**6.1 Initial treatment of DVT with thrombolytic drugs**

Thrombolysis has been traditionally advocated as an alternative strategy to heparins for the initial treatment of DVT, based on the assumption that early vein recanalization will result in a more favorable long-term outcome. This assumption is in agreement with the findings from several recent studies, which have identified that proximal location of the initial thrombosis is among the strongest predictors of PTS development (33,38,60), especially when the thrombus involves the ilio-femoral segments (39). Consistent with this assumption is the demonstration that post-thrombotic complications develop predominantly in those patients in whom the initial complaints tend to persist (39). Both the intravenous infusion of thrombolytic drugs and the use of catheter-directed thrombolysis are likely to result in a higher frequency of early vein patency as compared to heparin (89-92). However, whether these therapeutic approaches improve the long-term patients' outcome as well is controversial, as there is data in favour (93-96) and against (97,98) this possibility. In addition, the use of either intravenous or catheter-directed thrombolysis is associated with a higher risk of complications compared with treatment with anticoagulants alone (90,100). Thus, the routine use of early thrombolytic therapy for the prevention of long-term sequelae of DVT does not seem to be currently justified, but is the subject of ongoing multicenter randomized trials (100).

#### **6.2 Compression bandaging in the acute phase of DVT**

In order to assess the influence of immediate multilayer compression bandages before application of elastic stockings in the acute phase of DVT on development of the PTS, 69 patients with acute symptomatic DVT were recently randomized to immediate bandaging or no bandaging (36). While bandaging resulted in a considerable improvement of clinical symptoms and decrease of leg circumference in the first week of treatment, no difference in the development of late sequelae was observed between the two groups after one year. Thus, the early application of bandages in patients with DVT is unlikely to improve the long-term patients' outcome.

#### **6.3 Elastic compression stockings**

Elastic compression stockings have long been utilized for the prevention of the PTS in patients with acute DVT (72). However, their efficacy had not been systematically investigated until a few years ago.

The Post Thrombotic Syndrome 151

irrespective of the presence of post-thrombotic manifestations (106). Further studies are needed to show whether compression therapy is or is not indicated in asymptomatic

To our knowledge, there are no studies that have compared different compression strengths of stockings to prevent PTS. It would be worth studying the effectiveness of lighter compression (20-30 mm Hg) stockings as they are easier to apply, especially for elderly patients, than 30-40 mm Hg stockings. Of note, in a study of stockings to prevent recurrent venous ulcer, there was no difference in effectiveness between class 2 and class 3 stockings

Interestingly enough, immediate mobilization in patients with acute DVT may reduce the rate of PTS development, provided that patients are provided with adequate compression

An insufficient quality of oral anticoagulant therapy following the acute thrombotic episode has been found to be associated with an increased risk of the PTS (28,65). Conversely, the long-term use of LMWH has been found to reduce the PTS rate in comparison with vitamin K antagonists (35,109). We cannot exclude, therefore, the potential of a few emerging antithrombotic compounds (such as dabigatran etexilate and rivaroxaban), which can be administered orally in fixed daily dosage and have been found to be at least as effective and safe as conventional anticoagulation for the initial and long-term treatment of DVT

It is commonly believed that patients with established PTS have a poor prognosis, and that the majority will have sustained disability. In recent years, a few reports have suggested that prognosis of the PTS might not be as poor as previously reported (69-71). Indeed, when provided with elastic compression stockings and regularly supervised, more than 50% of patients either remain stable or improve during long-term follow-up, irrespective of the initial degree of PTS (69-71). Clinical presentation helps predict the prognosis, as the outcome of patients who have initially severe manifestations appears to be more favorable than that of patients whose symptoms progressively deteriorate over time (71). However, at

PTS is a frequent, burdensome and costly complication of DVT. Currently, there are few effective treatments for PTS. Until such treatments are identified, prevention of PTS will have the greatest impact on reducing the overall burden of PTS on patients and society. Preventing DVT recurrence is likely to reduce the risk of PTS. Daily use of graduated ECS after DVT appears to reduce the risk of PTS. As of yet, there is no established role for thrombolysis in preventing PTS, but trials are underway to address this important question. Research is also underway to identify biologic markers that may predict the risk of PTS in individual patients. Finally, a few emerging antithrombotic compounds may have the

present there is no way to reliably predict the course of PTS in individual patients.

potential to reduce the risk of PTS, however this requires further study.

