Rutosides for treatment of post-thrombotic syndrome

  • Review
  • Intervention

Authors


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.

Objectives

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

Search methods

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 9). Clinical trials databases were searched for details of ongoing and unpublished studies.

Selection criteria

Two authors (JM and DNK) 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 authors (JM and SEY) 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 deep venous thrombosis 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.

Main results

Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. One study compared rutoside 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 a 29% odds of an improvement in PTS in the rutoside treated group versus placebo or no treatment, and lower rates of improvement in PTS in the rutoside treated group when compared with ECS, however these were statistically non-significant. Lower rates of improvement in PTS were shown in the rutoside treated group when compared with an alternative venoactive remedy. More PTS deterioration was shown in the placebo or no treatment group when compared with rutosides but this was not statistically significant. Compared with ECS, rutosides showed higher odds of PTS deterioration but this was also not statistically significant. One study reported on adverse effects showing higher odds of mild adverse effects in the rutoside treated group compared to placebo but this was not statistically significant.

Authors' conclusions

There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited 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 for the use of rutosides in the treatment of PTS.

Résumé scientifique

Les rutosides pour le traitement du syndrome post-thrombotique

Contexte

Le syndrome post-thrombotique (SPT) est une complication à long terme de la thrombose veineuse profonde (TVP) qui se caractérise par des douleurs, un œdème, et des modifications cutanées dans le membre concerné. Un patient sur trois atteints de TVP aura des séquelles post-thrombotiques dans les cinq ans. Les rutosides sont un groupe de composés dérivés du marron d'Inde (Aesculus hippocastanum), un remède à base de plantes traditionnellement utilisé pour le traitement de la formation d'œdème dans l'insuffisance veineuse chronique (IVC). Cependant, on ne sait pas si les rutosides sont efficaces et sûrs dans le traitement du SPT.

Objectifs

Déterminer l'efficacité et l'innocuité des rutosides pour le traitement du SPT chez les patients atteints de TVP comparés à un placebo, l'absence d'intervention, des bas de contention élastiques (BCE) ou tout autre traitement.

Stratégie de recherche documentaire

Le coordinateur de recherche d'études du groupe Cochrane sur les maladies vasculaires périphériques a effectué des recherches dans son registre spécialisé (dernières recherches effectuées en octobre 2012) et CENTRAL (2012, numéro 9). Des recherches ont également été effectuées dans des bases de données d'essais cliniques pour obtenir des informations sur les études en cours et non publiées.

Critères de sélection

Deux auteurs (JM et DNK) ont évalué de manière indépendante les études en vue de leur inclusion. Les études ont été incluses afin de permettre la comparaison de rutosides à un placebo ou à l'absence de traitement, de rutosides aux BCE, et de rutosides à tout autre traitement. Deux auteurs (JM et SEY) ont extrait des données dans les essais. Les désaccords ont été résolus par la discussion.

Recueil et analyse des données

Des données ont été extraites à l'aide de formulaires spécifiquement conçus pour l'extraction des données. L'outil Cochrane d'évaluation des risques de biais a été utilisé pour toutes les études incluses pour faciliter l'évaluation de la qualité. Les principaux critères de jugement mesurés étaient la survenue d'ulcère de jambe au fil du temps (oui ou non) et toute amélioration ou aggravation du syndrome post-thrombotique (oui ou non). Les critères de jugement secondaires incluaient la réduction de l'œdème, les douleurs, la récidive de la thrombose veineuse profonde ou de l'embolie pulmonaire, le respect du traitement, et les effets indésirables. Toutes les mesures de critères de jugement ont été analysées en utilisant un modèle à effets fixes et des rapports de cotes de Mantel-Haenzel. L'unité d'analyse était le nombre de patients.

Résultats principaux

Dix rapports de neuf études ont été identifiés à l'issue de la recherche et trois études totalisant 233 participants ont rempli les critères d'inclusion. Une étude a comparé un rutoside à un placebo, une étude a comparé des rutosides aux BCE et des rutosides en plus des BCE aux BCE seuls, et une étude a comparé des rutosides à un remède veino-actif alternatif. Aucune des études incluses n'a rendu compte de la survenue d'ulcère de jambe. Il y avait une cote de 29 % d'une amélioration du SPT dans le groupe de patients traités par des rutosides comparés au placebo ou à l'absence de traitement, et des taux plus faibles d'amélioration du SPT dans le groupe de patients traités par des rutosides comparés aux BCE, même s'ils étaient statistiquement non significatifs. Des taux plus faibles d'amélioration du SPT ont été obtenus dans le groupe de patients traités par des rutosides comparés à un remède veino-actif alternatif. Une aggravation plus importante du SPT a été observée dans le groupe de traitement par placebo ou dans le groupe sans traitement par rapport aux rutosides mais elle n'était pas statistiquement significative. Comparés aux BCE, les rutosides ont montré une cote plus élevée d'aggravation du SPT mais celle-ci n'était pas statistiquement significative non plus. Une étude a rendu compte des effets indésirables révélant une cote plus élevée d'effets indésirables légers dans le groupe de patients traités par des rutosides comparés au placebo mais cela n'était pas statistiquement significatif.

