Rutosides for prevention 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. The current standard care for the prevention of PTS following DVT is elastic compression stockings. 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 prevention of post-thrombotic syndrome.

Objectives

To determine the effectiveness and safety of rutosides for prevention of PTS in patients with DVT, compared to placebo, no intervention, or reference medication.

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 Clinical trials databases were searched for details of ongoing and unpublished studies.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

We planned to include trials of rutosides versus any alternative (placebo, no intervention, or reference medication) in the prevention of PTS in patients with DVT.

Data collection and analysis

Two authors independently assessed studies for inclusion and intended to extract information from the trials.

Main results

No studies were identified comparing rutosides versus any alternative in the prevention of PTS.

Authors' conclusions

As there were no studies identified in this review it is not possible to support the use of rutosides in the prevention of PTS. Some studies suggest that rutosides may provide short-term relief of PTS symptoms. However, there is nothing published on their use as a preventative therapy for PTS. High quality randomised controlled trials of rutoside versus any alternative are required to build the evidence base in this area.

Résumé scientifique

Les rutosides pour la prévention 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. Le traitement de référence actuel pour la prévention du SPT suite à une TVP est le port de bas de contention élastiques. 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 la prévention du syndrome post-thrombotique.

Objectifs

Déterminer l'efficacité et l'innocuité des rutosides pour la prévention du SPT chez les patients atteints de TVP, comparés à un placebo, à l'absence d'intervention, ou au traitement de référence.

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

Nous avions prévu d'inclure les essais portant sur les rutosides comparés à tout traitement alternatif (placebo, absence d'intervention, ou traitement de référence) dans la prévention du SPT chez les patients atteints de TVP.

Recueil et analyse des données

Deux auteurs ont évalué les études à inclure de manière indépendante et devaient extraire des données dans les essais.

Résultats principaux

Nous n'avons identifié aucune étude comparant les rutosides à tout traitement alternatif dans la prévention du SPT.

Conclusions des auteurs

Comme aucune étude n'a été identifiée dans cette revue, il n'est pas possible d'appuyer l'utilisation des rutosides dans la prévention du SPT. Certaines études laissent entendre que les rutosides peuvent apporter un soulagement à court terme des symptômes du SPT. Cependant, il n'existe aucune publication sur leur utilisation en tant que traitement préventif du SPT. Il est nécessaire de réaliser des essais contrôlés randomisés de bonne qualité portant sur les rutosides comparés à tout traitement alternatif pour enrichir la base des preuves dans ce domaine.

Plain language summary

Rutosides for prevention 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, and also skin changes. At the current time the main way of preventing PTS is to wear compression stockings. However, it is known that patients frequently find the stocking uncomfortable and would prefer to take an oral medication to prevent the problem.

Rutosides are a herbal remedy which have been shown to reduce swelling and skin changes in other conditions affecting the veins such as in chronic venous insufficiency. This review aimed to evaluate the existing literature to see if there was evidence from randomised controlled trials for the effectiveness of rutosides in preventing PTS following a DVT. We also aimed to investigate whether there were any side effects from the treatment.

We searched existing databases for trials relating to the use of rutosides for the prevention of PTS following DVT. Two authors independently reviewed trials for inclusion and intended to extract results in line with prescribed criteria.

We did not find any trials of rutosides versus an alternative therapy for the prevention of PTS that were suitable for inclusion. We therefore have no evidence to support the use of rutosides in the prevention of PTS and high quality randomised controlled trials are required.

Résumé simplifié

Les rutosides pour la prévention 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, ainsi que des modifications cutanées. À l'heure actuelle, la principale manière de prévenir le 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 prendre un médicament par voie orale pour prévenir le problème.

Les rutosides sont des remèdes à base de plantes qui s'avèrent réduire l'œdème et les modifications cutanées dans d'autres maladies touchant les veines telles que l'insuffisance veineuse chronique. Cette revue avait pour objectif d'évaluer la littérature existante pour voir s'il existe des preuves issues d'essais contrôlés randomisés en faveur de l'efficacité des rutosides dans la prévention du SPT suite à une TVP. Nous avions aussi pour objectif d'évaluer si le traitement avait entraîné des effets secondaires.

