Liquid versus foam sclerotherapy

Abstract

Objectives

A systematic review to compare efficacy and safety of foam (F) sclerotherapy versus liquid (L) sclerotherapy for primary varicose veins of the lower limbs.

Methods

Systematic searches of electronic databases were conducted in April 2009 to identify relevant published studies. Database searches were augmented with abstracts from conference proceedings and electronic and hand searching of journals not consistently indexed in the major databases.

Results

For treatment of saphenous veins, six trials (four randomized controlled trials) were considered. Despite containing much less sclerosing agent, F was markedly more effective compared with L, the difference being put at between 20% and 50%. Four studies were included in a meta-analysis showing efficacy of F at 76.8% (95% confidence interval [CI] 71–82) versus L at 39.5% (95% CI 33–46), χ² = 60.9740; P ≤ 0.0001.

For reticular veins and telangiectases, only two comparative trials were found and do not at present provide any conclusive evidence to support the superiority of efficacy of one form over the other.

Statistically, the side-effects reported in all the available comparative trials do not differ between F and L forms, even if visual disturbances seem to be more common with F.

Conclusion

In the treatment of varices of the lower limbs, F shows much greater efficacy compared to L. Concerning the side effects, no statistical significant differences were found between L and F.

Keywords

foam sclerotherapy liquid sclerotherapy varicose veins varices saphenous vein

Introduction

In just a few years, the world of phlebology has been taken over and seduced by foam (F) sclerotherapy. Its users seem to feel that there is no question that it is more effective than liquid (L) sclerotherapy. Is there any published evidence to support this superiority, or are we just pressing forwards on the basis of empirical practices? Bear in mind that the first randomized controlled trial of a L sclerosant compared with placebo was only published in 2004.¹

This article reviews the published clinical trials comparing results for F sclerotherapy versus L sclerotherapy in the treatment of primary varicose veins. We will try to determine whether the foam is really more effective, and if so, whether this superiority is obtained at the cost of greater side-effects.

Literature-search strategy

Systematic searches of electronic databases (MEDLINE, PubMed, EMBASE, INIST) were conducted in April 2009 to identify published comparative studies evaluating efficacy and safety of F sclerotherapy versus L sclerotherapy for venous disease. Searches were not restricted by language or publication year. Database searches were augmented with abstracts from conference proceedings and electronic and hand searching of journals not consistently indexed in the major databases (particularly Phlébologie).

Keys words consisted of: #1

Search liquid AND foam

Search sclerotherapy OR sclerosing solution* OR sclerosing agent*

Search #1 AND #2

Types of studies considered were randomized controlled trials (RCTs) and non-randomized comparative studies.

Considered studies

We divided trials into two groups depending on the type of veins treated:

Saphenous veins;

Reticular veins and telangiectases.

Saphenous veins (Table 1)

Six trials^2–8 were found, five in English, one in French.² One of them is only available in abstract form,⁴ and one other has been the subject of two publications (short-term results⁵ followed by results at two years⁶).

Table 1

Saphenous veins – F versus L comparative studies

Study	Methods	Follow-up	Vein	Number of saphenous veinsTotal 1011	Diameter	Sclero. technique	Number of permitted sessions	Max. vol. permitted	FSuccess rate (DUSc) and (95% CI)	LSuccess rate (DUSc) and (95% CI)	F production	F mix (sclerosant + gas)	Sclerosing agent	Compression after sclero.
Demagny² Phlébologie 2002	ProspectiveMonocentre	6 months	GSVSSV	300F: 150; L 150100F: 50; L: 50	<9 mm	Direct puncture	2	4 mL	67%(59–75)84%(74–94)	47%(39–55)]64%(51–77)	- Monfreux or- two-way valve connector; manual	1 + 3 (air)	STS 1.5to 3%	None
Belcaro et al. ³ Angiology 2003	ProspectiveMulticentreRCT	10 years	GSV and segments?	286F: 150;L high dose:136	NI	NI	NI	F: NIL: 3–6 mL	80%(74–86)	76%(69–83)	Irvine technique; manual	NI	STS 3%	1 or 2 W
Raymond-Martimbeau⁴ UIP abstract 2003	ProspectiveMonocentreRCT	1 year	GSVSSVOthers	14F: 11; L: 333F: 21; L: 12	NI	Direct puncture	3(mean:F: 1.3;L: 2.4)	6 mL	81%(67–95)	60%(35–85)	NI	NI	STS 1%	NI
Hamel-Desnos et al. ⁵ Dermatol Surg 2003 Ouvry et al. ⁶ EJVES 2008	ProspectiveMulticentre(6)RCTECa	1 year2 years	GSV	95F: 47; L: 48	4–8 mm	Direct puncture	1	2.5 mL	84%(74–94)53%(39–67)	40%(26–54)12%(3–21)	DSS (2-way valve connector);manual	1 + 4 (sterile air)	POL 3%	None
Yamaki et al. ⁷ Dermatol Surg 2004	ProspectiveMonocentre	1 year	GSV	77F: 37; L: 40	NI	Direct puncture	1	1 mL(+2 mL 1% POL for tributaries)	67.6%(53–83)	17.5%(6–29)	Tessari (3-way stopcock);manual	1 + 5 (air)	POL 3%	Bandagefor 48 hourThenCl 2 stock.
Rabe et al. ⁸ EJVES 2008	ProspectiveMulticentre (11)RCTECa	1 year	GSV	106F: 54; L: 52	<12 mm (mean 7.9)	Venipuncture catheter	3(mean F: 1.3; L: 1.6)	F: 5 mL (mean 3.8)L: 6 mL (mean 3.3)	69%(57–81)	27%(15–39)	Turbofoam^® (2-way valve connector);machine	1 + 4 (sterile air)	POL 3%	30 mmHgStock. for14 D.

