Volume 36, Issue 3 , Pages 366-370, September 2008
Efficacy of Polidocanol Foam versus Liquid in Sclerotherapy of the Great Saphenous Vein: A Multicentre Randomised Controlled Trial with a 2-year Follow-up
Article Outline
- Abstract
- Introduction
- Materials and Methods
- Results
- Discussion
- Conclusion
- Acknowledgements
- References
- Copyright
Abstract
Objective
To compare the relative efficacy of polidocanol (Aetoxisclerol®, Kreussler, Germany) when used as a foam or liquid in the treatment of saphenous incompetence.
Materials and methods
Multicentre, prospective, randomised controlled trial conducted in patients with incompetence of the great saphenous vein (GSV) with a truncal diameter of 4–8
mm. The great saphenous vein was injected using a single injection 2–2.5ml of either 3% polidocanol or sclerosant foam containing one-fifth 3% polidocanol to four-fifths air (DSS technique). Clinical assessments and duplex ultrasound scanning were performed after 3 weeks and then every 6 months for 2 years. No re-injection was performed irrespective of the immediate result. The main outcome measure was elimination of GSV reflux.
Results
Ninety-five patients participated in the study, 47 were randomised to the foam sclerosant group and 48 to the liquid group. No significant difference between the 2 groups was found regarding sex, age, height, weight and saphenous vein diameter. At 3 weeks, complete elimination of reflux was obtained in 17 of the 48 patients (35%) who received liquid sclerotherapy, versus 40 of the 47 subjects (85%) in the foam group (p<0.001, Chi squared). The incidence of immediate venous spasm and the length of the sclerotic reaction, occlusion measured by echography, were significantly greater in the foam group. There was no difference in the incidence of ecchymosis, inflammatory reactions or other side effects. Follow-up of 6, 12, 18 and 24 months confirms our early results published in 2003. In total only 5 patients were lost to follow-up at 2 years (all of them were in foam group). These patients were included in the final outcome analysis as treatment failures (success rates at 2 years: 53% in foam group and 12% in liquid group).
Conclusion
The sclerosant foam used in this study was more than twice as effective as the liquid from which the foam was prepared.
Keywords: Varicose veins, Foam sclerotherapy, Polidocanol, Ultrasound guided sclerotherapy, Sclerotherapy
Introduction
In spite of interest in foamed sclerosing agents by some authors in the 1930s and 1950s,1, 2 these have only gained widespread popularity in the recent past.3, 4, 5, 6 While conventional sclerotherapy was previously used mainly for small diameter varices, large diameter veins, in particular saphenous trunks, can now be treated using ultrasound guided foam sclerotherapy.7, 8, 9, 10, 11, 12, 13, 14, 15, 16 In 2003 we published the short term results of the first randomised, prospective multicentre study comparing the efficacy of polidocanol foam to liquid sclerosant in the treatment of the great saphenous vein (GSV).13 This paper describes the 2-year follow-up results from the study.
The main aim of this research was to compare the relative efficacy of polidocanol (Aetoxisclerol®, Kreussler, Germany) when used as a foam or liquid in the treatment of saphenous incompetence. The outcome was judged by duplex ultrasound imaging to demonstrate the elimination of venous reflux in the saphenous trunk. As secondary objectives, the study examined differences in length of occlusion measured by B mode ultrasonography, the rate of recanalisation and incidence of side effects following treatment.
Materials and Methods
The methods of this trial were previously published and are be summarised as follows.
Inclusion criteria:mm inclusive (reflux greater than 1s; patient standing: manual compression of the calf, followed by release)
Exclusion criteria:
Study outline
After randomisation, patients were treated with a single echo-guided GSV injection of 3% polidocanol (Aetoxisclerol®, Kreussler, Germany) in either foam or liquid form. For veins of 4–6mm in truncal diameter, 2ml were injected; 2.5ml were injected in veins of 6–8mm. The mixture to produce the foam consisted of one part of 3% polidocanol to 4 parts of sterile air and the technique used was the DSS technique.11, 13 Patients lay supine during treatment. All injections were given under ultrasound guidance and performed using the direct puncture technique.13, 17
The injection was given at the junction between the upper and middle-third of the thigh.
No special precaution or manoeuvre was undertaken after the sclerotherapy (no elevation of the lower limb, no compression of the sapheno-femoral junction, no series of dorsiflexions by the patient). There was no special post-operative instruction regarding exercise and/or walking.