Nous avons effectué une recherche dans les bases de données existantes pour trouver des essais abordant l'utilisation de rutosides dans la prévention du SPT suite à une TVP. Deux auteurs ont évalué les essais à inclure de manière indépendante et devaient extraire les résultats conformes aux critères prescrits.

Nous n'avons trouvé aucun essai portant sur les rutosides par rapport à un traitement alternatif pour la prévention du SPT, éligible à l'inclusion dans la revue. Nous ne disposons, par conséquent, d'aucune preuve pour appuyer l'utilisation des rutosides dans la prévention du SPT et des essais contrôlés randomisés de bonne qualité sont nécessaires.

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 pain, swelling, and skin changes in the affected limb. One in every three patients with a DVT will develop post-thrombotic syndrome (PTS) within five years (Prandoni 1996). Symtoms vary from mild to significantly debilitating. In the acute phase of DVT, a fresh thrombus in the deep vein produces an obstruction. In the first few months following DVT recanalisation (a complex process involving fibrinolysis, thrombus organisation, and neovascularisation) occurs (Meissner 2002). This process can result in valve destruction. Damaged valves, insufficient closure or occlusion, or both, of the veins increase pressure in the veins (venous hypertension). It is suggested that this venous hypertension disturbs the normal flow in small capillaries resulting in increased capillary filtration, which leads to oedema in the lower leg and a number of skin changes (Widmer 1985). Whilst the anticoagulant treatment for DVT prevents clot extension and embolisation it does not break down the primary clot.

Description of the intervention

The standard therapy for both the prevention and treatment of PTS is elastic compression stocking (ECS) therapy of the legs. It is assumed to reduce oedema, accelerate venous blood flow, and improve venous pump function (Partsch 1991). However, compression treatment sometimes leads to discomfort and has associated poor compliance, which renders oral drug treatment an attractive option.

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 (CVI) (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 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 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 prevention of PTS.

Objectives

To determine the effectiveness and safety of rutosides for prevention of PTS in patients with DVT compared to placebo, no intervention, or reference medication.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) or controlled clinical trials (CCTs, also known as quasi-RCTs) evaluating rutosides in the prevention 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 evaluates rutosides in the prevention of PTS. The effects of rutosides on treatment of PTS are reported in the Cochrane review by Morling 2013.

Types of participants

  • Men and women of any age

  • Deep venous thrombosis (DVT) that has been objectively diagnosed within the year prior to the study. Methods considered acceptable for diagnosis were ultrasound, venography, and impedance plethysmography.

Types of interventions

  1. Primary intervention: rutosides in the first year after the diagnosis of a DVT.

  2. Comparator groups: no intervention, different dosages of rutosides, or any other treatments (for example ECS) in the first year after a diagnosis of DVT.

Where rutosides were being compared to a non-ECS alternative, ECS therapy was allowed if equal in all patient groups in the trial.

Types of outcome measures

Primary outcomes
  1. Development of post-thrombotic syndrome (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.

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

  2. Any development of pain (yes or no)

  3. Recurrence of DVT or pulmonary embolism (yes or no)

  4. Compliance with therapy

  5. Adverse effects

Search methods for identification of studies

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 trial databases were searched (9 October 2012) by the TSC for details of ongoing and unpublished studies using the terms post-thrombotic or postthrombotic:

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 and extracted information from the trials. Disagreement was resolved by discussion.

Data extraction and management

It was intended that the following data be extracted.

  • 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 (or limbs) 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 effects.

  • 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

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

Measures of treatment effect

We intended for dichotomous variables to be reported as the odds ratio (OR). All of the intended outcomes for this review were considered as dichotomous (present or absent).

Unit of analysis issues

The unit of analysis was intended to be the number of patients.

Dealing with missing data

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

If necessary, we intended to contact the original investigators to request missing data.

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

Assessment of heterogeneity

We planned to explore heterogeneity by examining factors that may be influential, such as definition of PTS used, 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 I2 statistic.

Assessment of reporting biases

Funnel plots were planned to consider reporting bias.

Data synthesis

Mantel-Haenzel fixed-effect model analyses were planned.

Subgroup analysis and investigation of heterogeneity

Where sufficient numbers of studies were identified, subgroup analyses were planned as described above.

