Graduated elastic compression stockings in the prevention of post-thrombotic syndrome: A systematic review and meta-analysis

Abstract

Background

The effect of graduated elastic compression stockings (ECS) in the prevention of post-thrombotic syndrome (PTS) has been questioned since a large randomized trial found no prophylactic effect of ECS.

Objective

To assess the effect of the wearing time of ECS on the incidence of post-thrombotic syndrome (PTS) after proximal deep venous thrombosis, we performed a meta-analysis of the incidence of PTS across randomized and observational studies.

Method

PubMed, Embase and Cochrane databases were searched until 12 June 2023 for studies on the effect of ECS on PTS. References of eligible studies were also screened in order to identify other potential studies that might have been missed during the search.

Results

Four studies comprising a total of 1467 patients met our inclusion criteria for early initiation and consistent use of ECS in patients with acute proximal DVT. ECS significantly reduced the incidence of mild-moderate PTS (OR: 0.48; 95% CI: 0.36–0.63) as well as severe PTS (OR: 0.44; 95% CI: 0.28–0.58).

Keywords

Deep venous thrombosis elastic compression stockings post-thrombotic syndrome

Introduction

Post-thrombotic syndrome (PTS) is a frequent, chronic consequence of deep vein thrombosis (DVT) in the legs. PTS results from insufficient recanalization of the thrombosed vein(s) and/or development of valvular insufficiency.¹ Various scoring systems have been used over the past decades to diagnose and classify PTS: Widmer classification, Villalta scale, CEAP (clinical, etiological, anatomical, and pathophysiological) classification, Brandjes scale, VCSS (venous clinical severity score), and Ginsberg measure.² The Villalta scale, published in 1994, was in 2009 recommended by Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis and is today the most used method.^3–5 In the Villalta scale, symptoms and clinical signs are assessed as shown in table 1.

Table 1.

The Villalta scale for diagnosis and definition of severity of post-thrombotic syndrome (PTS). Score <5: no PTS; 5-9: mild PTS; 10-14: moderate PTS; ≥15 or venous ulceration: severe PTS.

Symptoms and signs	Absent	Mild	Moderate	Severe
Symptoms
Pain	0	1	2	3
Cramps	0	1	2	3
Heaviness	0	1	2	3
Paresthesia	0	1	2	3
Pruritus	0	1	2	3
Objective clinical signs
Oedema	0	1	2	3
Hyperpigmentation	0	1	2	3
Venous ectasia	0	1	2	3
Redness	0	1	2	3
Skin induration	0	1	2	3
Pain on calf compression	0	1	2	3
Venous ulcer	Absent		Present

It is estimated that PTS occurs in half of all patients with DVT and in severe form in 5%–10% of symptomatic DVTs.⁶ Risk factors for the development of PTS are proximal localization of DVT, inadequate anticoagulation treatment, residual venous obstruction, recurrence of DVT, old age, male sex, high BMI, varicose veins and venous insufficiency.⁷ The most common symptoms of PTS are chronic oedema and heaviness in the leg. In more severe cases, cramping pain, difficulty walking (venous claudication) and irreversible skin changes such as hyperpigmentation, venous ectasia, lipodermatosclerosis and venous ulceration may occur. The more severe forms of PTS are associated with a significantly reduced quality of life, increased sickness absence and an annual cost to the healthcare system of $7000 per patient.⁸ The options for effective treatment of PTS are limited. Prevention is therefore important.

Suggested important measures to prevent PTS after lower extremity DVT are:

• Pharmaco-mechanical endovascular thrombus removal ± stenting in selected cases of iliofemoral DVT.

• Early anticoagulation treatment to stop the thrombotic process and prevent recurrence.

• Compression therapy by bandages or by graduated elastic stockings to prevent oedema formation in the leg and support venous drainage.

The aim of this article is to focus on the effect of using graduated elastic compression stockings (ECS) for the prevention of PTS. The first randomized studies on the use of ECS for the prevention of PTS were conducted a couple of decades ago and showed significant effect of ECS.^9,10 The ability of ECS to prevent PTS after DVT has, however, been questioned since the Canadian SOX study was published in 2014.¹¹ The SOX trial was larger than the two previous studies of ECS after DVT. Surprisingly and in contrast to previous studies, no PTS-preventive effect of ECS was found in the SOX trial. The results meant that guidelines in Canada, the United States and the United Kingdom stopped recommending the use of ECS after DVT.^12,13 In the rest of the world, attitudes have varied.