Conclusions des auteurs

Il n'existait aucune preuve que les rutosides avaient une efficacité supérieure à l'utilisation d'un placebo ou de BCE. Dans l'ensemble, les preuves actuellement disponibles indiquant que les remèdes 'veino-actifs' ou 'veinotoniques' tels que les rutosides réduisent les symptômes du SPT sont limitées. Des effets secondaires légers ont été notés dans une étude. Les trois études incluses dans la présente revue n'apportent aucune preuve en faveur de l'utilisation des rutosides dans le traitement du SPT.

Plain language summary

Rutosides for treatment of post-thrombotic syndrome 

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). This review aimed to evaluate the existing literature to see if rutosides were effective at 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. 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 compared rutoside with placebo, compression stockings alone or in addition to rutosides, and an alternative venoactive therapy (hidrosmina). The included studies used different doses of rutosides (900 to 2000 mg/day). We found no clear evidence from these trials that treatment with rutosides improved symptoms and signs of PTS or, in one trial, that patients taking rutosides had more side effects than those using a placebo.

This evidence is limited as only three small studies contributed to the review findings. Two of the studies appeared to be of good quality. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention.

Résumé simplifié

Les rutosides pour le traitement du syndrome post-thrombotique

Les caillots de sang dans les veines de la jambe sont un problème courant et sont appelés thrombose veineuse profonde (TVP). Un patient sur trois atteints de TVP développe une complication appelée syndrome post-thrombotique (SPT). Ce syndrome implique un œdème continu de la jambe affectée, des douleurs, des crampes, des brûlures ou des picotements, et des démangeaisons. Un brunissement de la peau en raison de l'augmentation de la pigmentation ainsi que des varices, une rougeur et une irritation cutanée peuvent également apparaître. À l'heure actuelle, la principale méthode de traitement du SPT consiste à porter des bas de contention. On sait toutefois que les patients trouvent souvent que les bas ne sont pas confortables, c'est pourquoi, ils préfèrent parfois prendre un médicament par voie orale pour traiter le problème. Les rutosides sont des remèdes à base de plantes qui s'avèrent être efficaces dans d'autres maladies touchant les veines (insuffisance veineuse chronique). Cette revue avait pour objectif d'évaluer la littérature existante pour voir si les rutosides étaient efficaces dans le traitement du SPT. Nous avons aussi évalué si le traitement avait entraîné des effets secondaires. Nous avons effectué une recherche dans toutes les bases de données existantes pour trouver des essais abordant l'utilisation de rutosides pour le traitement du SPT suite à une TVP. Deux auteurs de la revue ont indépendamment évalué les essais à inclure et extrait les résultats conformes aux critères que nous avons prescrits. Nous avons trouvé trois essais pertinents, totalisant 233 patients, et six essais non pertinents qui n'ont pas été inclus dans la revue.

Les études ont comparé un rutoside à un placebo, des bas de contention seuls ou en plus des rutosides, et un traitement veino-actif alternatif (hidrosmina). Les études incluses ont utilisé différentes doses de rutosides (900 à 2 000 mg/jour). Nous n'avons trouvé aucune preuve probante dans ces essais indiquant que le traitement par des rutosides a amélioré les symptômes et les signes du SPT ou, dans un essai, que les patients prenant des rutosides ont eu davantage d'effets secondaires que ceux sous placebo.

Ces preuves sont limitées car trois petites études seulement ont contribué aux conclusions de la revue. Deux de ces études semblaient avoir une bonne qualité méthodologique. Un système de notation subjectif a été utilisé pour obtenir les symptômes du SPT, il était donc important que les évaluateurs n'aient pas eu connaissance de l'intervention.

Notes de traduction

Traduit par: French Cochrane Centre 17th May, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Description of the condition

Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by chronic complaints, swelling, and skin changes in the affected limb. One in every three patients with deep vein thrombosis will develop post-thrombotic sequelae within five years (Prandoni 1996). Although there is no gold standard for the diagnosis of PTS, the presence of typical clinical features of venous insufficiency in a patient with previous DVT provides strong supporting evidence. The most commonly used diagnostic criterion for PTS is the Villalta Scale (Villalta 1994). This considers five symptoms (pain, cramps, heaviness, paraesthesias, and pruritus) and six signs (pre-tibial oedema, hyperpigmentation, venous ectasia, redness, skin irritation, and pain during calf compression) in the affected limb. Each element is scored on a scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe) and the scores totalled. Total scores are then used to diagnose PTS: 0 to 4 no PTS, 5 to 9 mild PTS, 10 to 14 moderate PTS, and > 14 or ulceration = severe PTS.

