PTS predictors have mainly used the Villalta scale for PTS assessment [
1,
2,
29,
35‐
41]. However, the predictors identified have not been consistent across studies and have included proximal DVT, recurrent ipsilateral DVT, provoked DVT, pre-existing chronic venous insufficiency, obesity, smoking, older age, thrombophilia, deep venous reflux, and persistent venous obstruction [
17,
34,
42]. Some studies have found men to be at higher risk; others have found the opposite [
2,
43,
44]. Recurrent ipsilateral DVT is a strong predictor in a number of these studies, however, the magnitude of the effect differs across the studies, which can be explained by variability in study populations, and PTS definitions [
17].
In the current study, we aimed to examine predictors of long-term PTS as defined by the four predefined clinical criteria in line with clinical practice [
5,
32].
Discussion
When defining PTS by four mandatory and predefined clinical criteria in line with clinical practice, we found that younger age and a higher baseline Villalta score were independent predictors of long-term PTS in patients with a prior high proximal DVT.
Our findings are likely to contribute to the limited knowledge of predictors for long-term PTS, and identifying patients at risk is an important step towards developing improved treatment strategies for the prevention of PTS [
17,
45]. Also, our findings may indicate that PTS remains a common chronic complication for up to ten years following a first-time high proximal DVT. Younger age was an independent predictor of PTS which is in contrast to previous studies reporting that older age is a predictor for PTS [
1,
2,
44,
46,
47]. Lower leg comorbidity is likely to be more common in older patients, and may have contributed to confounding in previous studies. This possible confounding was avoided in our study as obvious comorbid leg symptoms and signs excluded PTS according to the predefined criteria.
The baseline Villalta score is likely to indicate the symptom burden at the time of DVT diagnosis, and a higher baseline score was an independent predictor of long-term PTS. Others have also found that a higher baseline Villalta score predicts a less favorable long-term outcome. Rabinovich et al. developed a prediction model for PTS based on the SOX study and found that patients with a Villalta score ≥ 4 at baseline, in addition to pelvic DVT and body mass index ≥35 kg/m
2, predicted increased risk of PTS [
48]. In addition, Kahn et al. found that higher Villalta score at one-month post-DVT was a strong predictor for PTS [
2].
Previous studies have also found iliofemoral DVT [
2,
44], recurrent ipsilateral DVT [
2,
39,
46,
49], and high body mass index (BMI) [
29] as strong predictors for PTS [
44,
48]. DVT with pelvic vein involvement were included in our multivariate model but was not a significant predictor in our study. The incidence of recurrent ipsilateral DVT was low, and data on baseline BMI was collected only in a subset of patients. Thus, neither of these two variables could be evaluated in the present study.
The introduction of CDT for PTS prevention was based upon the “open vein hypothesis”, where an accelerated thrombus removal is thought to prevent venous valve incompetence and incomplete recanalization [
3,
50]. At the six months follow-up of the CaVenT trial [
42] the lack of iliofemoral patency and deep venous reflux were found to be independent predictors of PTS in the treatment group receiving CDT; and PTS was defined by the Villalta scale [
40]. Prandoni et al. reported an increased risk of PTS in patients with persistent venous obstruction or popliteal reflux at six months follow-up [
25]. In the current study, neither lack of iliofemoral patency nor deep venous reflux came out as independent predictors of PTS. This could be due to selection bias as only 52% of the still eligible patients were included, the lack of power, or the use of a different definition of PTS.
It is acknowledged that the clinical presentation of PTS is non-specific and conditions as primary venous insuffiency, trauma, central venous hypertension, and arthrosis may present with similar clinical manifestations [
26,
32]. Moreover, reported predictors of PTS are overlapping with predictors of primary venous insufficiency [
30,
34]. Galanaud et al. used data from the REVERSE study to assess risk factors for PTS in patients with a first unprovoked proximal DVT who were free of clinically significant primary venous insufficiency with an effort to remove biased evaluation of PTS. After excluding patients with primary venous insufficiency, only obesity remained an independent predictor of PTS [
29]. Previous studies have shown that Villalta scores in the ipsilateral and contralateral legs are strongly correlated, indicating that cases considered as PTS may reflect pre-existing chronic venous disease [
17,
26,
51,
52]. When assessing PTS by the four clinical criteria, we excluded patients with complaints likely to be explained by primary venous insufficiency and other lower limb comorbidity.
A major limitation of this study includes the PTS assessment with no previously validated diagnostic tool. We assessed PTS in line with clinical practice [
5,
26,
27,
32]. The reported chronic complaints in the present study were to a great extent included in the Villalta scale. However, the scale does not include the typical pain and tightness in the thigh/calf during exercise with relief during rest, i.e., venous claudication which is often seen in persistent vein obstruction following iliofemoral DVT [
53]. Furthermore, the Villalta scale does not require symptoms or signs to be chronic, or consider whether the complaints could be explained by other conditions, i.e., comorbidity, we consider the four mandatory predefined clinical criteria to be relevant and contribute to improved diagnostic accuracy. However, without a previously validated diagnostic tool, our findings can only be considered as preliminary, hypothesis generating, and further research is needed.
Another limitation was that one study investigator performed all study visits and assessments. As only 52% of the eligible patients gave consent to participate in the current study there is a possibility for selection bias, however the participants and non-participants did not differ except for more leg comorbidity among non-participants [
32]. Comparisons between DVT with and without pelvic involvement in our material are uncertain, as pelvic involvement was not routinely assessed in patients randomized to the control group [
3]. Moreover, we were not able to assess BMI as patients’ height and weight were not systematically collected at baseline. We do not have data on time in therapeutic range (TTR), thus, we were not able to evaluate the quality of anticoagulation as a possible predictor for PTS. A strength of the current study is the long follow-up time.
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