Injection sclerotherapy for varicose veins

Ricardo de Ávila Oliveira; Rachel Riera; Vladimir Vasconcelos; Jose CC Baptista-Silva

doi:10.1002/14651858.CD001732.pub3

Tratamiento con escleroterapia para las varices

Declaraciones de intereses de los autores

Versión publicada: 10 diciembre 2021 Historial de versiones

https://doi.org/10.1002/14651858.CD001732.pub3

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Resumen

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Antecedentes

Las varices son venas dilatadas y tortuosas que afectan hasta a un tercio de la población mundial. Pueden ser una causa de insuficiencia venosa crónica, caracterizada por edemas, pigmentación, eczema, lipodermatoesclerosis, atrofia blanca y úlceras venosas cicatrizadas o activas. La escleroterapia por inyección (líquida o de espuma) se utiliza ampliamente para el tratamiento de las varices con el objetivo de transformarlas en un cordón fibroso. Sin embargo, la evidencia sobre su efectividad y seguridad es limitada, especialmente en los pacientes con enfermedad más grave. Esta es la segunda actualización de la revisión publicada por primera vez en 2002.

Objetivos

Evaluar la efectividad y la seguridad de la escleroterapia por inyección para el tratamiento de las venas varicosas.

Métodos de búsqueda

El documentalista del Grupo Cochrane Vascular realizó búsquedas en las bases de datos del Registro especializado del Grupo Cochrane Vascular (Cochrane Vascular), en las bases de datos CENTRAL, MEDLINE, Embase, AMED, CINAHL y LILACS, así como en los registros de ensayos de la Plataforma de registros internacionales de ensayos clínicos de la Organización Mundial de la Salud y ClinicalTrials.gov hasta el 20 de julio de 2021.

Criterios de selección

Se incluyeron ensayos controlados aleatorizados (ECA) (incluidos los ensayos aleatorizados por conglomerados los ensayos cruzados de primera fase) que utilizaron la escleroterapia por inyección para el tratamiento de las varices.

Obtención y análisis de los datos

Dos autores de la revisión de forma independiente evaluaron, seleccionaron y extrajeron los datos. Las discordancias fueron cotejadas por un tercer autor de la revisión. Se utilizó la herramienta de Cochrane de riesgo de sesgo para evaluar el riesgo de sesgo. Los desenlaces de interés fueron el aspecto estético, las complicaciones, las varices residuales, la calidad de vida (CdV), la persistencia de los síntomas y las varices recurrentes. Se calcularon las razones de riesgos (RR) o la diferencia de medias (DM) con intervalos de confianza (IC) del 95%. Se utilizó el peor de los casos en la imputación de datos dicotómicos para los análisis por intención de tratar. Para los datos continuos, se usó la imputación de la última observación realizada cuando hubo pérdidas de seguimiento equilibradas. La certeza de la evidencia se evaluó mediante el método GRADE.

Resultados principales

En esta actualización se incluyeron 23 ECA nuevos, lo que proporciona un total de 28 estudios con 4278 participantes. Los estudios diferían en su diseño y en el método de escleroterapia, la sustancia o la concentración utilizadas. Ninguno de los ECA incluidos comparó la escleroterapia con ninguna intervención o con algún tratamiento farmacológico. La certeza de la evidencia se redujo por el riesgo de sesgo, los pocos estudios que proporcionan información para cada desenlace, los escasos participantes, las diferencias clínicas entre los participantes de los estudios y los IC amplios.

Escleroterapia versus placebo

La escleroterapia con espuma podría mejorar el aspecto estético medido por el IPR‐V (escala de revisión fotográfica independiente ‐ varices visibles) en comparación con el placebo (polidocanol 1%: diferencia de medias [DM] ‐0,76; IC del 95%: ‐0,91 a ‐0,60; dos estudios, 223 participantes; evidencia de certeza muy baja); sin embargo, las tasas de trombosis venosa profunda (TVP) podrían aumentar ligeramente en este grupo de intervención (RR 5,10; IC del 95%: 1,30 a 20,01; tres estudios, 302 participantes; evidencia de certeza muy baja). Las tasas de varices residuales podría disminuir tras el polidocanol 1% en comparación con el placebo (RR 0,19; IC del 95%: 0,13 a 0,29; dos estudios, 225 participantes; evidencia de certeza muy baja). Tras el uso de polidocanol 1%, podría haber una posible mejora de la CdV evaluada mediante el cuestionario VEINES‐QOL/Sym (DM 12,41; IC del 95%: 9,56 a 15,26; tres estudios, 299 participantes; evidencia de certeza muy baja), y una posible mejora de los síntomas de las varices evaluados mediante la puntuación de la Venous Clinical Severity Score (VCSS) (DM ‐3,25; IC del 95%: ‐3,90 a ‐2,60; dos estudios, 223 participantes; evidencia de certeza baja). En esta comparación no se informó sobre las varices recurrentes.