Description of the intervention

The standard intervention for both the prevention and treatment of PTS is elastic compression stocking (ECS) therapy of the legs. Compression therapy of the legs is assumed to reduce oedema, accelerate venous blood flow, and improve venous pump function (Partsch 1991). It is the treatment of first choice for PTS (Partsch 1991). However, compression treatment sometimes leads to discomfort and has been associated with poor compliance, which renders oral drug treatment an attractive option. In addition, the benefits of ECS for PTS have not been fully proven, furthering the need to investigate alternative interventions.

Rutosides are a group of compounds derived from horse chestnut (Latin name: Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (Bombardelli 1996). The active component of horse chestnut seed extract (HCSE) is escin (also spelled aescin) (Guillaume 1994; Lorenz 1960; Schrader 1995). Rutosides and escin are known as 'venoactive' or 'phlebotonic' remedies.

How the intervention might work

In chronic venous insufficiency (CVI) patients, white blood cells accumulate in the affected limbs (Moyses 1987; Thomas 1988) resulting in activation of enzymes which degrade the protein within the capillary walls (Sarin 1993). Studies have shown that escin inhibits these enzymes thereby preventing fluid leakage and swelling due to loss of capillary wall patency (Facino 1995).

Why it is important to do this review

There is evidence to support the use of rutosides for rapid relief of signs or symptoms in CVI and microangiopathy (Cesarone 2005). A Cochrane review of 17 trials comparing HCSE against placebo, ECS, or other medications concluded that HCSE is effective for short-term treatment of CVI symptoms such as leg pain and oedema, and that adverse events were mild and infrequent (Pittler 2006). However, it is not known whether rutosides are effective and safe in the treatment of post-thrombotic syndrome.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating rutosides in the treatment of PTS. Trials which use allocation processes that are transparent before assignment, such as open list of random numbers, case record, day of the week, surname, and so forth, are classified as CCTs.

This review evaluated rutosides in the treatment of PTS. The effects of rutosides on prevention of PTS are reported in the Cochrane review by Morling 2013.

Types of participants

Men and women of any age with complaints or clinical changes of the legs after a previous DVT, with PTS diagnosed by a recognised scoring system. Methods considered acceptable for diagnosis of DVT were ultrasound, venography, and impedance plethysmography.

Types of interventions

The primary intervention was rutosides (any formulation at any dose). Comparisons were with placebo or no intervention, ECS, and any other treatment (including an alternative type or dosage of rutosides and other venoactive remedies). Other kinds of concomitant treatment (including ECS) were equal in both groups, and they were not the comparator treatment.

Types of outcome measures

Primary outcomes
  1. Occurrence of leg ulceration over time (yes or no)

  2. Any improvement of PTS (yes or no)

  3. Any deterioration of PTS (yes or no)

The definitions used in each trial paper for PTS were accepted provided they included a systematic clinical history and scoring of physical examinations. Some trials may report only changes in complaints over time. These are less valid indicators of effectiveness as the complaints may vary.

Secondary outcomes
  1. Any reduction of oedema in PTS (yes or no)

  2. Any reduction of pain in PTS (yes or no)

  3. Any recurrence of DVT or pulmonary embolism (yes or no)

  4. Compliance

  5. Adverse effects after initiation of rutosides

Search methods for identification of studies

There was no restriction on language of publication or publication status.

Electronic searches

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched October 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 9), part of The Cochrane Library at www.thecochranelibrary.com. See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, and AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases (PVD) Group module in The Cochrane Library (www.thecochranelibrary.com).

The following trials databases were searched by the TSC (9 October 2012) for details of ongoing and unpublished studies, using the phrase (post-thrombotic or postthrombotic):

World Health Organization International Clinical Trials Registry (http://apps.who.int/trialsearch/);
ClinicalTrials.gov (http://clinicaltrials.gov/);
Current Controlled Trials (http://www.controlled-trials.com/).

Searching other resources

Reference lists of identified studies were scrutinised in order to identify further citations.

Data collection and analysis

Selection of studies

Two authors (JM and DNK) independently assessed studies for inclusion. JM and SEY independently extracted information from the trials. Disagreement was resolved by discussion.

Data extraction and management

Details of the studies were extracted and summarised using a data extraction sheet.

The following data items were collected, where available.

  • Trial setting (country, and whether primary or secondary care).

  • Method of randomisation.

  • PTS diagnosis assessment method, and whether blinded.

  • Length of follow-up.

  • Number of patients randomised.

  • Inclusion criteria.

  • Exclusion criteria.

  • Description of interventions and co-interventions.

  • Baseline characteristics of groups for important variables (e.g. first DVT, recurrent DVT).

  • Definition of PTS.

  • Results.

  • Compliance.

  • Adverse events.

  • Intention-to-treat analysis.

  • Number and reasons for withdrawals.

  • Source of funding.

  • Use of an a priori sample size or power calculation.

