Compression to prevent PTS: a controversy?

Abstract

Compression therapy, prescribed as elastic compression stockings, is the cornerstone in the management of post-thrombotic syndrome. The effectiveness of elastic compression stockings has recently been called into question in a large randomized placebo-controlled trial. The findings however may be less contradictory than assumed and presented. The mechanistic substrate for the effectiveness of compression therapy is based on its ability to counteract venous hypertension, which is a central aspect in the pathophysiology of post-thrombotic syndrome. Nevertheless, despite elastic compression stockings a significant percentage (20–50%) of patients develops post-thrombotic syndrome, suggesting that there are other factors to be considered next to compression. Every patient has an individual baseline risk value, constituted of non-modifiable and modifiable risk factors (i.e. age, sex, bodyweight etcetera). Straining patients at risk is therefore crucial. Exploring additional or alternative forms of therapy is desirable as well since these are in addition to the risk factors, costs aspects and quality of life, puzzle pieces in the management of post-thrombotic syndrome, which once pieced together enables multifactorial yet individualized therapy.

Keywords

Compression compression stockings deep vein thrombosis post-thrombotic syndrome

Introduction

Post-thrombotic syndrome (PTS) is a serious long-term complication of deep venous thrombosis (DVT), which occurs in 25–50% of patients, mostly within 2 years, after DVT diagnosis.^1,2 As the name indicates, PTS is diagnosed on the basis of a compilation of signs and symptoms including pain, edema and ulceration, rather than a specific disease entity. The exact aetiology of PTS, and hence the best strategy in prevention of PTS, has not been elucidated yet. For a long period of time, applying elastic compression stockings (ECS) has been considered the best approach to prevent PTS.³ Recently, however, the effectiveness of ECS is called into question.

In this review, we seek to outline the controversies concerning compression therapy, thereby focussing on pathophysiological aspects of PTS and mitigating patient factors. Moreover, we will explore additional treatment options and will make a proposal for optimisation of PTS management, balancing clinical effectiveness, cost aspects and implications for quality of life.

Contradictory findings?

ESC therapy used to be recommended for the prevention of PTS by several guidelines based on high-quality evidence.³ This evidence was primarily based on two randomized controlled studies, both of which showed a reduction in the incidence of PTS by 50%.^1,2 However, in a fairly recent large (N = 806) placebo controlled trial no effect of ECS on the incidence of PTS was observed.⁴ Since its publication, the trial results have stirred the discussion on the effectiveness of ECS. At the same time the trial has been criticized on many aspects, such as the lack of patient compliance, the use of placebo stockings, which might have had some therapeutic value and/or influence on the quality of life, the characteristics of the study population that possibly are not comparable to the previously mentioned studies and the fact that no instruction regarding the stockings was given to the patients by a physician.⁵ These factors could have undermined the validity of the outcomes. Therefore, findings regarding the effectiveness of ECS may be less contradictory than assumed and presented. Nevertheless, in addition to compression as a measure to counteract venous pressure, other factors may be of equal or perhaps even greater value for the prevention of PTS.

Pathophysiology of PTS, risk factors and indicators

Although the pathophysiological mechanisms underlying PTS have not been entirely clarified, venous hypertension is assumed to play a leading role.^5,6 In the acute phase of DVT, the formed thrombus blocks the venous outflow causing the pressure in the vein to rapidly increase. At the same time, inflammatory processes aimed at resolving the thrombus take place.^7–9 The process of thrombus resolution almost invariably causes collateral vein wall damage, and because of the preferred location of the thrombus in the area approximating the venous valves, in many cases the valves will also be damaged. In the sub-acute phase, vein-wall remodeling takes place resulting in vein-wall stiffness and thus less compliance of the vein wall.¹⁰ Vein-wall remodeling and valvular damage both contribute to venous hypertension. Moreover, if the thrombus resolution is incomplete, and this is the case in 50% of the patients, the residual thrombus also adds to increased venous hypertension and decreased flow.¹¹ The venous hypertension overloads the capillaries and provokes capillary leakage. As a consequence, edema is formed and subsequently followed by impaired microcirculation and hypoxia of the tissues, leading to various symptoms including skin ulceration and sensation of pain.^5,6 Figure 1 shows a schematic representation of the pathophysiology of PTS.