Escleroterapia con espuma versus escleroterapia con espuma con diferentes concentraciones

Tres ECA individuales no proporcionaron evidencia de una diferencia en el aspecto estético después de comparar diferentes concentraciones de la intervención; los datos no pudieron agruparse para dos de los tres estudios (RR 1,11; IC del 95%: 0,84 a 1,47; un estudio, 80 participantes; evidencia de certeza muy baja). Asimismo, no hubo diferencias claras en las tasas de complicaciones tromboembólicas al comparar una concentración de espuma con otra (RR 1,47; IC del 95%: 0,41 a 5,33; tres estudios, 371 participantes; evidencia de certeza muy baja). Tres ECA que investigaron concentraciones más altas de espuma de polidocanol indicaron que la tasa de varices residuales podría disminuir ligeramente en el grupo de espuma de polidocanol al 3% en comparación con el del 1% (RR 0,67; IC del 95%: 0,43 a 1,04; tres estudios, 371 participantes; evidencia de certeza moderada). No se detectó ninguna mejoría evidente en la CdV. Dos ECA comunicaron puntuaciones de VCSS mejores al aumentar las concentraciones de la espuma. En esta comparación no se informó sobre la persistencia de los síntomas. No hubo diferencias claras en las tasas de varices recurrentes (RR 0,91; IC del 95%: 0,62 a 1,32; un estudio, 148 participantes; evidencia de certeza baja).

Escleroterapia con espuma versus escleroterapia con líquido

Un ECA informó sobre el aspecto estético sin que haya evidencia de una diferencia entre la escleroterapia con espuma o con líquido (DM en la escala de satisfacción del paciente 0,2; IC del 95%: ‐0,27 a 0,67; un estudio, 126 participantes; evidencia de certeza muy baja). Ninguno de los ECA investigó las complicaciones tromboembólicas, la CdV ni la persistencia de los síntomas. Seis estudios mostraron por separado que podría haber un beneficio de la espuma de polidocanol 3% sobre la escleroterapia líquida en la reducción de la tasa de varices residuales; la agrupación de los datos de dos estudios mostró una RR de 0,51, con un IC del 95% de 0,41 a 0,65; 203 participantes; evidencia de certeza muy baja. Un estudio informó que no hubo diferencias claras en las tasas de varices recurrentes al comparar el tetradecilsulfato de sodio (TSS) en espuma o líquido (RR 1,10; IC del 95%: 0,86 a 1,42; un estudio, 286 participantes; evidencia de certeza muy baja).

Escleroterapia versus escleroterapia con diferentes sustancias

Cuatro ECA compararon la escleroterapia versus escleroterapia con cualquier otra sustancia. No fue posible combinar los datos debido a la heterogeneidad ni evaluar la certeza de la evidencia debido a la falta de datos.

Conclusiones de los autores

Existe evidencia de certeza muy baja a baja de que, en comparación con el placebo, la escleroterapia es un tratamiento eficaz y seguro para las varices en lo que respecta a la apariencia estética, las varices residuales, la calidad de vida y la persistencia de los síntomas. Las tasas de TVP podrían aumentar ligeramente y no hay datos sobre las varices recurrentes. Hubo evidencia limitada o nula para la comparación entre concentraciones de espuma; la espuma comparada con la escleroterapia líquida; la espuma comparada con cualquier otra sustancia; o una técnica comparada con otra. Se necesitan ensayos de alta calidad que utilicen dosis estandarizadas de esclerosante, con grupos de desenlaces básicos claramente definidos, y puntos temporales de medición para aumentar la certeza de la evidencia.

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Tratamiento con escleroterapia para las varices

Antecedentes

Las varices son venas agrandadas y abultadas, localizadas generalmente en las piernas. Pueden causar dolor, sensación de ardor, molestias y picor así como dolor generalizado, pesadez o hinchazón en las piernas. Sin embargo, algunas personas no atribuyen todos los síntomas a las varices y hay poca correlación entre estos síntomas y el grado o tamaño de las varices. La enfermedad de varices puede afectar a la calidad de vida, ya que estéticamente es poco atractiva, puede causar flebitis, hemorragias, pigmentación de la piel y úlceras.

La escleroterapia por inyección puede utilizarse para tratar las varices. La escleroterapia se consigue inyectando un líquido o una espuma irritantes en los vasos sanguíneos que transforma las varices en un cordón fibroso. Las posibles complicaciones incluyen la formación de coágulos sanguíneos, manchas en la piel, inflamación, úlceras y daño del tejido y reacciones a la sustancia esclerosante.