F, foam; L, liquid; STS, sodium tetradecyl sulphate; POL, polidocanol; DSS, double syringe system; DUSc, Duplex ultraSound criterion; RCT, randomized controlled trial; ECa, Ethics Committee approval; NI, no information; GSV, great saphenous veins; SSV, small saphenous veins; CI, confidence interval

Protocols

Four^3–6,8 of the six trials were RCTs, three of them multicentre trials^3,5,8; two were approved by an Ethics Committee.^5,8 Follow-up varied from six months to 10 years, depending on the trial. For all trials, the objective was clearly to compare the efficacy of F versus L for the treated veins, except for one trial,³ which consisted of six arms that were all compared with each other, i.e. (A) sclerotherapy; (B) high-dose sclerotherapy; (C) multiple ligations; (D) stab avulsion; (E) F sclerotherapy; (F) surgery followed by sclerotherapy.

Efficacy endpoints: Duplex ultrasound data (disappearance of abnormal reflux; vein occlusion) were used as the primary endpoint in all the trials. Depending on the trials, reflux was classified as abnormal at values of >0.5 second in two trials,^7,8 one second for one trial⁵ and three seconds for one other trial.³ The information was not available for two further trials.

Secondary endpoints were refilling time (air plethysmography) in three trials^3,7,8 and one trial included data on quality of life (chronic venous insufficiency quality-of-life questionnaire, CIVIQ) and patient satisfaction.⁸

One trial also measured changes in ambulatory venous pressure, and number of recurrent or new incompetent venous sites.³ All the trials concerned the great saphenous veins (GSVs); two trials also studied the small saphenous veins (SSVs)^2,4 and one of them studied other types of varices (perforating veins and tributaries) as well.⁴

The required diameters for treated saphenous veins were given for three trials;^2,5,8 they had to be less than 9 mm for one trial,² 12 mm (mean was 7.9 mm) for another⁸ and between 4 and 8 mm inclusive for the third.⁵ The injection method was direct puncture in four trials, venipuncture with catheter⁸ in one, and not described in another.³

In most cases, foam was produced using the Tessari method⁹ (3-way stopcock) or an equivalent (2-way valve connector), except in two trials.^2,3 For these two trials, in one² the method used was either the Monfreux technique (drawing back the plunger of a sealed glass) or a two-way valve connector; the other³ used the Irvine method which uses a contrast agent.

All the methods used for foam production were manual methods, except for the Rabe trial,⁸ in which F was produced using an automatic standardized method (Easyfoam^®kit and Turbofoam^® machine). In all cases the gas used was air; in two trials the air was sterile.^5,8

The respective volumes of the components in the sclerosing agent + air mixture were 1 + 3 (1 volume of sclerosing agent + 3 volumes of air) in one trial,² 1 + 5 in another⁷ and 1 + 4 in two trials^5,8; no information was given for two trials.^3,4

All the trial protocols allowed only small injection volumes in the saphenous vein at each session, with volumes varying from 1 mL to a maximum of 6 mL, depending on the trial (amount not given for one trial³). The number of sessions permitted varied from one to three (not given for one trial³). The sclerosing agent used was sodium tetradecyl sulphate (STS) in three trials^2–4 and polidocanol (POL) in the other three.^5–8 For saphenous veins, STS was used at concentrations ranging from 1% to 3%, while POL was used only at 3%. In all trials, follow-up visits had to include clinical and Duplex ultrasound assessments.

Side-effects were mentioned in all except one trial,³ but not always described in detail.