Figure 1.

Schematic representation of the pathophysiology of PTS.

The mechanistic substrate for the effectiveness of compression therapy

Compression therapy is aimed at improving the venous outflow as it counteracts venous hypertension, thereby reducing capillary leakage and edema development, which in its turn leads to improved microcirculation in the skin. In addition compression therapy supports muscle compression also reducing the diameter of the (deep) veins. Subsequently, the venous flow accelerates and the venous ejection fraction improves.¹² Venous flow has shown to influence the process of thrombus resolution; animal experimental studies show that reduced flow is associated with pronounced inflammatory reactions and causes excess remodeling of the vein wall and poor thrombus resolution.¹³ On the other hand improving venous flow diminished the inflammatory reactions. There are, however, uncertainties as to the starting point of the ECS as well as to the optimal duration of the therapy.¹⁴ A randomized controlled clinical study on individually tailored duration of ECS is currently being performed (NCT01429714).¹⁵ The sample size for inclusion (864) was reached in July 2015; the results of this study are to be expected autumn 2017. Despite the many indications for a probable mode of action of compression in the prevention of PTS, its success most likely will depend on the interplay with additional patient-related factors. Not all patients diagnosed with DVT will develop PTS and not all patients who receive compression therapy after DVT will benefit from it. We propose that every patient diagnosed with DVT will have an individual baseline risk value for the development of PTS. This baseline risk value may be expressed by age, gender, lifestyle-associated aspects, levels of biomarkers related to PTS etc.

What constitutes the individual baseline risk value?

Some risk factors such as age and gender are non-modifiable. Older people are more prone to thrombosis and therefore also to PTS. Men are at increased risk for both thrombosis and PTS. In addition it was observed in several studies that ECS therapy was less successful in men.^16,17

A risk factor that has the possibility to be modified is varicosities. Varicosities have been linked to increased risk of thrombosis as well as increased risk for PTS.¹⁸ Removal of superficial varicose veins may therefore decrease the risk of PTS.

Lifestyle is an important moderator of risk, as it affects risk factors such as smoking status, physical activity and obesity. Not only obesity but being overweight already increases the risk of PTS. A body mass index (BMI) of >25 kg/m² increases the risk 1.5 times, while a BMI >28 kg/m² has been shown to increase the risk to 3.5–4 fold.^16,19 However, one study also suggested an OR of 4.7 when the BMI amounted >22 kg/m². Several explanations have been postulated on the mechanism constituting this risk. First, abdominal fat may exert pressure on superficial veins, in turn deteriorating the venous flow, which promotes reflux. Second, overweight and obesity could indicate a lower level of physical activity, that has a negative influence on the calf muscle pump function.¹⁶ It is a two-sided sword for as the symptoms of PTS become prominent the level of physical activity lowers and is followed by weight gain.¹⁶ Furthermore, adipose tissue may promote inflammatory responses by stimulating various pro-inflammatory cytokines that alter adhesion molecules and affects the vascular wall. Finally, adipose tissue can act as an endocrine organ and produce leptin, which induces a thrombotic state.²⁰ Excessive abdominal fat expressed as a high waist circumference increases the risk of PTS almost three-fold.²¹ Henceforth, interventions aimed at reducing the BMI should gain more attention. Promotion of physical activity will serve two purposes; it will concomitantly induce weight loss as well as improve the calf muscle pump function.

More extended thrombosis reaching into the iliofemoral tract (IFDVT) is found to be a risk factor for PTS, increasing both the risk of PTS by two-fold and the risk of recurrent DVT. Recurrent DVT increases the risk of PTS, but it also holds true the other way around as PTS increases the risk of recurrent DVT.^22,23 In case of an increased risk of recurrence, hypercoagulability could very well be the underlying risk factor. Although thrombophilia has never been implicated as a risk factor for PTS, levels of D-dimer have been found to be two-fold increased in patients with PTS.²⁴

Several studies have identified various inflammatory biomarkers in association with PTS. Strong associations were found between levels of CRP and PTS.²⁵ In addition to these markers, associations with PTS were also found for interleukin (IL) 6, IL 8 and intracellular adhesion molecule 1(ICAM-1).²⁶ Due to extended heterogeneity between studies and differences in timing of blood sampling meta-analysis could not yet be performed for these biomarkers.