Esta revisión tuvo como objetivo investigar la efectividad y la seguridad de la escleroterapia al compararla con ningún tratamiento o con un tratamiento placebo (simulado); al comparar diferentes maneras de realizar la escleroterapia (incluyendo diferentes dosis, líquido versus espuma, técnicas de inyección, diferentes sustancias) o al comparar la escleroterapia con la compresión.

Características de los estudios y hallazgos clave

Se buscaron estudios relevantes y se identificaron 28 ensayos controlados aleatorizados con más de 4278 participantes (búsqueda vigente hasta el 20 de julio de 2021). Se observó la apariencia estética, las complicaciones, las tasas de varices residuales, la calidad de vida y la mejora de los síntomas relacionada con la escleroterapia. No hubo ensayos que compararan tratamiento con ninguna intervención, la escleroterapia en diferentes intervalos de tiempo ni la escleroterapia comparada con el tratamiento farmacológico.

Los resultados muestran que, comparada con el placebo, la escleroterapia podría mejorar la apariencia estética y la calidad de vida, y podría reducir las varices residuales y la persistencia de los síntomas, pero la evidencia es incierta. Las tasas de trombosis venosa profunda podrían aumentar ligeramente, pero la evidencia es incierta. No hubo datos sobre las varices recurrentes. No hubo suficiente información para concluir si una concentración de espuma fue mejor que otra, o si la espuma fue mejor que el líquido o cualquier otra sustancia; o si hubo algún beneficio de una técnica de inyección en comparación con otra.

Fiabilidad de la evidencia

La evidencia se calificó como de calidad muy baja a moderada para todos los desenlaces. La fiabilidad de la evidencia se redujo por las dudas suscitadas por el diseño de los estudios (riesgo de sesgo), los pocos estudios que proporcionan información para cada desenlace, la baja cifra de participantes, las diferencias clínicas entre los participantes de los estudios y los amplios intervalos de confianza. Se necesitan más ensayos de alta calidad que utilicen una metodología estandarizada para aumentar la confianza en los resultados.

Authors' conclusions

Implications for practice

There is a very low‐ to low‐certainty evidence that, compared to placebo, sclerotherapy is an effective and safe treatment for varicose veins concerning cosmetic appearance, residual varicose veins, QoL, and persistence of symptoms. Rates of DVT may be slightly increased and there were no data concerning recurrent varicose veins. There was limited or no evidence for one concentration of foam compared to another; foam compared to liquid sclerotherapy; foam compared to any other substance; or one technique compared to another.

Implications for research

The cost‐effectiveness of the treatment of varicose veins has significant implications for healthcare. Although there are some undesirable residual varicose veins, additional sclerotherapy sessions could be performed to resolve them (Hamel‐Desnos 2007). Sclerotherapy is a cheaper procedure when compared to any other surgical intervention for varicose veins, despite the issue of increasing costs with newer sessions; it might be the most cost‐effective treatment available (Carrol 2013). Sclerotherapy reaches veins which are impossible for treatment by other methods, so it could always be used as the main or the complementary choice of treatment. Possibly there is a dose‐response effect, and an increase in the concentrations of polidocanol foam decreased residual varicose veins up to polidocanol 3%. We do not know if increasing the polidocanol concentration even more could produce better results or if it could increase risks to patients. This question still needs to be answered with new studies.

There is a need for high‐quality RCTs with a large number of participants, with comparable CEAP clinical classification, standardised sclerosant dose, clearly defined outcomes and time points to measure. A core outcome set for varicose veins would be helpful in defining the best outcomes to be studied. Adverse events should be better evaluated, mainly for higher concentrations of polidocanol foam (e.g. 3%). There is a need for studies comparing varicose vein interventions versus no interventions to understand if the natural history of the disease is worse than the risks of the treatment.

There is a lack of RCTs using the same time point to reproduce results from cosmetic appearance after sclerotherapy. Ideally, cosmetic appearance should be evaluated after three to six months since this period is sufficient for phlebitis to disappear and to reabsorb the sclerosis material. One RCT described the same success rates at six months, with a need for new sclerotherapy sessions (Santos 2019). Probably, as described in another study, recanalisation occurrence is high and should be reviewed at six months (Hamel‐Desnos 2007). It is essential to avoid limiting the diameter of the vein studied. Instead, there should be strict criteria for varicose vein definition. We propose that only dilated, tortuous veins with loss of function are included. It is possible that a considerable number of veins treated with a low diameter and with reflux detected are not varicose veins. Greater diameter varicose veins are subject to events influencing sclerosing: 1) effect of Archimedes (greater veins depend on higher volumes to occupy the lumen); and 2) floating phenomenon (foam tends to fluctuate and treat the upper wall of the vein leaving the base untreated). These effects should be considered for a subgroup analysis using foam sclerotherapy in larger varicose veins.

