Timing and duration of compression therapy after deep vein thrombosis

Introduction

After deep vein thrombosis (DVT) 20–50%, of patients develop post thrombotic syndrome (PTS). PTS is characterized by chronic complaints of the leg affected by the DVT. Patients experience heaviness, pain, cramps, itching, and in severe cases venous ulceration of the leg may occur.^1–4

PTS reduces quality of life significantly and is associated with considerable costs.^1,5

Up till now, there is no effective treatment for PTS and prevention is therefore of major importance. Compression therapy after DVT, with elastic compression stockings (ECS), is the only available preventive measure for PTS. However, the usefulness, timing, and duration of compression therapy are matters of debate. In this review we summarize and appraise current literature on this subject.

Pathogenic substrate for compression therapy

The precise aetiology of PTS is not entirely understood. The signs and symptoms of PTS are thought to be the clinical manifestation of venous hypertension. Both the presence and the resolution of the thrombus initiate various pathogenic mechanisms. In the acute phase of DVT the thrombus itself, inflammatory cells, and enzymes involved in thrombus resolution damage the venous valves, resulting in valvular reflux. In the sub-acute phase, secondary vein wall remodelling and fibrosis take place, making the vein wall stiff and non-compliant.^6–8 Thrombus resolution is often incomplete, as residual vein thrombosis is present in 50% of legs 3 years after DVT. ⁹ Residual thrombosis increases venous outflow resistance. Valvular reflux, non-compliant vein walls, and increased outflow resistance increase blood pressure in the veins.^6–8 The increased venous pressure is transmitted to the capillaries, which dilate and start leaking plasma, proteins, and erythrocytes, leading to edema and skin changes. Microcirculation and blood supply to the muscles of the lower limb become impaired, eventually leading to the characteristic complaints of PTS and in severe cases instigating venous ulceration. ⁸ The use of compression therapy for the prevention of PTS is derived from compression practice in primary venous insufficiency. In patients with primary venous insufficiency, compression therapy was found to have several beneficial effects on venous haemodynamics. ECS therapy reduces ambulatory venous pressure and venous reflux, and improves calf muscle pump function.^10–12 ECS therapy was shown to improve the venous ejection fraction. The venous ejection fraction is a quantification of the venous pumping function, which is the ejection volume divided by the total venous volume. ¹³ Furthermore, external compression on the leg reduces the diameter of the vein, thereby accelerating blood flow and improving oxygen supply to the skin. ¹⁴ Since the end manifestations of primary and secondary venous insufficiency are similar, it seems likely that elastic compression therapy will have beneficial effects on PTS as well. It is however not clear whether and how elastic compression therapy can prevent PTS. Adequate flow is an important component of thrombus resolution as shown in animal experimental studies and therefore enhancing the venous ejection fraction may be the pivotal function of ECS therapy for the prevention of PTS. ¹⁵

Early compression

A large prospective cohort study following patients after DVT showed that early (1 month after DVT) severe post thrombotic manifestations are strong predictors of PTS at 2 years, whereas most patients with no or mild PTS 1 month after DVT had no or mild PTS after 2 years. ¹

Only three randomized controlled trials assessed the effect of immediate compression therapy in the acute phase after DVT on the development of PTS.

Partsch et al. compared early compression either with (1) compression bandages (Unna boot) or with (2) compression stockings and early mobilisation, to (3) bed rest without compression therapy. Forty-five patients were equally distributed over the three treatment groups. In the compression groups (1 + 2) pain was already significantly reduced at day 2 compared to day 0. This reduction in pain was not reached until day 5 in the bed rest group (3). In the compression groups leg circumference at day 9 was significantly lower, compared to the bed rest group. ¹⁶ After the initial 9 days all patients were prescribed elastic compression stockings for 2 years. Thirty-seven of these 45 patients were reinvestigated after 2 years. In the compression groups 8 of 26 patients (30.7%) had developed PTS (at cut-off >5 for the diagnosis of PTS), compared to 9 of 11 (82%) in the bed rest group (RR 0.37; 95% CI 0.27–0.72, p < 0.01). The stocking was worn for up to the time of follow-up by 13 of 26 (50%) patients in the compression groups and in 8 of 11(73%) patients in the bed rest group. ¹⁷

