Rutosides for treatment of post-thrombotic syndrome 

Background

Blood clots in the veins of the leg are a common problem and are termed deep vein thrombosis (DVT). One in three patients with a DVT develops a complication known as post-thrombotic syndrome (PTS). This syndrome involves ongoing swelling of the affected leg, pain, cramps, burning or prickling, and itching. Darkening of the skin because of increased pigmentation and varicose veins, redness and skin irritation can also occur. At the current time the main way of treating PTS is to wear compression stockings. It is known however that patients frequently find the stocking uncomfortable and so they may prefer to take an oral medication to treat the problem. Rutosides are a herbal remedy which has been shown to be effective in other conditions affecting the veins (chronic venous insufficiency).

Study characteristics and key results

This review aimed to evaluate the existing literature to see if rutosides were useful for treating PTS. We also investigated whether there were any side effects from the treatment. We searched all existing databases for trials relating to the use of rutosides for the treatment of PTS following DVT (current until 21 August 2018). Two review authors independently assessed the trials for inclusion and extracted results in line with our prescribed criteria. We found three suitable trials, with a total of 233 patients, and six unsuitable trials that were not included in the review.

The studies were small and undertaken very differently meaning they could not be combined. The studies used different comparisons with rutosides (placebo (inactive product), compression stockings alone or combined with rutosides, or hidrosmina (a venoactive drug, which acts on the vascular system). They also used different doses of rutosides (900 mg/day to 2000 mg/day). We found no clear evidence from any of the trials that treatment with rutosides improved symptoms and signs of PTS; or that there was any difference in side effects. Occurrence of leg ulceration was not reported in any of the included studies.

Quality of the evidence

Overall quality of evidence, using the GRADE approach, was low mainly due to the lack of both participant and researcher blinding. This means both investigators and participants knew what drug they were getting and this can effect the results. The quality of the evidence was further limited as only three small studies contributed to the review findings. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention.

Authors' conclusions: 

There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited low-quality evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence to support the use of rutosides in the treatment of PTS.

Read the full abstract...
Background: 

Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the treatment of PTS. This is the second update of the review first published in 2013.

Objectives: 

To determine the effectiveness (improvement or deterioration in symptoms) and safety of rutosides for treatment of post-thrombotic syndrome (PTS) in patients with DVT compared to placebo, no intervention, elastic compression stockings (ECS) or any other treatment.

Search strategy: 

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 21 August 2018.

Selection criteria: 

Two review authors independently assessed studies for inclusion. Studies were included to allow the comparison of rutosides versus placebo or no treatment, rutosides versus ECS, and rutosides versus any other treatment. Two review authors extracted information from the trials. Disagreements were resolved by discussion.

Data collection and analysis: 

Data were extracted using designated data extraction forms. The Cochrane 'Risk of bias' tool was used for all included studies to assist in the assessment of quality. Primary outcome measures were the occurrence of leg ulceration over time (yes or no) and any improvement or deterioration of post-thrombotic syndrome (yes or no). Secondary outcomes included reduction of oedema, pain, recurrence of DVT or pulmonary embolism, compliance with therapy, and adverse effects. All of the outcome measures were analysed using Mantel-Haenzel fixed-effect model odds ratios. The unit of analysis was the number of patients. We used GRADE to assess the quality of the evidence for each outcome.

Main results: 

Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. Overall quality of evidence using the GRADE approach was low, predominantly due to the lack of both participant and researcher blinding in the included studies. The quality of the evidence was further limited as only three small studies contributed to the review findings. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention. One study compared rutosides with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was no clear evidence to support a difference in PTS improvement between the rutosides or placebo/no treatment groups (OR 1.29, 95% CI 0.69 to 2.41; 164 participants; 2 studies; low-quality evidence); or between the rutosides and ECS groups (OR 0.80, 95% CI 0.31 to 2.03; 80 participants; 1 study ; low-quality evidence). Results from one small study reported less PTS improvement in the rutosides group compared to an alternative venoactive remedy (OR 0.18, 95% CI 0.04 to 0.94; 29 participants; 1 study; low-quality evidence). There was no clear evidence to support a difference in PTS deterioration when comparing rutosides with placebo/no treatment (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); with ECS (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); or an alternative venoactive remedy (OR 0.19, 95% CI 0.01 to 4.24; 29 participants; 1 study). No clear evidence of a difference in adverse effects between the rutosides and placebo/no treatment groups was seen ('mild side effects' reported in 7/41 and 5/42 respectively). In the study comparing rutosides with ECS, 2/80 could not tolerate ECS and 6/80 stopped medication due to side effects. The study comparing rutosides with an alternative venoactive remedy did not comment on side effects

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