Complications are rare events associated with sclerotherapy. The low number of events contributed to downgrading the certainty of the evidence. Therefore, RCTs focussing on complications should include a larger number of participants. There are complications limited to a short period of follow‐up (e.g. DVT and PE), and time points should have a rationale for those events. We propose time points for evaluating thromboembolic events up to 30 days after the last injection and between 30 days to six months. One other single source of bias is the amount of sclerosant injected in a single puncture or multiple ones. There is a lack of RCTs evaluating if the amount of sclerosant is important in ensuring the sclerosant agent reaches the deep venous system, providing a source of deep vein thrombosis. Comparing different volumes injected in each puncture could reduce the risk of including another source of bias for DVT, thrombophlebitis, and cerebrovascular complications. Skin pigmentation, on the other hand, should be better described at three, six, and 24 months since it appears later in the process and could also disappear later on.

Evidence from residual varicose veins and recurrent varicose veins is confused due to differences in definitions and time point measures. To date, the spasm frequently does not lead to venous occlusion and recanalisation is not recurrent varicose veins. So, we propose one week to one month ideally to verify residual varicose veins and occluded veins after a sclerotherapy session. After this period, it is possible to develop recurrent varicose veins. Evidence of occlusion should lead to the diagnosis of recanalisation. These aspects introduce a necessity to clarify outcomes and time points to measure them. We also understand that time intervals between sclerotherapy sessions could have a substantial impact on residual and recurrent varicose veins. Time‐interval sclerotherapy is a particularly important issue since every treatment for varicose veins may have an influence on the rate of recanalisation and pigmentation. If necessary, new sessions of sclerotherapy should be performed without increasing risk but with increments in effectiveness (Hamel‐Desnos 2007).

Despite the low number of RCTs describing quality of life, this is the critical factor for considering a varicose vein treatment. Quality of life is affected in many ways in the course of the disease. Indeed, we still need to know if different gases, substances, presentations (liquid versus foam), and many other comparisons could be the best way to treat varicose veins (e.g. using the same concentration of sclerosants which one would be the most effective to treat varicose veins?). Finally, further studies are needed to increase the number of events and so our confidence in the effect.

Different techniques, including proximal versus distal treatment sclerotherapy, need to be studied since proximal sclerotherapy could have other effects (e.g. reducing the diameter of distal varicose veins for future new sessions) and risks (e.g. DVT and PE).

There is a need for definitions of core outcome sets for varicose veins since some outcomes and the best way to measure them are still to be defined.

Summary of findings

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Summary of findings 1. Foam sclerotherapy versus placebo for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Foam sclerotherapy (polidocanol 1%) compared to placebo for varicose veins
Patient or population: participants with varicose veins^a Setting: clinical or hospital‐based study Intervention: polidocanol 1% foam sclerotherapy Comparison: placebo
Outcomes	Risk with placebo	Risk with polidocanol 1% foam sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance (IPR‐V) (Scale from: 0 to 4; 0 being the best appearance (0: none, 1: mild, 2: moderate, 3: severe, 4: very severe)) follow‐up: 8 weeks	The adjusted mean change from baseline in cosmetic appearance (IPR‐V) was ‐0.04	The MD was 0.76 lower (0.91 lower to 0.6 lower)	‐	223 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c
Complications ‐ DVT follow‐up: 8 weeks	Study population		RR 5.10 (1.30 to 20.01)	302 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e,f
Complications ‐ DVT follow‐up: 8 weeks	13 per 1000	68 per 1000 (17 to 265)	RR 5.10 (1.30 to 20.01)	302 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e,f
Residual varicose veins follow‐up: 8 weeks	Study population		RR 0.19 (0.13 to 0.29)	225 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c
Residual varicose veins follow‐up: 8 weeks	973 per 1000	185 per 1000 (127 to 282)	RR 0.19 (0.13 to 0.29)	225 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c
QoL (VEINES‐QOL/Sym; scale from: 0 to 50 with 0 being the worst and 50 better) follow‐up: 8 weeks	The mean change from baseline in QoL (VEINES‐QOL/Sym score) was 9.60	The MD was 12.41 higher (9.56 higher to 15.26 higher)	‐	299 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^f,g,h
Persistence of symptoms (VCSS) follow‐up: 8 weeks	The mean change from baseline in persistence of symptoms (VCSS score) was ‐1.14	The MD was 3.25 lower (3.9 lower to 2.6 lower)	‐	223 (2 RCTs)	⊕⊕⊝⊝ LOW ^g,h
Recurrent varicose veins	See comment		‐	‐	‐	No study evaluated recurrent varicose veins in this comparison
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT: deep vein thrombosis; IPR‐V: independent photography review ‐ visible varicose veins scores;MD: mean difference; QoL: quality of life; RCT: randomised controlled trial; RR: risk ratio; VCSS: venous clinical severity score; VEINES‐QOL/Sym: disease‐specific QoL instrument for chronic venous disorders of the leg
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^a There were CEAP C1 (11.63% in Ceulen 2007), C5 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), and C6 (Hamel‐Desnos 2007) participants included but there was no description of the proportion of these participants in the groups. Ceulen 2007 used the lower leg as the unit of analysis. In the remaining studies, the participant was the unit of analysis. ^b We downgraded the certainty of the evidence two levels as neither personnel nor participants were blinded (risk of bias concerns). ^c We downgraded one level for indirectness as Todd 2014 included 8.8% CEAP C5 and C6 in the placebo group and 3.4% CEAP C5 and C6 in the polidocanol 1% foam group. ^d We downgraded one level due to inconsistency ‐ clinical heterogeneity among studies (severity of disease). ^e We downgraded one level for imprecision due to low number of events; CI included both 'no difference' and a 'clinically important difference'. ^f We downgraded one level due to a wide CI. ^g We downgraded one level for imprecision ‐ low number of participants. ^h We downgraded one level for indirectness (8.8% CEAP C5 and C6 participants in the placebo group).