In the SOX trial, patients with first-time proximal lower extremity DVT were randomized to use knee-length ECS with an ankle pressure of 30–40 mmHg (N = 409) and matching placebo stockings (N = 394) with an ankle pressure of ≤5 mmHg.¹¹ The patients had measurements taken for the stockings during hospitalization, but they were only given them in a letter with two stockings within 2 weeks after returning home. DVT was treated with heparin followed by warfarin for 3–6 months. The duration of treatment was similar in the two groups.

The patients came for outpatient check-ups after 1, 6, 12, 18 and 24 months. At the outpatient check-up, the patients had to appear without socks and state how often they used the socks at home. Patients were considered users of the stocking if they had used it at least 3 days a week since the last check-up. This was the case for 86.4% of the patients at the first check-up after 1 month, but only 55.6% at the check-up after 24 months. At 24 months, the cumulative incidence of PTS was 14.2 in the ECS group versus 12.2% in the placebo group (HR: 1.13; 95% CI: 0.73–1.76; p = .58).

It has later been criticized that the patients themselves had to find out how to put the stockings into use and that there was no control as to whether the fit of the stockings was acceptable. These conditions may explain the poor adherence. The main problem, however, is that patients at the end of the study were considered users of ECS if they at just three of the five outpatient visits had stated that they had used the stocking at least 3 days a week. Other studies suggest that such sporadic use of ECS is insufficient for the prevention of PTS.

Ziegler et al., in a retrospective study of 56 patients 10–20 years after proximal DVT and isolated distal DVT (ID-DVT), found that 28% of patients who had used compression stockings at least 4 days per week had developed PTS, while PTS occurred in 50% of patients who had used compression stockings less than 4 days a week.¹⁴

Prandoni et al. compared in a prospective cohort study of 861 patients with proximal DVT the effect of compression stockings in 511 patients who used the stocking at least 70% of the day for 2 years (group A) with 350 patients who used the stocking less often or not at all (group B).¹ After a mean follow-up of 5 years, 31.7% of patients in group A had developed PTS versus 50.6% in group B (HR: 0.64; 95% CI: 0.51–0.79; p < .001).

These two studies indicate that consistent use of compression stockings during the day is of decisive importance for the effect of the treatment. In the randomized studies before the SOX study, ECS were used at least 70% of the day.

Methods

For the meta-analysis, relevant papers were identified through systematic searches of the PubMed, Embase and Cochrane databases (1970 to June 2023). The inclusion criteria were as follows: (1) studies comparing patients wearing ECS with those not wearing or wearing placebo; (2) Use of ECS was initiated shortly after the diagnosis of proximal DVT was made; (3) studies reporting use of ECS at least 4 days a week for 2 years and (4) studies reporting the incidence rate of PTS. The exclusion criteria were as follows: (1) studies using ECS for prevention of DVT; (2) studies focussing on use of ECS after the diagnosis of PTS and (3) studies focussing on non-DVT patients. Searches were augmented by manually reviewing the reference lists of all original articles and all systematic review articles, with each study being evaluated for inclusion. Figure 1 shows the study selection process.

Previous and current meta-analyses

A large number of meta-analyses have been performed to assess the PTS preventive effect of ECS.^15–25 Various studies have been included in the analyses, some of which must be considered irrelevant and others directly misleading for the results of the analysis. Figure 2 shows an overview of previous meta-analyses and the studies included in these analyses, as well as which studies are included in the current meta-analysis.

In the current meta-analysis, the following studies were excluded:

• Belcaro, 1993²⁶: The incidence of PTS is not mentioned.

• Ziegler, 2001¹⁴: Patients with isolated distal DVT were included.

• Ginsberg, 2001²⁷: Randomization occurred after 1 year of treatment for DVT.

• Partsch, 2004²⁸: ECS immediately in acute DVT versus after 9 days of bed rest without ECS. No control group not wearing ECS.

• Aschwanden, 2008²⁹: Randomization occurred after 6 months of treatment for DVT.

• Roumen-Klappe, 2009³⁰: Multilayer compression bandaging was used, not ECS.

• Kahn, 2014¹¹: Most patients used compression stockings less than 4 days a week.

• Jayaraj, 2015³¹: The study is a comparison of the Villalta score and the Venous Clinical Severity Score to assess the severity of PTS. The incidence of PTS is not listed.