Assessment of risk of bias in included studies

Two authors (JM and SEY) independently assessed bias using the Cochrane risk of bias tool. Disagreement was resolved by discussion. Five key domains were examined for bias: selection bias; performance bias; attrition bias; detection bias; and reporting bias. These were assessed and classified as either at a low risk of bias or a high risk of bias. Where insufficient detail was reported in a study to assess the risk, this was reported as 'unclear'. In addition, any other form of bias noted in the study was reported.

Measures of treatment effect

For dichotomous variables the odds ratio (OR) was reported. All of the outcomes for this review were considered as dichotomous (present or absent).

Unit of analysis issues

For all outcomes the unit of analysis was the number of patients.

Dealing with missing data

Where outcome variables were not reported the available data were analysed. For missing data related to losses to follow-up the data were assumed to be missing at random.

The potential impact of missing data was considered by the authors when making their final conclusions.

It was not necessary for the review authors to contact the original investigators to request missing data.

Assessment of heterogeneity

We planned to explore heterogeneity by examining factors that may be influential, such as the definition of PTS used by the trialists, care setting, time of follow-up, and incidence of recurrent DVT. In the absence of clinical heterogeneity we intended to test for statistical heterogeneity using the Chi2 test.

Assessment of reporting biases

Funnel plots were planned to consider reporting bias.

Data synthesis

Mantel-Haenzel fixed-effect model analyses were planned.

Cross-over trials were analysed examining the first treatment period only.

Subgroup analysis and investigation of heterogeneity

Where sufficient numbers of studies were identified, subgroup analyses were undertaken for the differing comparator groups (versus placebo or no treatment, versus ECS, and versus alternative venoactive remedies).

Sensitivity analysis

If applicable, RCTs and CCTs were analysed separately to access the efficacy of the effect estimation, calculated with the Mantel-Haenszel test. Where sufficient trials were available we reanalysed the data excluding low quality trials.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Searching identified 10 reports of nine studies from which three studies were included. Briefly, these were two RCTs and an open cross-over study. The included studies allowed three comparisons to be examined: rutosides versus placebo or no treatment (De Jongste 1989; Prandoni 2005), rutosides versus ECS (Prandoni 2005), and rutosides versus an alternative venoactive remedy (Monreal 1994). See Included studies and Excluded studies for further details of each study.

Results of the search

See Figure 1. Seaching of the Cochrane PVD Group Specialised Register and CENTRAL identified 10 reports of nine studies. Following consideration of the inclusion and exclusion criteria, three studies (four reports) were suitable for inclusion with six studies excluded. No additional papers were identified from searching the reference lists.

Figure 1.

Study flow diagram.

Included studies

De Jongste 1989

This was a multi-centre, double blind, RCT to assess the use of 0-(β-hydroxyethyl)-rutosides (1200 mg/day) in 84 patients with unilateral PTS of at least six months duration and a venography proven DVT in the affected leg. Consenting ambulant outpatients (referred by their general practitioner (GP)) were randomised by a computer system to receive either rutosides or placebo for eight weeks. There were 48 male and 35 female participants (mean age 53 to 54 years). Each patient was followed up at four weeks and eight weeks. At each visit a standard questionnaire recorded tiredness, pain, heaviness, feeling of swelling, restless legs, cramps, presence of pitting oedema on a scale of: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. In addition, minimum ankle circumferences were recorded as well as both the patients' and the (blinded) doctors' opinion of the efficacy of the treatment.

This study provided data for the comparison: rutosides versus placebo or no treatment.

Monreal 1994

This was an open cross-over study of 0-(β-hydroxyethyl)-rutosides (900 mg/day) versus hidrosmina (600 mg/day), each for six months. Hidrosmina is an alternative venoactive remedy. Twenty-nine outpatients with unilateral PTS of at least 12 months duration following a venography proven lower limb DVT were randomised. The Kakkar and Lawrence scoring system was used to record the severity of symptoms and signs. The initial drug was taken for six months. The drug was then discontinued and the alternative taken for a further six months. Following discontinuation of both drugs, patients were examined at three and six months. For this review only the first treatment period was considered.

This study provided data for the comparison: rutosides versus hidrosmina (an alternative venoactive remedy).

Prandoni 2005

This was a randomised controlled pilot study comparing the efficacy of elastic compression stockings (ECS), hydroxyethylrutosides (HR) (2000 mg/day), or both in the treatment of PTS in ultrasound proven lower limb DVT. A total of 120 consecutive patients were randomised by a computer system, with 40 patients in each of the three groups. They received treatment for 12 months. In order to assess the efficacy of HR, this Cochrane review compared the use of HR and ECS with elastic compression stockings alone. There were 36 male and 84 female participants (aged 24 to 91 years). Each patient was followed up at three months, six months, and 12 months. At each visit an investigator blind to the participant's treatment scored the presence and severity of PTS according to the Villalta scale. Those whose scores fell to below five or that had a 30% reduction were considered to have a PTS improvement, those that had an increase by at least 30% were considered to have a PTS deterioration. Compliance with treatment was also recorded.