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Summary of findings 2. Foam sclerotherapy versus foam sclerotherapy for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Foam sclerotherapy (polidocanol 3%) compared to foam sclerotherapy (polidocanol 1%) for treating varicose veins
Patient or population: participants with varicose veins^a Setting: hospital or clinical setting Intervention: polidocanol 3% foam sclerotherapy Comparison: polidocanol 1% foam sclerotherapy
Outcomes	Risk with polidocanol 1% foam sclerotherapy	Risk with polidocanol 3% foam sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance (self‐described cosmetic improvement) follow‐up: mean 1 year	Study population		RR 1.11 (0.84 to 1.47)	80 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e
	675 per 1000	749 per 1000 (567 to 992)	RR 1.11 (0.84 to 1.47)	80 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e
Complications ‐ thromboembolic follow‐up: range 3 weeks to 6 months	Study population		RR 1.47 (0.41 to 5.33)	371 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^d,f,g
	16 per 1000	24 per 1000 (7 to 86)	RR 1.47 (0.41 to 5.33)	371 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^d,f,g
Residual varicose veins follow‐up: range 6 months to 2 years	Study population		RR 0.67 (0.43 to 1.04)	371 (3 RCTs)	⊕⊕⊕⊝ MODERATE ^f
	364 per 1000	244 per 1000 (156 to 378)	RR 0.67 (0.43 to 1.04)	371 (3 RCTs)	⊕⊕⊕⊝ MODERATE ^f
QoL	See comment		‐	‐	‐	No study evaluated QoL for this comparison
Persistence of symptoms	See comment		‐	‐	‐	No study evaluated persistence of symptoms for this comparison
Recurrent varicose veins follow‐up: mean 2 years	Study population		RR 0.91 (0.62 to 1.32)	148 (1 RCT)	⊕⊕⊝⊝ LOW ^c,h
Recurrent varicose veins follow‐up: mean 2 years	446 per 1000	406 per 1000 (276 to 589)	RR 0.91 (0.62 to 1.32)	148 (1 RCT)	⊕⊕⊝⊝ LOW ^c,h
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; QoL: quality of life; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aCeulen 2007 included 12.5% C1 participants. The studies included participants from C2 to C6 clinical classes without description of the proportions of C5 and C6 participants. ^b We downgraded by one level as most risk of bias domains were judged as "unclear". ^c We downgraded by one level due to imprecision ‐ single study. ^d We downgraded by one level due to imprecision ‐ wide confidence interval. ^e We downgraded by one level due to imprecision ‐ low number of participants. ^f There were CEAP C1 (11.63% in Ceulen 2007), C5 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), and C6 (Hamel‐Desnos 2007) participants included but there was no description of the proportion of these participants in the groups. Ceulen 2007) used the lower leg as the unit of analysis. In the remaining studies, the participant was the unit of analysis. We downgraded by one level for indirectness. ^g We downgraded by one level due to imprecision ‐ low number of events. ^h There were participants from C5 and C6 clinical classes included (Hamel‐Desnos 2007) but there was no description of the proportion of these participants in the groups. We downgraded by one level for indirectness.