In addition to the above-mentioned study by Prandoni et al., a recent study by Yang et al. was included in the current meta-analysis. Yang et al. randomized patients with proximal DVT to ECS (N = 113) and no ECS (N = 119).³² At 24 months, the incidence of PTS was 42.0% in the ECS group and 57.8% in the control group (RR: 0.73; 95% CI: 0.55–0.97; p = .024). Furthermore, they found higher quality of life and less severity of symptoms among ECS users (VEINES-QoL scores: 63.7 ± 4.6 vs 60.6 ± 6.9; p < .001; VEINESSym scores, 45.8 ± 5.1 vs 43.8 ± 6.1; p = .014).

The current meta-analysis confirms the results of the landmark study by Brandjes et al.⁹ By using ECS from the acute phase of DVT and 2 years onwards, the incidence of PTS can be halved, provided there is good patient compliance. This applies to both mild-moderate PTS (OR: 0.48; 95% CI: 0.36–0.63) as well as severe PTS (OR 0.44; 95% CI 0.28–0.58) (Figure 3).

Compression therapy had no impacts on the incidence of recurrent venous thromboembolism (OR: 0.00; 95% CI: −0.04 to 0.03) probably because the risk of recurrence primarily depends on whether the patient has discontinued anticoagulant treatment or not. None of the studies provided detailed information on the duration of anticoagulant treatment. In our meta-analysis, we have focused on studies with high level of patient compliance. From this point of view, ECS seems to have good PTS preventive effect. There are, however, still a number of unresolved questions.

Unsettled issues

ECS immediately upon detection of DVT or later

Partsch et al. found in a retrospective study a lower frequency of PTS among patients who were mobilized with ECS immediately after detection of proximal DVT (mean Villalta score 5.1) than among patients who only received ECS after 9 days of bed rest (mean Villalta score 8.2), p < .01.²⁸ Bed rest for 8–10 days after DVT was previously common for fear of provoking pulmonary embolism. Rather, bed rest may contribute to the progression of DVT, and the value of the study is therefore questionable.

Arpaia et al. randomized patients with acute DVT to application of compression with class II elastic hosiery (23–32 mmHg at the ankle) immediately after diagnosis (N = 36) or 2 weeks later (N = 37).³³ After 90 days, a total of 28/34 occluded venous segments (82%) in the early group and 18/30 (60%) in the late group showed complete recanalization (OR: 0.27; 95% CI: 0.07–0.89). Recanalization of popliteal DVT veins, expressed as the reduction of compressed vein diameter, was more pronounced in the early compression group than controls (3.7 ± 3 vs 2.1 ± 1.7 mm; p = .014). None of the patients had PTS, but the results of the study support the assumption that early initiation of ECS use can help prevent PTS as residual venous thrombosis is an important risk factor for the development of PTS.³⁴

In a specified subgroup analysis of the IDEAL study comprising 592 patients with proximal DVT, ultrasound examination after 6 months showed residual venous thrombosis in 46.3% of 520 patients who started treatment with ECS or compressive dressing immediately after detection of DVT, versus 66.7% of 72 patients, who received ECS only after acute oedema resolved (OR: 0.46; 95% CI: 0.27–0.80; p = .005).³⁵ PTS occurred significantly less often among patients without residual venous thrombosis than among patients with residual venous thrombosis (OR: 0.66; 95% CI: 0.46–0.96). The study thus partly supports the assumption that inadequate recanalization is a risk factor for the development of PTS, and partly that early use of ECS prevents PTS better than later onset. It was, however, a subgroup analysis and although the above-mentioned studies provide some support for the assumption that straight initiation of compression treatment is preferable, we still lack the definitive proof.

Short or long ECS

In most studies, below-knee ECS has been used. The argument for this has been that the symptoms of severe PTS are particularly felt distally on the leg, where oedema and skin changes can lead to venous ulcers. Another argument is that long stockings curl up at the knees in a sitting position and can thereby cause stasis distally.

In a randomized study, 267 patients with a first episode of proximal DVT were randomly allocated to wear either thigh-length or a below-knee graded ECS (ankle pressure: 30–40 mmHg) of the affected leg after wearing elastic bandages for the first few days at the discretion of attending physicians.³⁶ The ECS had to be used during the day for a period of 2 years. Patients were followed for up to 3 years. PTS developed 32.6% of patients randomized to thigh-length and in 35.6% allocated to below-knee ECS (adjusted HR: 0.93; 95% CI: 0.62–1.41). Severe PTS occurred in three patients in both groups. The thigh-length ECS were significantly less well tolerated than the below-knee ECS. Only 67% of the patients allocated to thigh-length ECS used their garments for at least 70% of the time during the day, compared with 83% of patients allocated to the below-knee ECS. Although thigh-length ECS are more difficult to use, some patients with severe thigh swelling will prefer these stockings. For these patients, a personalized choice of stockings should be considered, although below-knee stockings seem to prevent PTS just as well.