This study provided data for the comparisons: rutosides versus placebo or no treatment, and rutosides versus ECS.

Excluded studies

Following application of the inclusion and exclusion criteria, six studies were excluded. Four of the studies investigated the effect of rutosides on the treatment of deep venous insufficiency with a mixed causality, not PTS (Cospite 1986; Diebschlag 1994; Incandela 2002; Rose 1970). Two studies either presented no results or it was not possible to extract the results related to PTS (De Jongste 1986; Nill 1970).

Risk of bias in included studies

See Figure 2 for a summary of the risk of bias assessment.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All three studies used random assignment of participants to each of the study groups. Both De Jongste 1989 and Prandoni 2005 specified computer randomisation schedules. Monreal 1994 did not specify the randomisation schedule.

Blinding

The three studies included in this review all used slightly different trial methodologies, making the blinding process slightly different for each. De Jongste's traditional RCT (intervention versus placebo) stated double blinding, suggesting that both participants and study personnel were unaware of which treatment the individual was receiving (De Jongste 1989).

Prandoni 2005 had three trial arms. Participants were not blinded as patients received either elastic stockings, oral HR treatment, or both and it is difficult to use a placebo for the patients in the non-elastic stockings groups although sham devices are available. Some of the measured outcomes in this study were mostly based on severity of clinical symptoms, which could potentially be influenced by patients’ perspectives. Other measured outcomes were based on clinical signs, which are unlikely to be influenced by patients’ perspectives. There was no placebo in the ECS alone group so participants would be aware of whether they were receiving the trial medication. Study personnel recording outcome data were unaware of the treatment allocation and the results of previous measurements.

In the Monreal 1994 open cross-over trial it was not stated if patients were blinded to the treatment allocation. In addition, some of the measured outcomes in this study were based on the subjective severity of clinical symptoms and might potentially be influenced by patients' perspectives. All patients were examined by the same physician to increase the standardisation of measurement. It was not stated if the study personnel were blinded.

Incomplete outcome data

All excluded patients were accounted for and satisfactory reasons for exclusion given in all three included studies.

Selective reporting

In all included studies the pre-specified outcomes of interest in this review were reported.

Other potential sources of bias

There were no additional significant bias concerns.

Effects of interventions

Key effects of the intervention are shown in the data analysis table below. For each of the studies the final time point outcome was reported. It should be noted that the duration of each study differed. The results reported from the three studies allowed three comparisons to be made.

1. Rutosides versus placebo or no treatment.

2. Rutosides versus ECS.

3. Rutosides versus hidrosmina (an alternative venoactive remedy).

Occurrence of leg ulceration over time

None of the studies reported on the development of ulceration. Monreal 1994 noted a statistically non-significant increase in ulcer healing in the rutoside group (2/15) compared with hidrosmina (1/14) (P = 0.59).

Improvement of PTS

Different reporting methods were used by each study. Whilst not measured in identical ways these were comparable.

Analysis 1.1 shows a combined OR of 1.29 (95% CI 0.69 to 2.41, P = 0.42) for rutosides versus placebo or no treatment (De Jongste 1989; Prandoni 2005) (Figure 3). This was supplemented by De Jongste 1989 reporting on the improvement of each component of PTS: tiredness (rutosides 46%, placebo 26%); heaviness (rutosides 41%, placebo 29%); restless legs (rutosides 17%, placebo 14%); and cramps (rutosides 34%, placebo 36%).

Figure 3.

Forest plot of comparison: 1 Rutosides for the treatment of PTS, outcome: 1.1 Improvement in PTS.

For rutosides versus ECS, Prandoni 2005 found a marginal statistically non-significant lower proportion of patients improving in the rutoside treated group (rutosides improvement 26/40, ECS improvement 28/40, P = 0.63) (Analysis 2.1).

For rutosides versus hidrosmina, Monreal 1994 found statistically significantly more patients with improvement of PTS in the hidrosmina treated group (hidrosmina improvement 9/15, rutoside improvement 3/14, P = 0.04) (Analysis 3.1).

Deterioration of PTS

Different reporting methods were used by each study. Whilst not measured in identical ways these were comparable.

Prandoni 2005 (Analysis 1.2) found higher rates of PTS deterioration in the rutoside group compared with the placebo or no treatment group but this was not statistically significant (rutosides deterioration 9/40, placebo or no treatment deterioration 6/40, P = 0.39).

In Prandoni 2005, for rutosides versus ECS there was more deterioration in the rutoside group (rutoside deterioration 9/40, ECS deterioration 6/40, P = 0.39) (Analysis 2.2) but this was not statistically significant.

For rutosides versus hidrosmina, Monreal 1994 reported deterioration of PTS in 0/14 patients in the rutoside group and deterioration in 2/15 patients in the hidrosmina group (P = 0.29) (Analysis 3.2).