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Summary of findings 3. Foam sclerotherapy versus liquid sclerotherapy for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Foam sclerotherapy compared to liquid sclerotherapy for varicose treating veins
Patient or population: participants with varicose veins^a Setting: hospital or clinic‐based Intervention: foam sclerotherapy using the same agent and concentration of the control Comparison: liquid sclerotherapy using the same agent and concentration of the intervention
Outcomes	Risk with liquid sclerotherapy	Risk with foam sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance (patient satisfaction scale, the higher the better) follow‐up: long‐term (365 days)	The mean cosmetic appearance of the patient satisfaction scale was 7.2	The MD was 0.2 higher (0.27 lower to 0.67 higher)	‐	126 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^a,b,c	Alos 2006 reported no difference when using polidocanol 0.75% to 1.25% foam versus polidocanol 1.5% to 2.5% liquid. Different concentrations and different vein diameters were compared, reducing our confidence in these results
Complications ‐ DVT	See comment		‐	‐	‐	No study evaluated DVT or thromboembolic events for this comparison
Residual varicose veins follow‐up: range 3 months to 2 years	Study population		RR 0.51 (0.41 to 0.65)	203 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d
	842 per 1000	429 per 1000 (345 to 547)	RR 0.51 (0.41 to 0.65)	203 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d
QoL	See comment		‐	‐	‐	No study evaluated QoLfor this comparison
Persistence of symptoms	See comment		‐	‐	‐	No study evaluated persistence of symptoms for this comparison
Recurrent varicose veins follow‐up: mean 5 years	Study population		RR 1.10 (0.86 to 1.42)	286 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^a,e,h
Recurrent varicose veins follow‐up: mean 5 years	433 per 1000	477 per 1000 (373 to 615)	RR 1.10 (0.86 to 1.42)	286 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^a,e,h
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT; deep vein thrombosis; MD: mean difference; QoL: quality of life;RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^a Did not describe randomisation method. Due to the nature of the intervention was probably impossible to blind interventionist. We did not find a protocol. Risk of bias concerns ^b Single study. We downgraded by one level for imprecision. ^c Compared different concentration of the same substances for different vein diameter. Used different concentrations of the drug if liquid or foam ^d We downgraded by one level for risk of bias concerns (query about randomisation method). ^e We downgraded by one level for risk of bias concerns (intervention was presumably not blinded (foam vs liquid) due to the nature of the intervention). ^f One study (Ouvry 2008) included participants from CEAP C2 to C6 without discriminating between them. Rabe 2008 included 1 CEAP C5 participant in the foam group (1.85%) and 4 CEAP C5 participants in the liquid group (7.69%). We downgraded by one level for indirectness. ^hBelcaro 2003b used a tensioactive substance (ultrasound contrast agent) to produce foam. This is not a standard way to produce foam. We downgraded by one level for indirectness.

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Summary of findings 4. Sclerotherapy versus sclerotherapy with different substances for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Sclerotherapy with STS 1% compared to sclerotherapy with polidocanol 1%^a
Patient or population: participants with varicose veins^b Setting: clinical or hospital‐based study Intervention: STS 1% sclerotherapy Comparison: polidocanol 1% sclerotherapy
Outcomes	Risk with polidocanol 1% sclerotherapy	Risk with STS 1% sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance follow‐up: 12 to 16 weeks	See comment		‐	‐	‐	Two RCTs compared sclerotherapy with sclerotherapy with different substances but used a range of concentrations, formulations and drug volumes. We were unable to pool the data or draw conclusions
Complications ‐ DVT follow‐up: 16 weeks to 12 months	See comment		‐	‐	‐	Two RCTs reported on DVT but we were unable to pool the data or draw conclusions
Residual varicose veins follow‐up: 12 months	See comment		‐	‐	‐	One RCT reported on residual varicose veins but we were unable to draw conclusions
QoL	See comment		‐	‐	‐	No study evaluated QoL in this comparison
Persistence of symptoms	See comment		‐	‐	‐	No study evaluated persistence of symptoms in this comparison
Recurrent varicose veins	See comment		‐	‐	‐	No study evaluated recurrent varicose veins in this comparison
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT: deep vein thrombosis; QoL: quality of life; RCT: randomised controlled trial: RR: risk ratio; STS: sodium tetradecyl sulphate
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^a Four RCTs compared sclerotherapy with sclerotherapy with different substances but used a range of concentrations, formulations and drug volumes so we were not able to pool the data (Goldman 2002; Rao 2005; Schadeck 1995a; Wright 2006). None of these compared STS 1% sclerotherapy versus sclerotherapy with polidocanol 1% which we had planned to present in this table. ^b Three studies did not describe CEAP classification of participants (Goldman 2002; Rao 2005; Schadeck 1995a). One study compared Varisolve with polidocanol 1% to any marketed sclerosant at any marketed concentration liquid or foam (Wright 2006)