No compression was applied after the treatment; a class 2 compression stocking (15–20mmHg) was only recommended combined with paracetamol if secondary pain or inflammation developed.
Patients were seen for clinical examination and duplex ultrasound scanning after 3 weeks and then every 6 months for 2 years. The endpoint of treatment failure was considered to have been reached if venous reflux persisted in the GSV after initial treatment or recurred during the 2-year follow-up period.
The main outcome measure was elimination of saphenous reflux as assessed by duplex ultrasonography. Secondary outcome measures were the length of saphenous vein occluded by treatment assessed by B mode ultrasonography and the incidence of adverse events (painful inflammation, deep vein thrombosis, cutaneous necrosis, or any other adverse event).
Statistical analysis
Descriptors used in this study were the mean and standard deviation for quantitative variables, size and distribution for qualitative variables. Statistical significance was assessed by an ANOVA and contingency tables were analysed with a Chi squared test. Correlation between spasm and sclerotherapy results was studied and the predictive and negative values of the spasm were calculated. The 2-year follow-up of the results between foam and liquid sclerotherapy was analysed with Kaplan–Meier survival analysis. The level of statistical significance was taken to be 0.05. All data process was done with SAS software 8.2 Version.
Ethical aspects
The protocol was approved by the French Ethics Committee in Medical Research (CCPPRB – Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) of Haute Normandie on March 15, 2001. It complies with the Declaration of Helsinki (1964) according to its latest version (Hong Kong, 1989). Patients who gave informed written consent were considered for inclusion in the study.
Results
Between May 2001 and March 2002, 95 patients were included in 6 Normandy phlebology centres of whom 7 were male and 88 female; 49 right GSV and 46 left GSV. After randomisation, liquid was injected in 48 patients, 47 received foam. There were no significant differences between the groups when considering age, weight, height, ratio between sexes, diameter of saphenous vein (Table 1). Injection was immediately followed by venous spasm in 15 of the cases injected with liquid (31%) and in 31 of those injected with foam (66%) (p<0.001).
Table 1. Foam versus liquid – Hamel-Desnos. Baseline patient data in the 2 study groups
| Liquid | Foam | ||
|---|---|---|---|
| Age | 55 S.D. 16 | 54 S.D. 14 | NS |
| Weight (kg) | 66 S.D. 10 | 67 S.D.10 | NS |
| Height (cm) | 163 S.D. 5.0 | 165 S.D. 6.3 | NS |
| BMI | 25 S.D. 3.6 | 24 S.D. 3.3 | NS |
| Female (%) | 94 | 92 | NS |
| Saphenous diameter (mm) | 5.3 S.D. 1.0 | 5.5 S.D. 1.2 | NS |
3-Week follow-up
Elimination of saphenous reflux was successful in 17 of the liquid injection group (35%) and in 40 of the foam group (85%) p<0.001. The length of occluded vein measured by ultrasonography was also significantly longer in the foam group (average length=9.1cm in the liquid group versus 26cm in the foam group) (p<0.0001).
Significance of immediate venous spasm13, 18
Spasm at the time of injection was not associated with therapeutic success in the liquid group. There was, however, a strong correlation between spasm and success in the foam group p<0.0001, with a positive predictive value of 100%. In the absence of spasm, negative predictive value was poor (44%), treatment being immediately successful in more than 1 out of 2 cases.
Technical problems
In 1 case, extra vascular injection of a small quantity of foam occurred, which was without clinical repercussions.
Incidents and side effects
There were 2 immediate incidents: a vaso-vagal response which resolved without treatment and a sensation of heat in the mouth immediately following the injection. There were no additional consultations for adverse effects. At 3 weeks there were 5 cases of persistent inflammation of the thigh, 2 cases of bruising, with no difference between the 2 treatment groups. Pain was judged by the patient to be absent in 84 cases, mild in 8 cases, moderate in 1 case and serious in 2 cases, without significant differences in the 2 groups. No patient used analgesics.
Related adverse effects (N=6): 2 thrombophlebitis of the leg (with extension of sclerosis to saphenous tributaries), 1 of which was treated with compression and NSAID, and 1 with thrombectomy and compression; 1 case of asthenia lasting 15 days, which resolved without treatment; 1 case of headache on the evening of the injection, treated with aspirin; and 2 cases of pain in the thigh and knee, 8 days post-injection, which resolved without treatment. There were no cases of visual disturbance, chest symptom, deep or superficial vein thrombosis or cutaneous necrosis.