Arpaia et al. looked specifically into the effect of immediate compression on vein recanalization. Seventy-three patients were randomized to either early compression with class II ECS (n = 36) or start of compression with class II ECS after 14 days (n = 37). Complete vein segment recanalization was significantly more often reported in the early compression group (28 of 34 (82%) patients) compared to the control group (18 of 30 (60%) patients), yielding an odds ratio (OR) of 0.27 (95% CI 0.07–0.89). Popliteal vein diameter at day 14 and day 90 of follow-up was significantly lower in the early compression group (p = 0.035; p = 0.014), as was the popliteal patency score at day 14 (p = 0.0047). However, none of the patients had symptoms of PTS at day 90 of follow-up and there were no differences in leg circumference between the two groups. ¹⁸

Roumen-Klappe et al. studied immediate compression bandaging in the acute phase after DVT. Sixty-nine patients were randomized to either immediate multilayer compression bandaging (n = 34) or no bandaging (n = 35). Improvement of clinical symptoms and decrease of leg circumference was significantly better and faster in the bandage group in the first 7–30 days. However, after 1 year the incidence of PTS was equal in both groups, according to both the CEAP classification; 39% versus 42% (RR 0.91, 95% CI 0.50–1.66) and the Villalta score; 29% versus 33% (RR 0.87, 95% CI 0.41–1.8). In addition, there were no significant differences in venous outflow resistance, thrombosis score, or reflux between the two groups. ¹⁹

Effectiveness and duration of ECS therapy

After the acute phase, when the acute edema has been resorbed, nowadays it is common practice to prescribe ECS for a period of 24 months to prevent PTS. This is mainly based on the results of 2 randomized controlled trials performed by Brandjes et al. in 1997 and Prandoni et al. in 2004. In both trials patients after DVT were randomized to either 24 months ECS or no ECS.^20,21 In the study by Brandjes et al. in the stocking group (n = 96) 19 patients developed mild to moderate PTS and 11 patients developed severe PTS. In the other group (n = 98) 46 patients developed mild to moderate PTS and 23 patients developed severe PTS. These differences are highly significant: p < 0.001. In the stocking group, 89 of the 96 (93%) patients reported to wear their stocking always or more than 80% of time. ²⁰ Prandoni et al. found a 24-month cumulative PTS incidence of 24,5% (95% CI 15,6–33,4) in the ECS group (n = 90) and 49,1% (95% CI 38,7–59,4) in the no ECS group (n = 90). This amounts to a hazard ratio (HR) of 0.49 (95% CI 0.29–0.84) after correction for baseline characteristics. Seventy-eight of the 90 patients (87%) in the stocking group wore the stocking at least 80% of daytime during the 2-year period. ²¹

Very recently, the results of a large placebo controlled trial have been published. Eight hundred and six patients were randomized to either active ECS (n = 410) or placebo ECS (n = 396). No differences between active ECS and placebo ECS could be demonstrated in terms of PTS prevention. Cumulative PTS incidence (from 6 to 24 months follow-up) rated according to the Ginsberg score was 14,2% in the active ECS group and 12,7% in the placebo ECS group, generating a non-significant HR of 1,13 (95% CI 0.73–1.76). Compliance to ECS was equal in both groups, at the 24 month visit 378 patients (69,1%) still wore the stocking of whom 304 patients (55,6%) wore the stocking 3 days or more per week. ²²

The timing and especially the optimal duration of compression therapy after DVT have not been addressed in these three studies. A few studies did assess timing and duration of therapy. Ginsberg et al. showed that active ECS, applied one year after the event of DVT in patients without symptoms of PTS but with confirmed venous valvular incompetence by plethysmography or duplex, did not significantly reduce the incidence of PTS compared to placebo ECS. In the active ECS group (n = 24) no patients developed symptoms of PTS during follow-up, in the placebo ECS group (n = 23) one patient developed symptoms of PTS during follow-up (p = 0.49). ²³