Reduction of oedema or swelling

Only De Jongste 1989 reported on improvement in swelling, with the rutosides group showing more improvement than the placebo or no treatment group (20/41 versus 18/42) but this was not statistically significant (P = 0.59) (Analysis 1.3).

Monreal 1994 reported mean ankle and calf circumferences at six, 12, and 18 month intervals. During treatment with both rutosides and hidrosmina Monreal 1994 reported a gradual reduction in mean values, however this was not sustained following withdrawal of treatment.

Reduction of pain

De Jongste 1989 was the only study to report reduction in pain, with slightly higher rates of pain reduction in the rutosides group than the placebo or no treatment group (16/41 versus 14/42) but this was not statistically significant (P = 0.59) (Analysis 1.4).

Recurrence of DVT or pulmonary embolism

Prandoni 2005 was the only study to report reoccurrence of DVT or pulmonary embolism (PE). This event occurred once in each of the rutosides, ECS, and placebo or no intervention groups (Analysis 1.5; Analysis 2.3).

Compliance

Prandoni 2005 was the only study to report on compliance, with 70/80 wearing stockings for ≥ 80% of the study and 64/80 taking ≥ 80% of the study medication. Note the numbers included all three groups (rutosides versus ECS versus rutosides + ECS) as it was not possible to separate them.

Adverse effects after initiation of rutosides

De Jongste 1989 reported 'mild side effects' in 7/41 of the rutoside group and 5/42 of the placebo or no intervention group (P = 0.51) (Analysis 1.6). As above, Prandoni 2005 did not separate the outcomes fully with 2/80 not tolerating ECS and 6/80 stopping the medication due to side effects, described as mainly gastrointestinal. Monreal 1994 did not comment on side effects.

Because of the limited number of included studies we were unable to undertake heterogeneity, subgroup, reporting bias, and sensitivity analyses.

Discussion

Summary of main results

Participants had 29% higher odds of improvement in PTS if they received rutosides compared to placebo or no intervention based on two studies. Rates of deterioration in PTS were also higher in the group receiving rutosides versus placebo or no treatment but lower than in those receiving an alternative venoactive remedy. However, none of the results were statistically significant.

When compared with ECS, participants had lower odds of improvement and higher odds of deterioration of PTS in the rutoside group (again not statistically significant).

When two different venoactive remedies were compared, PTS improvement was more pronounced in the hidrosmina treated group compared to rutoside treatment, however this group also had higher rates of PTS deterioration (not statistically significant).

There was little reported on compliance and adverse effects, with slightly higher rates of mild adverse effects in the rutoside group compared with placebo or no treatment, reported by a single study, with no reports for the other comparisons.

Overall completeness and applicability of evidence

This review considered DVT at any site without separate analysis of upper and lower limbs. A separate analysis would have been limited in this review given the inclusion of only three studies but should be considered for future updates.

Quality of the evidence

The body of the evidence is limited by the small number of studies contributing to this review. Aside from this, the included studies appear to be of good quality with the exception of Monreal 1994 as it was not blinded. Further to this, the data were generated using a subjective scoring system for PTS, however this is unavoidable. The alternative would be repeated invasive pressure measures, which would be unacceptable to participants and potentially less useful than clinical symptom outcomes. Scoring systems differed across the studies but were all similar. Another notable difference in the included studies was the varied dosage of rutosides used (900 to 2000 mg/day).

Potential biases in the review process

The Cochrane PVD Group Specialised Register is a comprehensive and weekly updated register of all publications relating to PVD. As a result, when searched in combination with CENTRAL we believe that all trials with the potential for inclusion will have been accessed. The search strategy was developed in conjunction with experts in the field to maximise study identification. It was not possible to contact any PTS specialists to recover any additional unpublished or ongoing studies. The search criteria identified nine studies and reference list scrutiny found no additional trials, we remain confident in our study identification. Data collection and analysis methods were robust.

Agreements and disagreements with other studies or reviews

Six studies were excluded following the searches and of these only one referred to PTS. This double blind randomised placebo controlled study (De Jongste 1986) reported its data in a way which made it impossible to extract for inclusion in this review. However, in summary, a greater reduction in oedema and greater patient reported improvement of symptoms were noted in the rutoside treated group. This is in keeping with the findings of this Cochrane review. It was not possible to identify any additional studies to assess agreement or disagreement with.

Our study agrees with the findings of a recent meta-analysis by Cohen 2012 for the outcomes we included. In addition, Cohen 2012 chose to analyse the risk of adverse effects, combining De Jongste 1989 and Prandoni 2005, and found a non-significant increased risk (RR 2.04, 95% CI 0.76 to 5.51). Cohen 2012 did not identify any studies additional to those we identified that compared the effects of rutosides versus placebo, no intervention, ECS, or any other treatment.