2-Year follow-up
86 patients were seen for all follow-up visits, 5 showed up for some and 5 patients dropped out. The 5 patients lost to follow-up were all in the foam group: 3 at 6 months, 1 at 1 year and 1 at 2 years.
After 3 weeks, only 17 “successes” were left in the liquid group whereas there were still 40 in the foam group; it is therefore not surprising that all patients who were lost to follow-up were in the foam group.
At 2 years, the success rates (success=no recanalisation) were 12% in the liquid group (4 patients) and 53% in the foam group (25 patients). The patients lost to follow-up were taken into account and considered as treatment failures.
Fig. 1 presents a duration curve calculated with Kaplan–Meier's method: the x-axis indicates the time (in weeks), the y-axis the probable duration of the absence of reflux (calculated according to Kaplan–Meier's method). The Log Rank test (comparing the 2 curves) shows that the 2 curves are statistically different. It can therefore be concluded that the recurrence of reflux is more frequent over time for the “liquid” group (p<0.0001).
Figure 1
Kaplan–Meier analysis of the immediate outcome of treatment and 2 years of follow-up in the 2 groups. Proportion of successful outcomes is shown on the vertical axis.
Evolution of vein diameter following recanalisation
At 6 months, recanalisation had occurred in 15 patients, 10 in the liquid and 5 in the foam group (p<0.01). In these patients, lumen diameter was on average 3.3mm while the saphenous vein had an initial average diameter of 5.4mm (reduction: 38%). Reduction in diameter was greater in the foam group (52%) than in the liquid group (28%) (N.S.).
Discussion
These 2-year follow-up outcomes confirm early results (1-year follow-up or less),13, 19, 20, 21 e.g. foam sclerosant is twice as effective as the liquid despite containing 5 times less sclerosing agent. The rate of immediate success in the foam group (85%) is relatively low when compared to the literature.7, 8, 9, 10, 12, 14, 15, 22, 23 This is probably due to the fact that in this study, treatment consisted of only a single injection small volume and no re-injection whatever the immediate result. The goal, however, was not to measure the efficacy of foam sclerotherapy, but to compare foam to liquid. Spasm at the time of injection was predictive of immediate success but the absence of spasm was a poor negative predictor.
A follow-up period of 2 years might appear short when the goal of treatment is improvement measured in tens of years. This is true for treatments such as surgery, which are meant to be definitive and where recurrences are difficult to treat. Where sclerotherapy is concerned, this thinking must be put into context. In the presence of recanalisation, diameter has decreased and the dosage used to achieve that result years earlier is known. Thus, treatment has every chance of being quick and effective and re-treatment is generally easier.
Conclusion
Use of polidocanol foam doubles the efficacy of GSV sclerotherapy over the liquid form. Treatment is quick, well tolerated and relatively stable over time. This is a viable alternative to surgery and it would appear reasonable to extend the indication to the small saphenous vein and to post-surgery recurrences. Also noteworthy is the advantageous cost/effectiveness ratio when compared to surgical or thermal endoluminal techniques, making it an excellent choice in countries where financial considerations in the treatment of varices remain problematic. Several authors have used foam made with a weaker concentration, often titrated to 1%.23, 24, 25, 26 Moreover, small volumes seem to achieve good efficacy and are recommended.27 The next step therefore would appear to be to determine dose to be injected (concentration and volume) and method of creating the foam in order to obtain the best effectiveness/tolerance ratio. According to Jia's literature review,28 more randomised controlled trials (RCTs) are necessary.
Acknowledgements
We acknowledge all the investigators: Jean-Michel Escalard MD, Didier Gangloff MD, Hervé Guenneguez MD, Bruno Mermin MD. We are extremely grateful to Professor Carpentier for his invaluable help in preparing this study and to the Scientific Advisory Committee of the French Society for Vascular Medicine (SFMV) for its support and logistic assistance.