Background

Description of the condition

Varicose veins are enlarged and tortuous veins. They are subcutaneous and at least 3 mm in diameter (Eklöf 2004; Hamdan 2012). It is difficult to find a satisfactory definition of varicose veins upon which consensus has been reached since reticular varicose veins can also be enlarged and tortuous. In 2012, the Vein Consult program cohort reported the epidemiology of chronic venous disease of a large international population of 91,545 adult patients' cohort across a diverse geographic area, including Europe, Latin America, the Middle East, and the Far East (Rabe 2012). Rabe and colleagues reported that 41.4% of these patients had early stage chronic venous disease (CEAP class C0s–C1) and 84% had any class of chronic venous disease greater than C0s (Rabe 2012).

There are different prevalences of varicose vein disease described around the world, depending on factors such as personal lifestyle, obesity, and age (Davies 2019).

The symptoms attributable to varicose veins, and their correlation with the extent of venous reflux (reversal of blood flow through the valves of veins during standing or sitting), are not clearly defined. Epidemiological evidence suggests that even in the presence of 'trunk' varicose veins, defined as varicose from great or short saphenous veins or their first or second order branches, most lower‐limb symptoms have a non‐venous cause (Bradbury 1999). The Edinburgh Vein Study has demonstrated superficial venous reflux in 9% of randomly selected men and 15% of women as well as deep vein reflux in 22% of men and 11% of women (Allan 2000). Subjects with visible varicose veins have a higher incidence of reflux on Duplex ultrasound, although in many cases of documented reflux, there are no visible varicose veins. There is also little correlation between symptoms of varicose veins and their extent or size on examination. However, commonly reported symptoms include local discomfort of the varicose veins (pain, burning discomfort, aching and itching), generalised lower limb symptoms (aching, heaviness, and swelling), as well as complaints about cosmetic appearance.

Swelling and night cramps are commonly reported signs and symptoms of varicose veins in pregnancy and the treatment options for pregnant women have been evaluated in another Cochrane Review (Smyth 2015; Young 1998).

Clinicians use the classification system based on clinical manifestations (C), aetiologic factors (E), anatomic distribution (A), and underlying pathophysiology (P) (Eklöf 2004).

The majority of outcome measures, following treatment of varicose veins, are assessed subjectively, i.e. symptomatic improvement, cosmetic appearance, and quality of life measures. Outcomes that can be objectively evaluated include varicose vein recurrence and complication rates.

Varicose vein treatment options include conservative treatments (stockings, lifestyle modifications, sick leave, and medications) (Hamdan 2012), and a variety of surgical interventions. Traditionally, surgery is commonly used to treat 'main stem' varicose veins (where the vein is stripped). Endovascular procedures (where the vein is treated but not stripped) include endovenous laser therapy, radiofrequency ablation therapy, and sclerotherapy. Endovenous laser therapy and radiofrequency ablation therapy use specific catheter devices to heat and cause thrombotic and fibrotic closure (Piazza 2014) damaging the endothelium and the inner media. Sclerotherapy is another endovascular procedure that aims to obliterate the varicose veins using liquid or foam preparations injected inside the lumen of the varicose vein. The option of treatment to use is driven by the patient preference for less invasive procedures, the location of the vein, the size, aetiology, and the costs of the treatment options (Carrol 2013; Hamdan 2012; Piazza 2014).

Description of the intervention

Traditionally, sclerotherapy is defined as hardening of the vein. It is carried out by a needle puncture and injection of sclerosant (a substance that cause thrombosis and fibroses of the vein leading to reabsorption and resolution of the varicose vein). Vascular surgeons and dermatologists also use sclerotherapy to treat thread veins, telangiectasias, and reticular veins. In larger veins, it involves injecting liquid or foam medicines to cause sclerosing. Foam sclerotherapy is performed by mixing the liquid sclerosant agent with air. Despite presenting similar endpoints of other treatment options (for instance, phlebectomy, laser, radiofrequency), injection sclerotherapy can treat collateral veins which are sometimes difficult to treat with laser or radiofrequency and, probably, with lower costs (Carrol 2013).

How the intervention might work

The procedure of injecting sclerosants directly into the vessel damages the varicose vein without taking it out. This damage directly affects the endothelium and media wall causing inflammation and apoptosis (cell death) in up to 300 μm of the media vein wall (Whiteley 2016). This produces a fibrous cord known as sclerosis with a functional result similar to surgery (Rabe 2010), that is, occluding the varicose vein and eliminating the reflux (O'Hare 2010).