Authors' conclusions

Implications for practice

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

Implications for research

Numerous in vitro studies conclude that rutosides reduce microvascular permeability both in healthy vessels and vessels showing signs of inflammation hence decreasing capillary flux or filtration, leakage, and swelling, with a potential improvement in signs and symptoms of PTS. Since PTS is not only dependent on platelets but also coagulation, fibrinolysis, and flow, studies have also shown that rutosides inhibit the aggregation of human red cells and platelets in vitro. Despite these in vitro research findings the effects have yet to be fully translated into human clinical trials. Also, not all studies have yet adopted the standardised Villalta Scale for the diagnosis and monitoring of PTS symptoms (Kahn 2009), which is essential in future work. Larger, longer duration RCTs are required to confirm the effectiveness of rutosides for treating PTS and also to examine their long-term benefits and any benefits over the current standard therapy of ECS.

Acknowledgements

The authors would like to thank Dr Martin Prins for his work on the study protocol.

Data and analyses

Download statistical data

Comparison 1. Rutosides versus placebo or no comparator for the treatment of PTS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in PTS2164Odds Ratio (M-H, Fixed, 95% CI)1.29 [0.69, 2.41]
2 Deterioration in PTS1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Reduction of oedema/swelling1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Reduction of pain1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Recurrence of DVT/PE1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
6 Adverse effects1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Rutosides versus placebo or no comparator for the treatment of PTS, Outcome 1 Improvement in PTS.

Analysis 1.2.

Comparison 1 Rutosides versus placebo or no comparator for the treatment of PTS, Outcome 2 Deterioration in PTS.

Analysis 1.3.

Comparison 1 Rutosides versus placebo or no comparator for the treatment of PTS, Outcome 3 Reduction of oedema/swelling.

Analysis 1.4.

Comparison 1 Rutosides versus placebo or no comparator for the treatment of PTS, Outcome 4 Reduction of pain.

Analysis 1.5.

Comparison 1 Rutosides versus placebo or no comparator for the treatment of PTS, Outcome 5 Recurrence of DVT/PE.

Analysis 1.6.

Comparison 1 Rutosides versus placebo or no comparator for the treatment of PTS, Outcome 6 Adverse effects.

Comparison 2. Rutosides versus ECS for the treatment of PTS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in PTS1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Deterioration in PTS1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Recurrence of DVT/PE1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Rutosides versus ECS for the treatment of PTS, Outcome 1 Improvement in PTS.

Analysis 2.2.

Comparison 2 Rutosides versus ECS for the treatment of PTS, Outcome 2 Deterioration in PTS.

Analysis 2.3.

Comparison 2 Rutosides versus ECS for the treatment of PTS, Outcome 3 Recurrence of DVT/PE.

Comparison 3. Rutosides versus hidrosmina for the treatment of PTS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in PTS1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Deterioration in PTS1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 Rutosides versus hidrosmina for the treatment of PTS, Outcome 1 Improvement in PTS.

Analysis 3.2.

Comparison 3 Rutosides versus hidrosmina for the treatment of PTS, Outcome 2 Deterioration in PTS.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Rutin] explode all trees 157

#2 *rutoside*:ti,ab,kw 182

#3 (*Rutin*):ti,ab,kw 558

#4 *ruton*:ti,ab,kw 47

#5 Paroven:ti,ab,kw 14

#6 (buckwheat or bioflav*):ti,ab,kw 58

#7 MeSH descriptor: [Quercetin] this term only 95

#8 quercetin*:ti,ab,kw 141

#9 MeSH descriptor: [Quercetin] this term only 95

#10 MeSH descriptor: [Escin] explode all trees 53

#11 aesculus* near hippocastan*:ti,ab,kw 16

#12 escin* or aescin* or essaven*:ti,ab,kw 101

#13 rosskastani*:ti,ab,kw 2

#14 horse* near (chestnut or chest-nut):ti,ab,kw 45

#15 venosta*:ti,ab,kw 20

#16 horsechestnut:ti,ab,kw 4

#17 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 968

#18 MeSH descriptor: [Postthrombotic Syndrome] explode all trees 15

#19 (postthrombotic or (post near/3 thrombot*)):ti,ab,kw 114

#20 PTS:ti,ab,kw 1744

#21 MeSH descriptor: [Postphlebitic Syndrome] explode all trees 27

#22 postphlebit* or post-phlebit*:ti,ab,kw 48

#23 #18 or #19 or #20 or #21 or #22 1866

#24 #17 and #23 11 in Trials

History

Protocol first published: Issue 1, 2006
Review first published: Issue 4, 2013

DateEventDescription
3 November 2008AmendedConverted to new review format.

Contributions of authors

Joanne Moring: selected trials, developed data extraction tool, extracted data, assessed risk of bias, undertook analyses, wrote the review.
Su Ern Yeoh: extracted data, assessed risk of bias, wrote the review.
Dinanda Kolbach: wrote the protocol, checked the review.

Declarations of interest

Dr Morling is supported by a Diabetes UK Clinical Training Fellowship, a 3-year fellowship grant covering research costs and salary. This research grant does not conflict with this review.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The PVD Group editorial base is supported by the Chief Scientist Office.