References
- . The modern treatment of varicose veins. Med Press Circular. 1939;201:404–410
- . Etamolin foam in the treatment of varicose veins: a new method. Acta Derm Venereol. 1953;33:435–436
- . Elargissement des limites de la sclérothérapie: nouveaux produits sclérosants. Phlébologie. 1997;50:181–188
- . Traitement sclérosant des troncs saphèniens et leurs collatérales de gros calibre par la méthode MUS. Phlébologie. 1997;50:351–353
- . Nouvelle technique d'obtention de la scléro-mousse. Phlébologie. 2000;53(1):129
- . New technique in producing sclerosing foam in a disposable syringe. Dermatol Surg. 2000;26(7):705–706
- . Echosclérose par mousse de tétradécyl-sulfate de sodium et de polidocanol: deux années d'expérience. Phlébologie. 2000;53(4):431–435
- . Treatment of varicose long saphenous veins with sclerosant in micro-form foam: long term outcomes. Phlebology. 2000;15:19–23
- Polidocanol microfoam sclerotherapy for long saphenous varicose veins. Phlebology. 2001;16:41–50
- . Treatment of varicose veins by foam sclerotherapy: two clinical series. Phlebology. 2002;17:13–18
- . Nouveautés thérapeutiques dans la prise en charge de la maladie variqueuse: Echosclérothérapie et mousse. Phlébologie. 2003;56:41–48
- . Aktualler Stand der Sclerosierungtherapie von Varizen. Hautarzt. 2003;54:1065–1072
- Evaluation of the efficacy of polidocanol in the form of foam compared with liquid form in sclerotherapy of the greater saphenous vein: initial results. Dermatol Surg. 2003;29:1170–1175
- . Microfoam ultrasound guided sclerotherapy of varicose veins in 100 legs. Dermatol Surg. 2004;30:6–12
- . Microfoam UGS treatment for varicose veins in a subgroup with diameters at the junction of 10 mm or greater compared with a subgroup of less than 10 mm. Dermatol Surg. 2004;30:1386–1390
- . Chronic venous disease treated by ultrasound guided foam sclerotherapy. Eur J Vasc Endovasc Surg. 2006;32:577–583
- . L'échosclérothérapie à la mousse en 2004 – Technique de la ponction-injection directe. Phlébologie. 2004;57(3):289–300
- . Duplex scanning in the mechanism of the sclerotherapy: importance of the spasm. Phlebology. 1995;1(Suppl):574–576
- . Comparative study of duplex-guided foam sclerotherapy and duplex-guided liquid sclerotherapy for the treatment of superficial venous insufficiency. Dermatol Surg. 2004;30(5):718–722
- . A phase III study of efficacy and safety of the treatment of varicose veins with standardized Polidocanol (Aethoxysklerol) foam – ESAF study. Phlebologie. 2006;4:A36
- . Efficacy and safety of great saphenous vein sclerotherapy using standardised polidocanol foam (ESAF): a randomised controlled multicentre clinical trial. Eur J Vasc Endovasc Surg. 2008;35:238–245
- . Efficacy and safety of sclerotherapy using polidocanol foam: a controlled clinical trial. Eur J Vasc Endovasc Surg. 2006;31:101–107
- Varisolve® polidocanol microfoam compared with surgery or sclerotherapy in the management of varicose veins in the presence of trunk vein incompetence: European randomized controlled trial. Phlebology. 2006;21(4):180–190
- Outcomes and side effects of duplex-guided sclerotherapy in the treatment of great saphenous veins with 1% versus 3% polidocanol foam: results of a randomized controlled trial with 1-year follow-up. Dermatol Surg. 2007;33:276–281
- . Outcome of ultrasound-guided sclerotherapy for varicose veins: medium-term results assessed by ultrasound surveillance. Eur J Vasc Endovasc Surg. 2007;33:116–121
- Comparison of 1% and 3% polidocanol foam in ultrasound guided sclerotherapy of the great saphenous vein: a randomised, double-blind trial with 2 year-follow-up: “the 3/1 study”. Eur J Vasc Endovasc Surg. 2007;34:723–729
- . 2nd European consensus meeting on foam sclerotherapy 2006. Tegernsee, Germany: Vasa; 2008;S/713–29
- . Systematic review of foam sclerotherapy for varicose veins. Br J Surg. 2007;94:925–936
PII: S1078-5884(08)00225-6
doi:10.1016/j.ejvs.2008.04.010
© 2008 European Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
Volume 36, Issue 3 , Pages 366-370, September 2008