ECS in pressure class III or II

For the prevention of PTS after DVT, it has so far been standard to use ECS pressure class III with an ankle pressure of 30–40 mmHg. Although a number of different hosiery aids are available, many patients find it difficult to put on and take off heavy stockings, which can lead to decreased adherence. ECS pressure class II, delivering an ankle pressure of 20–30 mmHg, is easier to manage, but has so far been expected to provide inferior PTS prophylaxis. The study by Arpaia et al. showed that early onset of use of class II ECS promotes recanalization of occluded veins but the follow-up was too short to assess the effect on the development of PTS.³³

In a recent study, patients with proximal DVT were randomized to ECS 35 mmHg and 25 mmHg.³⁷ After 2 years, PTS was found in 25/154 (29%) in the 25 mmHg group and in 52/148 (35%) in the 35 mmHg group (RR: 0.83; 95% CI: 0.60–1, 16). The study thus suggests that ECS class II is at least as effective as class III but the results need to be confirmed by larger studies.

It should be mentioned that the level of compression of ECS in classes I–IV is not unambiguous.³⁸ Different standards exist in North America and Europe (Table 2). Studies on the effect of ECS should therefore always provide information on the pressure gradient in mmHg for the ECS used.

Table 2.

Classification of compression stockings.

Level of compression	North American Thrombosis Forum (NATF standard) (mmHg)	European Union classifications (RAL standard) (mmHg)	British Standards Institute (BSI standard) (mmHg)	Association Française de Normalization (AFNOR standard) (mmHg)
Class 1	<20	18–21	14–17	10–15
Class 2	20–30	23–32	18–24	15–20
Class 3	30–40	34–46	25–35	20–36
Class 4	40–50	47+		36+

ECS for isolated distal DVT (ID-DVT)

Most randomized trials of ECS for the prevention of PTS after DVT have only included patients with proximal DVT, as the risk of severe PTS is significantly higher after proximal DVT than after ID-DVT. However, the incidence of PTS after ID-DVT is not negligible.³⁹ A recent meta-analysis of seven studies of the frequency of PTS after ID-DVT showed that PTS occurs in one out of five patients.⁴⁰ The severity of PTS was reported in three of the studies comprising a total of 302 patients: 78% were mild (Villalta score 5–9); 11% were moderate (Villalta score 10–14) and 11% were severe (Villalta score 15 or more). The results support the need for further research on the risks and benefits of anticoagulants and use of ECS for the treatment of ID-DVT.

Optimal duration of use of ECS

Brandjes et al. compared the incidence of PTS 2 years after DVT among patients with and without ECS.⁹ In the subsequent randomized studies, it has been standard to continue to assess the incidence of PTS after 2 years.

Aschwanden et al. randomized patients with a first or recurrent proximal DVT to discontinue ECS after 6 months (N = 84) versus to continue use of ECS (N = 85).²⁹ After 8 years of follow-up, the incidence of PTS was highest among patients who had used ECS for 6 months (20.0% vs 13.1%) but the difference was not statistically significant.

In the Dutch OCTAVIA study, patients with proximal DVT and no signs if PTS after 12 months were randomized to stopping ECS therapy (N = 256) versus continuing for further 12 months (N = 262).⁴¹ After 24 months, the total incidence of PTS was 19.9% in the 12-month group and 13.0% in the 24-month group (HR: 1.6; 95% CI: 1.02–2.0). In a subsequent evaluation of data, the authors identified the following risk factors for the development of PTS: Villalta score 2–4 at baseline (OR: 4.5; 95% CI: 2.5–8.2), residual vein thrombosis (2.4; 1.1–5.1), duration of symptoms before DVT diagnosis >7 days (2.3; 1.4-3.9) and BMI >25 (1.9; 1.1–3.4).⁴²

In another Dutch study of 125 consecutive patients with a first-time or recurrent proximal DVT, no difference was found in the incidence of PTS after 24 months among patients who had used ECS throughout the period versus patients who had discontinued ECS after 6–12 months if they at two consecutive outpatient checks after 3, 6 and 12 months had Villalta scores <5.⁴³ Twenty percent of the patients stopped ECS therapy after 3 months (on their own account), 49% after 6 months, 13% after 12 months and 17% continued for 24 months or indefinitely.