Only one study so far investigated whether prolonged duration of ECS therapy after 6 months is superior to only 6 months ECS therapy. In this study by Aschwanden et al. patients were randomized 6 months after the event of DVT to either prolonged ECS therapy (n = 84) or discontinuation of ECS therapy (n = 85). The occurrence of post thrombotic skin changes was not significantly different between the two groups. Eleven patients in the prolonged ECS group versus 17 patients in the other group developed post thrombotic skin changes (HR 0.60 (95% CI 0.28–1.28); p = 0.19). However, a sub analysis showed that women did benefit significantly from prolonged ECS therapy (HR 0.11 (95% CI 0.02–0.91). Non-adherence, defined as wearing the stocking <4 days a week, was reported in 8,4% of follow-up visits (11% in men, 3.6% in women). ²⁴ Ten Cate-Hoek et al. performed a management study, in which duration of ECS therapy was tailored based on the patients’ individual signs and symptoms of PTS. In a cohort of 125 patients, the cumulative PTS incidence at the 2-year follow-up was 21.1% (95% CI 13.51–28.69). Fifty percent of patients did not need ECS therapy for as long as 24 months, while the overall incidence of PTS was comparable to the published incidences after 24 months ECS therapy. ²⁵ A randomized controlled trial comparing individually tailored duration of ECS therapy to standard duration of 24 months ECS therapy is currently underway. (NCT01429714)

Discussion

Compression therapy has been shown to have beneficial effects on the venous circulation in the setting of primary venous insufficiency.^10–13 This may explain its presumed benefit after DVT both for the reduction of symptoms as well as for the prevention of PTS. Although the rationale behind compression therapy is very intuitive, we do not know what patients will benefit most and what the optimal timing of onset and subsequent duration of compression therapy following DVT should be.

According to the limited evidence available, compression therapy in the acute phase after DVT reduces pain and swelling. Yet, the effect of early compression on the long term development of PTS is still unclear as studies performed so far have conflicting outcomes.^16–19 The studies performed all had limited sample sizes and used different definitions for PTS; therefore a sufficiently large study is needed to assess the effect of early compression on PTS development in order to provide us with a definitive answer. Besides the clear benefits for the patient’s wellbeing such as reduction of pain and edema, it may be prudent to start ECS therapy, with its perceived benefit of restoring the venous ejection fraction and counteracting the exudation of venous fluids, as soon as possible after the DVT. As early severe post thrombotic complaints have been shown to be a strong predictor for PTS later on. ¹ The effectiveness of ECS therapy initiated in the sub-acute phase was assessed in three large randomized controlled trials. The 50% risk reduction of ECS therapy found in the trials by Brandjes et al. and Prandoni et al. is in stark contrast to the lack of effectiveness found in the trial by Kahn et al.^20–22 At least part of the beneficial effect of ECS is thought to be accountable to the open label design of the first two trials. Subjective complaints form a large part (about half) of the diagnosis of PTS, and therefore the true effect of the stocking can be overestimated due to an imagined benefit. However, it seems unlikely that such a substantial reduction in PTS incidence can be dismissed as a placebo effect. If an average placebo effect of 20% were to be assumed, a risk reduction of 30% would still be expected to remain. A more likely explanation for the apparent lack of effectiveness in the study by Kahn et al. therefore can be found in the reduced compliance to ECS therapy. At the 24 months follow up visit 55.6% of patients did wear the stocking 3 days or more per week. In contrast, Brandjes et al. reported that 93% of patients did wear their stocking always or more than 80% of time. Moreover, Prandoni et al. reported that 87% of patients wore the stocking at least 80% of daytime during the 2-year period, thus, showing much higher compliance rates.^20–22 It is therefore likely that suboptimal compliance in the active ECS group could have undermined the effectiveness of ECS therapy in the study by Kahn et al.

As for the optimal duration of ECS therapy, a certain conclusion has yet to be drawn. Only one study assessed whether 6 months of ECS therapy was inferior to prolonged treatment of ECS and did not find a difference. ²⁴ To optimize treatment duration tailoring of ECS therapy based on the patients’ individual signs and symptoms may be a promising strategy. ²⁴ On the other hand, there are also patients who do not develop PTS even without any ECS therapy at all. As shown by the study of Ginsberg et al. where start of ECS therapy as late as 1 year after the event of DVT in patients without complaints did not influence the onset of PTS. ²³ Therefore identification of patients who most likely will benefit from ECS therapy as well as the optimal ECS treatment strategy remain subjects for further study.

In conclusion, PTS is a long-term chronic and debilitating complication of DVT of the leg. Counteracting increased pressure in the venous vasculature is the rationale for ECS therapy after DVT. The function of ECS therapy for the prevention of PTS is not yet fully understood; enhancing the venous ejection fraction may be a pivotal factor. For the practical application it is still undecided what the optimal timing of onset and subsequent duration of compression therapy following DVT should be, and in addition it is uncertain how patients who are likely to benefit most from ECS therapy can be identified.