Results

The results were presented for numbers of saphenous veins treated and 95% CIs were calculated (Table 1). A total of 1011 saphenous veins consisted of 896 GSVs and 115 SSVs.

Efficacy

According to Duplex ultrasound criteria, taking all trials together, the lowest efficacy rates were 57% for F and 12% for L, and the highest were 84% for F and 76% for L.

All results were in favour of F and the differences in efficacy rates between F and L were Demagny 20%; Belcaro 4%; Raymond-Martimbeau 21%; Hamel-Desnos 44% (short term)–Ouvry 41% (2 years); Yamaki 50.1%; and Rabe 42%.

Secondary endpoints were in agreement with these, in favour of F.

Side-effects

Overall, side-effects were rare for all the trials, and one trial even reported no side-effects.⁷ Demagny² reported five cases of visual disturbances (VD) lasting for less than two minutes, in the F group, out of 200 F procedures (2.5%); there were no VD in the L group, but one allergic skin reaction was reported.

According to Raymond-Martimbeau,⁴ side-effects (not listed in detail) were 0.2% for F and 2.4% for L.

Hamel-Desnos/Ouvry^5,6 reported few side-effects. Local reactions were rare, moderate and with no significant difference between the two groups. No neurological or respiratory effects, thrombotic events or skin necrosis were reported.

Rabe et al. ⁸ reported similar results; in this study there was no difference between the two groups. Three patients reported a metallic taste and one reported paresthesia in the L group and three patients experienced paresthesia or dysesthesia in the F group.

Reticular veins and telangiectases (Table 2)

There are fewer published data concerning comparative trials of F versus L in reticular veins and telangiectases as we only have two trials, one of which, in the French language, is a pilot study of only 20 cases for four centres.¹⁰

Table 2

Reticular and telangiectases – F versus L comparative studies

Study	Methods	Follow-up	Vein	Number of patients	Number of permitted sessions	Injected volumes	Number of injections per session	FPatients satisfactory score	LPatients satisfactory score	F production	Sclerosing agent	Compression after sclero.
Benigni et al. ¹⁰ Phlébologie 1999	ProspectiveMulticentre(4)	75 days	Reticulartelangiectases	20F: 10 L: 10	5	Mean total per patientF: 7.25 mL*L: 19.8 mL	F: 27.3L: 35.3	80%	60%	Monfreux	0.25% POL	NI
Kern et al. ¹¹ Dermatol Surg 2004	ProspectiveMonocentreRCTECa	Five weeks	Reticulartelangiectases	F: 51 L: 45	1	Max. 10 mL	60–100	60.2%(95% CI 53.7–66.7)	59.3%(95% CI 52.3–66.3)	Monfreux	0.25% POL	Elastic band or stockingFor one week

*Means that 7.25 mL of liquid sclerosant were used to make foam, no information about foam volume

F, foam; L, liquid; NI, no information; RCT, randomized controlled trial; ECa, Ethics Committee approval; POL, polidocanol

The primary objective of the second trial¹¹ was not to compare F versus L but rather to compare two sclerosing agents: chromated glycerin versus POL, in either L or F form. This Kern trial is a single-centre RCT in 96 cases of POL, with 51 patients treated with F and 45 with L.

In both studies, treatment was applied to the lateral thigh and the F was produced using the Monfreux method with 0.25% POL. Efficacy endpoints were based on a patient and investigator satisfaction score, and side-effects were assessed.

The Kern et al. ¹¹ trial also included a photographic evaluation by two experts blinded to the sclerosant used.

The Bénigni trial allowed five sessions, while Kern allowed only one.

Results

Efficacy

In the Bénigni trial, the satisfaction score was in favour of F (80% versus 60%) for both patients and experts.

There was no significant difference in median patient satisfaction scores in the Kern trial, i.e. 60.2% for F and 59.3% for L. There was also no significant difference in the expert reading scores, which were 5.71–6.24 for F and 5.26–5.67 for L.

Side-effects

Local side-effects (pigmentation, microthrombi, matting) seem to be more common with F than with L for both trials, but it was not possible to extract statistically significant values.

In the Kern trial, three patients in the F group had VD, which resolved rapidly.

Bénigni reported no neurological effects or VD.

No thrombotic events were reported in either trial.

Others

Alos et al. ¹² published an RCT comparing F versus L sclerotherapy in reticular veins and postsurgical varices with one year of follow-up. Patients acted as their own controls, with one vein treated by F and another vein, either of the same limb or the other limb, treated by L sclerotherapy. The POL F was produced using the Tessari method with room air (1 + 3). The POL concentration was lower by half for F compared with L and varied according to vein diameter. The sclerotherapy method was direct puncture.

Patients had to wear a compression stocking (25–35 mmHg) for 48 hours.