(110,111), for further reducing the incidence and the severity of the PTS.

patients who have completed an initial 6-month period.

**6.4 The potential of new anticoagulant drugs** 

(107).

therapy (108).

**7. Prognosis** 

**8. Conclusion** 

In 1997, the results of a prospective randomized Dutch study on the prevention of the PTS became available (19). In this trial, 194 consecutive patients with confirmed proximal DVT were allocated to wear or to not wear elastic compression stockings. A predefined scoring system was used to classify patients into three categories: no, mild-to-moderate, and severe PTS. After a median follow-up of 76 months, mild-to-moderate PTS occurred in 19 (20%) and severe PTS in 11 (11.5%) of the 96 patients with stockings, while these occurred in 46 (47%) and 23 (23.5%) of the 98 patients without stockings, respectively (p<0.001).

These results were recently confirmed by a prospective, controlled, randomized study performed in Italy (29), in which 180 consecutive patients with a first episode of symptomatic proximal DVT who were planned to receive conventional anticoagulant treatment were randomized to wear or to not wear below-knee compression (30-40 mm Hg at the ankle) elastic stockings for two years. Follow-up was performed for up to 5 years. Post-thrombotic sequelae, as assessed with the Villalta scale, developed in 44 of the 90 control patients (severe in 10), and in 23 of the 90 patients who were randomized to wear elastic stockings (severe in 3). After adjustment for baseline characteristics, the hazard ratio for the PTS in the stockings group as compared to the control group was 0.5 (0.3 to 0.8). A large, multicenter randomized trial is currently underway in North America to compare active versus placebo stockings to prevent PTS after proximal DVT (64).

Although the results of an investigation conducted in Canada (101) were not consistent with those of the above described studies (19,29,37), a recent meta-analytic review emphasized the role of graduated compression stockings for preventing long-term post-thrombotic sequelae (102). Accordingly, the latest edition of the American College of Chest Physicians has recently recommended elastic stockings beside conventional anticoagulation in all patients with acute symptomatic DVT, if feasible (99). While the effectiveness of compression stockings to prevent PTS after distal DVT has not been studied, it would be reasonable to offer compression stockings to patients with severe symptoms related to distal DVT.

Knee-length and thigh-length compression elastic stockings have similar physiologic effects in decreasing venous stasis of the lower limb, but the former are easier to apply and are more comfortable (103). A recent systematic review of knee versus thigh length graduated compression stockings for the prevention of DVT concluded that knee length were as effective as thigh length stockings and offer advantages in terms of patient compliance and cost (104). In order to directly compare the effectiveness and tolerability of below-knee versus thigh length stockings at the time of acute DVT to prevent PTS a randomized clinical trial has been conducted at our institution, whose results will be available soon (105).

The optimal duration of the treatment with elastic stockings has received little attention. In a recent trial, 169 patients with a first or recurrent proximal DVT who had received 6 months of standard compression treatment were randomized to wear or to not wear graduated elastic stockings for an additional 18 months (37). Overall, after 6 years of follow-up, prolongation of compression therapy failed to confer an additional advantage - according to the CEAP classification – over and above the initial 6-month period. However, when the analysis was confined to women, there was a statistically significant advantage to prolonging treatment with compression stockings. In a prospective cohort management study, the discontinuation of elastic stockings in patients free from PTS complaints who had been offered at least six months of compression therapy did not increase the rate of PTS development over patients in whom stockings had been used for at least two years

