Systematic Review of Pharmacologic and Compression Therapies for Treatment of Post-Thrombotic Syndrome

Post-thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT) characterized by chronic pain, swelling and other signs in the affected limb that can severely impact individuals' quality of life. There are no widely accepted treatments for PTS, although varied treatment strategies have been proposed.

Objective: To systematically review evidence for the effectiveness and safety of pharmacologic and compression therapies for treatment of PTS.

Randomized controlled trials (RCTs) of PTS treatments were sought in a search of PubMed and by reverse citation searches.

A total of 121 titles were reviewed and 12 full-text publications were assessed for inclusion. Seven trials were selected for inclusion in the review. Four trials (3 parallel RCTs, 1 crossover RCT) including 521 patients assessed the effectiveness of various drugs for treatment of PTS. These pharmacotherapies included rutosides, hidrosmin, and defibrotide and treatment durations ranged from 2–12 months. Three trials (1 parallel RCT, 2 crossover RCTs) including 82 patients assessed compression therapies. Two used intermittent pneumatic compression (IPC) devices worn for 4–8 weeks, while one used continuous compression in the form of graduated compression stockings (GCS) worn for at least 1 year. Follow-up in these studies ranged from 8 weeks to over 1 year. All studies identified PTS as occurring after DVT in the same leg, often requiring objective diagnosis of DVT. One study used CEAP criteria for venous insufficiency, including patients classified as C2, C3 or C4. Another required participants to have had deep venous insufficiency (not further defined) for at least 12 months. Two studies used the Villalta scale to classify patients as having PTS, while one study only included patients with a score >14, corresponding to severe PTS. Another study defined PTS as the presence of chronic and typical pain and swelling 1 year post-DVT, and another defined it as intractable symptoms causing significant limitations of lifestyle and/or morbidity. In one study, PTS was not defined. Indicators used to assess the success of the interventions varied. Clinical signs and symptoms were often assessed with a quantitative scoring system. Validated scales used included Kakkar & Lawrence, Villalta, and VEINES-Sym. Calf and ankle circumference were often measured, where significant differences in these measures were used to attest to the success of an intervention; however, the clinical significance of these changes may be questionable. The IPC studies defined treatment success based on factors such as perceived benefit, patient preference for the active treatment, and willingness to continue to use the intervention. The GCS study defined treatment failure based on symptom deterioration, work absences, and development of venous ulcer. Only 1 study assessed the effect on quality of life, using the VEINES-QOL questionnaire. Studies of pharmacotherapies demonstrated minimal benefit on symptom scores, reduced calf and ankle circumference, and ulcer healing. In one study that continued to follow-up subjects for 6 months after treatment was terminated, the effect of drug treatment was not sustained (50% of ulcers returned). Studies of compression therapy did not convincingly demonstrate benefits of GCS; but for the IPC devices, treatment success was more likely than on the placebo devices. None of these treatments were associated with any important side effects and hence, compliance was acceptable in all studies that reported it. Studies of pharmacologic and compression therapies for treatment of PTS suffer from study design limitations including lack of blinding and wash-out periods that have the potential to introduce bias. Short duration of treatment in some studies may limit the extent to which the interventions were found to be effective. Sustained effectiveness was not assessed except for one study.

Conclusions: There is limited and low quality evidence for the effectiveness of rutosides, hidrosmin, and defibrotide to treat PTS. There is also limited and low quality evidence for the effectiveness of GCS, but IPC devices seem to provide at least short term relief from PTS. More rigorous studies are needed to assess the effectiveness and sustainability of pharmacologic and compression treatments for PTS, and study endpoints should focus on clinically important improvements in patient condition.

No relevant conflicts of interest to declare.