At three months, for the 75 patients in the study, the efficacy rate (ultrasound examination) was 94.4% for F versus 53% for L. No neurological or visual disorders or thrombotic events occurred. Local side-effects were more common with F. The satisfaction score was identical for the patients in both groups.

Discussion

Saphenous vein trials

First of all, it should be remembered that the primary objective of the authors of these various trials was to compare the efficacy of a sclerosing agent in both F and L forms.

The corollary of this option is that the protocols specified low doses and few sessions, or even a single session. So efficacy rates alone are not relevant; it is the difference between the two groups which is particularly important. All trials found that F was clearly superior. Excluding the Belcaro³ trial (4%), F was 20–50% superior to L.

In a 2007 literature review based on three RCTs (Belcaro et al.,³ Raymond-Martimbeau,⁴ Hamel-Desnos et al.⁵), Jia et al.¹³ wrote that the results seem to be in favour of F (RR 1.39 [95% CI 0.91–2.11]), but that heterogeneity across the studies was very high.

Since the Jia review was published, two-year results⁶ for the trial carried out by Hamel-Desnos and co-authors and the German study by Rabe and co-authors⁸ have been published.

The data from these two publications are new and important. The solidly designed Rabe trial confirms the superiority of F over L. The two-year results from the Hamel-Desnos/Ouvry trial demonstrate that the difference in efficacy persists for at least two years.

Although in 2009 available trials (Table 1) still seem to be relatively diverse, it is nevertheless true that, irrespective of the protocol used, F is always shown to be markedly superior to L in the treatment of saphenous veins.

Only the Belcaro³ trial appears to be less convincing. This was an RCT with 10-year follow-up, but interpretation of the results of this trial with six arms is complicated and contributes little for the purposes of this review. In addition, in that trial the F was produced using the Irvine method, with contrast agent. This is a method that is not widely used, and it is very different from the F production method used in other trials described here. The physical characteristics of the product thus obtained are probably closer to a sclerosing L containing bubbles than a true F.

Demagny² used two different forms of F and follow-up was six months only.

We included three RCTs (Raymond-Martimbeau,⁴ Hamel-Desnos/Ouvry,⁶ Rabe⁸) and the Yamaki⁷ the study in a meta-analysis.

Efficacy results were greatly in favour of F: F 76.8% (95% CI 71–82) versus L 39.5% (95% CI 33–46), χ² = 60.9740; P ≤ 0.0001.

Calculations including the Demagny study² also do not change the significance (χ² = 67.7271; P ≤ 0.0001).

In all these comparative trials, there were few or no side-effects, including neurological disorders, and overall there were far fewer side-effects than in the general literature on F.¹³

This may be partly explained by the use of small volumes in all the trials. Only Demagny² reports VD (2.5% of F patients). In this trial, some of the patients were treated with F produced using the Monfreux method, which does not produce microbubbles.

Is bubble size an explanation for these VD? Guex et al.¹⁴ felt that VD occurred more frequently during sclerotherapy for telangiectases, partly because the F used is of poor quality and unstable, and thus the bubble diameter is larger.

Nevertheless, in the Gillet et al.¹⁵ registry, which concerns only treatment of saphenous veins by sclerosing F (more than 1000 cases), the level of VD is 2%, i.e. not lower than the mean published level for all F studies taken together (1.4%).¹³

Trials concerning reticular veins and telangiectases

The two available trials are very different from each other and contribute little to the objectives of this review. One of them is a pilot study, and the main objective of the other was not to compare F versus L. In both studies the F was produced by the Monfreux method, using glass syringes. This method has become almost obsolete.

Nowadays practitioners tend to use the Tessari method instead or the two-way valve connector. Changes in practice should be taken into account for new trials.

Compression sclerotherapy

In accordance with the general literature on sclerotherapy, in all the trials reviewed here, compression was applied after sclerotherapy in different ways or not at all, without apparently having any effect on the efficacy results or side-effects (Tables 1 and 2).

Experts' consensus without evidence-based medicine is a temporary solution; comparative studies of compression versus non-compression are needed for an accurate determination of the expected role of compression in sclerotherapy, together with a protocol for its application.^16,17

Conclusion

In sclerotherapy for saphenous veins, the analysis of the published comparative trials found that, despite containing much less sclerosing agent, F was markedly superior to L, the difference being put at between 20% and 50%.

For reticular veins and telangiectases, comparative trials do not at present provide any conclusive evidence to support the superiority of efficacy of one form over the other.

Statistically, the side-effects reported in all the available comparative trials do not differ between F and L forms, even if VD seem to be more common with the F.

Footnotes

Acknowledgement

We would like to thank Dorothee Schliephake PhD, for her valuable and effective logistical help.

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