Alternate forms of therapy and additional therapies to compression

Although physicians may be hesitant to prescribe physical activity during the acute phase of DVT, because blood flow increases and this may worsen the symptoms, exercise does not seem to be associated with exacerbation of symptoms or increased rate of recurrent venous thromboembolism (VTE).^27,28 Physical activity has actually shown to be beneficial for symptom relief. Also in the sub-acute and chronic phases exercise may be beneficial. Padberg and colleagues²⁹ conducted a trial in 31 patients with chronic venous insufficiency in which the intervention group was offered a 6-month exercise program (3 months supervised and 3 months unsupervised). The results showed that the calf muscle pump function had returned to normal and improvement in muscle strength occurred. The intervention was offered on top of regular therapy consisting of ESC and oral anticoagulation. Another trial showed that the application of ESC in patients with a history of DVT during the actual exercise sessions had no effect.³⁰

Besides physical activity, devices directed at improving the muscle pump function are noteworthy. O’Donnel and colleagues³¹ investigated a wave-generating device in relation to PTS severity and found that the quality of life improved significantly in patients wearing the device. There was no significant difference in clinical effectiveness. The authors conclude based on the improvement of quality of life that venowave may therefore be applied in addition to compression therapy or as stand-alone.

As an alternative option in PTS treatment, lymphatic drainage could be also considered. This intervention has been investigated in the management of venous insufficiency and is aimed at stimulating venous blood flow and the lymphatic vessels, to remove excessive interstitial fluid. As a consequence edema and its related symptoms are reduced. Addition of lymphatic drainage to ECS in patients with PTS did overall not show significant improvement, but might have the potential to improve the treatment effect in patients with more severe PTS.³²

Pharmacotherapeutic interventions are underestimated and understudied alternative forms of preventive therapy for PTS. Six possible candidate drugs may be considered. Some are known as veno-active drugs (VADs): rutosides and micronized purified flavonoid fraction (MPFF). Other drugs are currently used for other indications but may be used for PTS prevention. These drugs comprise: sulodexide, low-molecular-weight heparins (LMWHs), anti-inflammatory drugs and statins. Table 1 summarizes the pharmacotherapeutic options and their effects. Rutosides are drugs derived from horse chestnut that is traditionally prescribed in treatment of edema in patients with chronic venous disease (CVD). Based on its edema-reducing characteristics, it is assumed that rutosides may be of benefit in the treatment of PTS. Rutosides cause vasoconstriction through stimulation of alpha-a1 receptors and are found to reduce the calf circumference in patients with PTS.³³ In patients with CVD, rutoside appeared to lower the number of ulcerations in addition to reduction of edema.³⁴ MPFF acts as edema-limiting agents by inhibiting hypoxia-induced endothelial activation as consequence of impaired microcirculation. MPFF improves the lymphatic drainage and shortens ulceration healing time.³⁵

Table 1.

Candidate drugs for the management of post-thrombotic syndrome.

Candidate drugs for the management of post-thrombotic syndrome
Pharmacotherapy	Effects
Rutosides	Vasoconstriction by stimulating alpha-a1 receptors
MPFF	Alter the leukocytes-endothelium interaction, prolonging the vasoconstrictive effect of norepinephrine
Sulodexide	Influence the trans-endothelial adhesion and migration of monocytes. Protects the vascular glycocalix
LMWH	Influence the trans-endothelial adhesion and migration of monocytes
Anti-inflammatory drugs	Down regulate the inflammatory response
Statins	Down regulate inflammatory response, have anti-thrombotic effect by reducing PAI-1 en TF and tPA expression

MPFF: micronized purified flavonoid fraction; LMWH: low-molecular-weight heparin, PAI-1: plasminogen activator inhibitor-1; TF: tissue factor; tPA: tissue plasminogen activator.