In the Dutch-Italian IDEAL DVT study, 865 patients with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (CEAP score <C3) were randomly assigned to receive either individualized duration of ECS (class III: 30–40 mmHg) or standard duration of therapy for 24 months following an initial treatment period of 6 months.⁴⁴ The criteria for stopping use of ECS were the same as in the pilot study.⁴³ Fifty-five percent of the patients receiving individualized duration of therapy stopped ECS therapy after 6 months and 11% at 12 months. In 3%, therapy was permanently reinstated because of persistent leg complaints. At 24 months, PTS occurred in 125 (29%) of 432 patients receiving individualized duration of therapy and in 118 (28%) of 424 receiving standard duration of therapy (odds ratio for difference 1.06; 95% CI: 0.78 to 1.44). Adherence to treatment was >70% and similar in both groups. A cost-effectiveness analysis of the study concluded that use of an individualized approach to ECS therapy for the prevention of PTS after DVT compared with the standard of 2 years of therapy could lead to substantial costs savings without loss in health-related quality of life.⁴⁵

Discussion

Although PTS is the most common complication of DVT, many uncertainties remain regarding its diagnosis, prevention, and treatment. The Villalta scale has become the standard diagnostic tool for detecting and assessing the severity of PTS. However, the Villalta scale is not specific for PTS. Patients with primary chronic venous insufficiency may be diagnosed with PTS after DVT even if their symptoms and signs are unchanged compared to before DVT.⁴² The Villalta scale is thus rather a means of assessing chronic venous disease in the legs.

PTS develops gradually over months and years after DVT. The diagnosis of PTS cannot be made within the first months after DVT, where there are acute changes that can disappear if the veins are recanalized and the venous valve function is preserved. However, a positive Villalta score at baseline is associated with an increased risk of later development of PTS.⁴² PTS is considered proven if the Villalta score is ≥ 5 after 6 months. A lower Villalta score does not exclude that PTS may develop later on.^29,41

European guidelines consider anticoagulation and compression therapy the mainstays of preventing PTS after DVT.^46,47 In selected patients with iliofemoral DVT, endovascular thrombus removal strategies ± stenting should be considered as initial treatment.⁴⁷ Treatment with anticoagulants and ECS should be started as soon as possible after DVT is diagnosed. A delay of just a few weeks decreases the likelihood of venous recanalization and preserved venous valve function.^33,35 Prevention of PTS with ECS requires high adherence to treatment. For optimal PTS-preventive effect of ECS, the stockings should be worn daily during the treatment period. Our meta-analysis suggests that in this way the risk of PTS can be halved.

It has been suggested that some of the reasons why the SOX trial showed no effect of ECS were that treatment was started too late and that patient contact was insufficient to achieve adequately high adherence.⁴⁸ Patient compliance is an essential precondition for assessing the effectiveness of ECS. However, patient compliance with use of ECS has not previously received sufficient attention.⁴⁹ There are now a number of proposals for how patient compliance can be improved.^50–53

So far, it has been standard to recommend the use of ECS for at least 2 years after proximal DVT. However, recent studies have shown that the risk of developing PTS is low in patients who, during follow-up after 3 and 6 months, are without symptoms or signs of PTS. In practice, this means that 6 months of treatment with ECS may be sufficient for approximately half of patients with proximal DVT.^43,44

Patients with ID-DVT are generally at lower risk of PTS than patients with proximal DVT, however, a minority of patients develop severe PTS and would likely benefit from ECS. There are currently no studies that can shed light on this.⁵⁴ ID-DVT is the most frequent form of DVT.⁵⁵ Future studies should therefore include patients with ID-DVT who are assessed to be at high risk for PTS. So far, it is still debated whether ECS should be used in proximal DVT. Our meta-analysis indicates that this is the case, but further documentation is warranted. The ongoing multicenter randomized trial, CHAPS (Compression Hosiery to Avoid Post-thrombotic Syndrome) (ISRCTN73041168) aiming to recruit 864 participants, will hopefully clarify the potential PTS-preventing effect of ECS.^56,57

Conclusion

Our meta-analysis suggests that consistent use of ECS for at least 2 years can halve the risk of developing mild-moderate PTS (OR: 0.48; 95% CI: 0.36–0.63) as well as severe PTS (OR: 0.44; 95% CI: 0.28-0.58) after proximal DVT. The IDEAL DVT trial suggests that therapy with ECS can be individualized and stopped if Villalta score has been <5 in the past 6 months. Compression therapy had no impacts on the incidence of recurrent venous thromboembolism.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

Jørn Dalsgaard Nielsen

ORCID iD

Jorn Dalsgaard Nielsen

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