In 1997, the results of a prospective randomized Dutch study on the prevention of the PTS became available (19). In this trial, 194 consecutive patients with confirmed proximal DVT were allocated to wear or to not wear elastic compression stockings. A predefined scoring system was used to classify patients into three categories: no, mild-to-moderate, and severe PTS. After a median follow-up of 76 months, mild-to-moderate PTS occurred in 19 (20%) and severe PTS in 11 (11.5%) of the 96 patients with stockings, while these occurred in 46

These results were recently confirmed by a prospective, controlled, randomized study performed in Italy (29), in which 180 consecutive patients with a first episode of symptomatic proximal DVT who were planned to receive conventional anticoagulant treatment were randomized to wear or to not wear below-knee compression (30-40 mm Hg at the ankle) elastic stockings for two years. Follow-up was performed for up to 5 years. Post-thrombotic sequelae, as assessed with the Villalta scale, developed in 44 of the 90 control patients (severe in 10), and in 23 of the 90 patients who were randomized to wear elastic stockings (severe in 3). After adjustment for baseline characteristics, the hazard ratio for the PTS in the stockings group as compared to the control group was 0.5 (0.3 to 0.8). A large, multicenter randomized trial is currently underway in North America to compare

Although the results of an investigation conducted in Canada (101) were not consistent with those of the above described studies (19,29,37), a recent meta-analytic review emphasized the role of graduated compression stockings for preventing long-term post-thrombotic sequelae (102). Accordingly, the latest edition of the American College of Chest Physicians has recently recommended elastic stockings beside conventional anticoagulation in all patients with acute symptomatic DVT, if feasible (99). While the effectiveness of compression stockings to prevent PTS after distal DVT has not been studied, it would be reasonable to offer compression

Knee-length and thigh-length compression elastic stockings have similar physiologic effects in decreasing venous stasis of the lower limb, but the former are easier to apply and are more comfortable (103). A recent systematic review of knee versus thigh length graduated compression stockings for the prevention of DVT concluded that knee length were as effective as thigh length stockings and offer advantages in terms of patient compliance and cost (104). In order to directly compare the effectiveness and tolerability of below-knee versus thigh length stockings at the time of acute DVT to prevent PTS a randomized clinical

trial has been conducted at our institution, whose results will be available soon (105).

The optimal duration of the treatment with elastic stockings has received little attention. In a recent trial, 169 patients with a first or recurrent proximal DVT who had received 6 months of standard compression treatment were randomized to wear or to not wear graduated elastic stockings for an additional 18 months (37). Overall, after 6 years of follow-up, prolongation of compression therapy failed to confer an additional advantage - according to the CEAP classification – over and above the initial 6-month period. However, when the analysis was confined to women, there was a statistically significant advantage to prolonging treatment with compression stockings. In a prospective cohort management study, the discontinuation of elastic stockings in patients free from PTS complaints who had been offered at least six months of compression therapy did not increase the rate of PTS development over patients in whom stockings had been used for at least two years

(47%) and 23 (23.5%) of the 98 patients without stockings, respectively (p<0.001).

active versus placebo stockings to prevent PTS after proximal DVT (64).

stockings to patients with severe symptoms related to distal DVT.

irrespective of the presence of post-thrombotic manifestations (106). Further studies are needed to show whether compression therapy is or is not indicated in asymptomatic patients who have completed an initial 6-month period.

To our knowledge, there are no studies that have compared different compression strengths of stockings to prevent PTS. It would be worth studying the effectiveness of lighter compression (20-30 mm Hg) stockings as they are easier to apply, especially for elderly patients, than 30-40 mm Hg stockings. Of note, in a study of stockings to prevent recurrent venous ulcer, there was no difference in effectiveness between class 2 and class 3 stockings (107).

Interestingly enough, immediate mobilization in patients with acute DVT may reduce the rate of PTS development, provided that patients are provided with adequate compression therapy (108).