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 excluded studies.

See Figure 1

Figure 1.

Study flow diagram.

Results of the search

We did not identify any trials of rutosides versus alternative treatment for the prevention of PTS. Searching identified only one study, an open randomised pilot study of hidrosmina (an alternative venoactive remedy) versus no treatment for prevention of PTS (Monreal 1997).

Included studies

There were no studies identified for inclusion.

Excluded studies

Monreal 1997

This was an open, randomised, pilot study to assess the use of hidrosmina (600 mg daily) compared with no treatment for prevention of PTS. One hundred consecutive patients with objectively confirmed DVT were randomly allocated using a randomisation schedule to receive either the intervention (n = 52) or no additional treatment (n = 48), at the point of hospital discharge. There were 49 male and 51 female participants (aged 17 to 76 years). In total, 89 patients had a unilateral lower limb DVT and 11 had bilateral events. Each patient was followed up at 4-month intervals for three years. At each follow-up appointment the participants were questioned regarding PTS symptoms in both the affected and unaffected leg (or both affected limbs for bilateral disease). Clinical examination was undertaken and PTS scored using the Society of Vascular Surgery/International Society for Cardiovascular Surgery scoring system (Iafrati 1994). The funding source was not declared. This study was excluded because hidrosmina is not a rutoside but an alternative venoactive remedy.

Risk of bias in included studies

There were no studies identified for inclusion.

Effects of interventions

There were no studies identified for inclusion.

Discussion

Summary of main results

We did not identify any studies comparing the use of rutosides versus any alternative intervention in the prevention of PTS so there is currently no clinical trial evidence that supports or opposes the use of rutosides over any other treatment in the prevention of PTS.

Overall completeness and applicability of evidence

We did not identify any evidence to support or oppose the use of rutosides for the prevention of PTS.

Quality of the evidence

With no identified evidence it is clear that there is a need for high quality studies in this area if the potential for rutosides to be used as a preventative intervention for PTS is to be pursued.

Potential biases in the review process

There are no included or excluded studies, therefore we were unable to assess the potential bias of the review process beyond the stage of trial selection.

The Cochrane PVD Group Specialised Register is a comprehensive, 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 identified. 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 only identified one potentially relevant study, which was ultimately excluded because the treatment was not a rutoside but an alternative venoactive remedy. After reference list scrutiny no additional potentially relevant trials were identified and we remain confident in our study identification process.

Agreements and disagreements with other studies or reviews

It was not possible to assess agreement or disagreement with other studies as no studies on the prevention of PTS using rutosides were identified. Similarly, limited evidence is available regarding the treatment of PTS using rutosides (Morling 2013).

Authors' conclusions

Implications for practice

As there were no studies identified in this review it is not possible to support the use of rutosides in the prevention of PTS. Some studies suggest that rutosides may provide short-term relief of PTS symptoms. However, there is nothing published on their use as a preventative therapy for PTS. High quality randomised controlled trials of rutoside versus any alternative intervention are required to build the evidence base in this area.

Elastic compression stockings remain the gold standard for the prevention of PTS in proximal DVT (Kolbach 2004).

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. Rutosides may be a viable option for PTS prevention, and their use would benefit from a large blinded RCT using an agreed standard definition for PTS (the Villalta Scale) and against the current gold standard intervention (ECS).

Acknowledgements

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

Data and analyses

Download statistical data

This review has no analyses.

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, and wrote the review.
Su Ern Yeoh: wrote the review
Dinanda Kolbach: selected trials, wrote the protocol, and 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 Cochrane PVD Group editorial base is supported by the Chief Scientist Office.

Differences between protocol and review

The co-primary outcomes defined in the protocol (development of oedema and development of PTS) were amended to a single primary outcome: the development of PTS. This reflects that the development of PTS includes oedema and that to develop oedema without PTS would not fulfil the objective of the review.

According to Cochrane guidelines the assessment of the quality of the trials is now described using the Cochrane risk of bias tool (Higgins 2011).

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Monreal 1997This study did not investigate the use of rutosides; it compared the use of hidrosmina (an alternative venoactive remedy) versus no treatment in the prevention of PTS.

Ancillary