Sulodexide is a vasculoprotective drug and comprises glycosaminoglycans including LMWH and dermatan sulfate. Its effectiveness is based on its ability to protect the vascular glycocalix and hence the endothelium, as the glycocalix plays a role in the permeability of the endothelium. Sulodexide, in addition to compression, was observed to reduce the PTS incidence in patients with DVT.³⁶ Moreover, sulodexide after anticoagulant treatment showed association with reduced rate of VTE recurrence.³⁶ LMWH, in addition to their antithrombotic effect, is another group of endothelium-protective drugs that are shown to attenuate the symptoms of PTS.³⁷

Of anti-inflammatory drugs and statins it is assumed that they might play a role in PTS prevention; however, thus far little is known on what their actual effect might be. Anti-inflammatory drugs have not been studied in relation to PTS. Statins have been investigated in the context of venous thrombosis and were shown to have anti-inflammatory effects; the expression of the biomarkers IL6, IL8, CRP, as well as tissue factor, plasminogen activator inhibitor-1 and monocyte chemotactic protein1 (MCP-1) was reduced by the use of statins. Elevated levels of the latter is linked to vein wall fibrosis which in turn is associated with PTS.³⁸

All drugs mentioned might prove useful as adjunctive therapeutic options in the management of PTS. However, well-designed studies, preferably with a multifactorial design, are required to elucidate their exact role.

Cost aspects and implications for quality of life

Severe PTS is associated with substantial disability, work absenteeism, reduced quality of life and increased health care costs.^39–42 There is a dose-dependent association between PTS severity and quality of life, where quality of life worsens with increasing severity of PTS.³⁹ Therefore it is of the utmost importance to assess the influence of the different forms of therapy that are suggested for the prevention and treatment of PTS on patient-reported outcomes (symptoms, signs, functioning and ultimately quality of life). This includes not only the influence on (prevention of) PTS but also the potential harms in terms of side effects. The latter includes the tolerability of pharmacological treatment and the impact of elastic compression therapy on autonomy in persons who are unable to put on the stockings themselves.

A 15-year retrospective cohort study conducted in Sweden estimated the costs of a primary DVT to be $6000 and the average costs of treating its complications $4659; this suggests that medical care-related expenditure in a patient with DVT who develops complications, including PTS, is approximately $10,000 over a period of 15 years.⁴⁰ A cost analysis of treatment of PTS in Brazil showed more or less similar results: the average annual costs per patients ranged from $426 in those with mild PTS to $1188 in those with severe PTS.⁴² A literature-based Markov model was developed for estimation of direct medical costs related to long-term complications of primary DVT in USA. The model indicated that PTS-associated discounted costs are about $7000 per patient.⁴¹ Investing in new therapeutic options for the prevention of PTS is therefore a very attractive scenario. The population at risk is large (20–50% of all patients with DVT) and the potential benefits both for the increase in quality of life and for the decrease in costs are substantial.

Conclusion

In this review, we have elaborated on the controversies of ECS in the treatment and the prevention of PTS. We have mentioned the yet unclear aspects such as the timing and duration of compression therapy and the possible mode of action in relation to PTS pathophysiology. In addition we have touched upon the risk markers, discussed the possible alternative treatments and reflected on quality of life and cost aspects. All these aspects can be seen as pieces of the puzzle for the management of PTS (Figure 2). These puzzle pieces stand on their own and some may not even have substantial influence when regarded solely, together however, they might work synergistically. We argue that piecing this puzzle is the future direction, in which the management of PTS is multifactorial, yet individualized (Figure 3). To this end, it is essential that for each and every patient the individual risk for PTS occurrence is established. Because diagnostic methods and (preventive) therapies differ from one another in regard to costs and burden placed on patients, it is of importance to take these aspects into account as well.

Figure 2.

Pieces of the puzzle for PTS: modifiable and non-modifiable risk factors, treatment options, patient-related outcomes.

Figure 3.

Multifaceted approach weighing individual risks (predictive rules), combining therapeutic options (compression, pharmacotherapy (including anticoagulation) and lifestyle interventions), considering cost aspects and patient-related outcomes (QOL).

In practice this means that for patients with swelling and severe symptoms the need for compression treatment is evident in spite of controversial study outcomes, while in patients with milder complaints and minor symptoms the added value of compression as a preventive measure may be assessed on an individual basis depending on patients’ risk for PTS.

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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: EA is supported by a grant from Zon-mW the Netherlands grant number 171102007.

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