Differences between protocol and review

According to Cochrane guidelines the quality of the trials was assessed using the Cochrane risk of bias tool (Higgins 2011).

The original protocol listed only negative primary outcomes regarding PTS. In order to present a balanced view we added a third primary outcome: 'any improvement in PTS (yes or no)'.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

De Jongste 1989

Methods

Randomised, double blind, placebo controlled trial

Treatment period: eight weeks

Participants

Conducted in outpatient department of three Dutch hospitals

Total number randomised: 84 (males 48, female 36)

Mean age: intervention 53 (SD 12), placebo 54 (SD 13) years

Interventions

Arm 1: 0-(β-hydroxyethyl)-rutosides 1200 mg daily (in four divided doses)

Arm 2: placebo

Outcomes

Deterioration of PTS

Presence of pain

Side effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "patients were randomly assigned ..... with the use of a computerised random assignment method".

Comment: The randomisation schedule was specified.

Allocation concealment (selection bias)Low riskQuote: "A series of coded sealed envelopes for decoding any particular case was supplied to the local hospital pharmacy".
Comment: Unlikely patients and personnel were aware of the randomisation schedule.  
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "double-blind".

Comment: Suggesting both participants and study personnel were unaware of which treatment the individual was receiving.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Quote: "double-blind", "All the assessments were performed by the same investigators at each center..."

Comment: Not reported if investigators were aware of blinding.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: All excluded patients were accounted for and satisfactory reasons for exclusion given.
Selective reporting (reporting bias)Low riskComment: The study's pre-specified outcomes that are of interest to this review have been reported.
Other biasLow riskNo additional significant bias concerns.

Monreal 1994

Methods

Randomised, open, cross-over trial

Phase 1: first treatment period, six months

Phase 2: second treatment period, six months

Phase 3: washout period, four weeks

Participants

Conducted in single centre, outpatient department, Spain

Total number randomised 29 (males 21, female 8)

Mean age: 60 years (range 39 to 80)

Interventions

Arm 1: 0-(β-hydroxyethyl)-rutosides 900 mg daily (in three divided doses)

Arm 2: hidrosmina 600 mg daily (in three divided doses)

OutcomesPresence of pain (Kakkar and Lawrence Scoring System)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "patients were randomly assigned".

Comment: The randomisation schedule was not specified.

Allocation concealment (selection bias)Low riskComment: Unlikely patients were aware of the randomisation schedule.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen cross-over pilot study.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen cross-over pilot study.
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: All excluded patients were accounted for and satisfactory reasons for exclusion given.
Selective reporting (reporting bias)Low riskComment: The study's pre-specified outcomes that are of interest to this review have been reported.
Other biasLow riskNo additional significant bias concerns.

Prandoni 2005

Methods

Randomised, single blind, controlled trial

Treament period: 12 months

Participants

Single centre Italian study

Total number randomised 120 (males 33, female 87)

Age range: 24 to 91 years

Interventions

Arm 1: 0-(β-hydroxyethyl)-rutosides 2000 mg daily (in two divided doses)

Arm 2: elastic compression stockings (below knee, 30 to 40 mmHg at ankle)

Arm 3: 0-(β-hydroxyethyl)-rutosides 2000 mg daily (in two divided doses) and elastic compression stockings (below knee, 30 to 40 mmHg at ankle)

Outcomes

Deterioration of PTS (Villalta Scale)

Improvement of PTS (Villalta Scale)

Compliance with therapy

Side effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "consenting patients were randomly allocated ..... according to a computer generated list".

Comment: The randomisation schedule was specified.

Allocation concealment (selection bias)Low riskComment: Unlikely patients were aware of the randomisation schedule.
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded as patients received either elastic stockings, oral HR treatment or both and it is difficult to use a placebo for the patients in the non-elastic stockings groups although sham devices are available. Some of the measured outcomes in this study are mostly based on severity of clinical symptoms which could potentially be influenced by patients’ perspectives. Other measured outcomes were based on clinical signs which are unlikely to be influenced by patients’ perspectives.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessment was carried out by an investigator who was aware as to the side of the index DVT but was unaware of the treatment allocation and the results of previous measurements.
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: All excluded patients were accounted for and satisfactory reasons for exclusion given.
Selective reporting (reporting bias)Low riskComment: The study's pre-specified outcomes that are of interest to this review have been reported.
Other biasLow riskNo additional significant bias concerns.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Cospite 1986Not post-thrombotic syndrome
De Jongste 1986No results presented suitable for data extraction or consistent with review outcomes
Diebschlag 1994Not post-thrombotic syndrome
Incandela 2002Not post-thrombotic syndrome
Nill 1970Not possible to extract post-thrombotic syndrome data alone, and the outcome reported is not relevant for this review
Rose 1970Not post-thrombotic syndrome

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