Why it is important to do this review

Currently, varicose veins may be treated by either conventional surgery, or newer techniques such as foam sclerotherapy, endovenous laser ablation (EVLT), and radiofrequency ablation (RFA). There is limited evidence to aid choice of which treatment is more effective. This update will provide the current evidence regarding injection sclerotherapy for varicose veins to inform health policymakers, health professional and consumers.

This review is the second update of a systematic review first published in 2002 and updated in 2006.

Objectives

To assess the effectiveness and safety of injection sclerotherapy for the treatment of varicose veins.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised controlled trials (RCTs) ‐ including cluster‐randomised trials and first phase cross‐over studies ‐ that used injection sclerotherapy for the treatment of varicose veins. Quasi‐randomised controlled trials, where the method of allocation was known but not considered truly random (e.g. alternation, date of birth), were excluded (Higgins 2017a).

Types of participants

We included all participants referred to a surgical outpatient clinic or primary care practitioner with symptomatic or cosmetic varicose veins, defined by clinical and/or ultrasound criteria as follows.

Clinical criteria: CEAP C2, C3, and C4. CEAP C2 was defined as varicose veins more than 3 mm in diameter, C3 as a limb with oedema related to venous disease, and C4 as a limb with skin and subcutaneous changes (including pigmentation or eczema, and lipodermatosclerosis or atrophie blanche) related to venous disease (Eklöf 2004).
Ultrasound criteria: handheld Doppler or duplex ultrasound defining varicose veins with or without the description of the depth of the vein related to the skin.

We excluded people diagnosed as having CEAP C1 (including telangiectasias and reticular varicose veins), people with a healed venous leg ulcer (CEAP C5), and people with a venous leg ulcer (CEAP C6).

Types of interventions

We included studies which used any injection sclerotherapy technique to treat varicose veins. We considered:

Any sclerosant (e.g. sodium tetradecyl sulphate (STS), ethanolamine, polidocanol (Sclerovein, Aetoxysclerol, Aethoxysklerol, Aethoxysclerol, Atoxisclerol, Sotrauerix, Laureth 9), chrome alum (Scleremo), hypertonic saline (NaCl 17.55%);
Any formulation (e.g. liquid, foam, and gas in foam (ambient air, O₂, CO₂));
Any dosage (e.g. STS 0.2%, 0.5%, 1%, 3%, polidocanol 1%, 3%);
Using any technique (e.g. injection in empty veins, bandaging and compression techniques and repeat treatment intervals).

We included studies comparing sclerotherapy with nonsurgical interventions (no intervention, conservative treatment including pharmacological therapy and/or graduated compression stockings, or sclerotherapy). Studies which compared sclerotherapy with an open surgical procedure (e.g. stripping), other endovascular approaches (laser or radiofrequency), and studies which investigated compression after sclerotherapy were not relevant for this review. They will be covered in other Cochrane Reviews.

We included the following comparisons:

Sclerotherapy versus no intervention or no active intervention (placebo);
Sclerotherapy versus sclerotherapy (sclerosant versus different sclerosant/formulation/dose/technique);
Sclerotherapy versus different conservative treatment (including pharmacological therapy and/or graduated compression stockings when sclerotherapy was the intervention being tested). We excluded studies investigating compression after sclerotherapy treatment.

Types of outcome measures

We considered RCTs that assessed at least one of the following outcomes.

Primary outcomes

Cosmetic appearance (assessed by any validated tool)
Complications (including haematoma formation, skin pigmentation, ulceration and necrosis, superficial thrombophlebitis, thromboembolic complications (deep vein thrombosis and pulmonary embolism as defined by the authors of primary studies), and anaphylactic reaction)

Secondary outcomes

Frequency of residual varicose veins (number of veins that failed obliteration, assessed clinically and/or by ultrasound examination)
Quality of life measures (measured as any specific and validated questionnaires such as Assessment of Burden in Chronic disease – Venous (ABC‐V), VEnous INsufficiency Epidemiological and Economic Study on Quality of Life (VEINES‐QOL), Freiburg Life Quality Assessment (FLQA), Specific Quality of life and Outcomes Response – Venous (SQOR‐V), ChronIc Venous Insufficiency Questionnaire (CIVIQ), and Aberdeen Varicose Vein Questionnaire (AVVQ) (Launois 2015))
Frequency of persistence of symptoms (such as pain, burning discomfort, aching, itching, limb heaviness, oedema and nocturnal cramps)
Frequency of recurrent varicose veins and venous flare formation

We were guided by the time points reported in the individual studies.

Search methods for identification of studies

There were no restrictions on language, date, or status of publication.

Electronic searches

For this update, the Cochrane Vascular Information Specialist (CIS) first searched the following databases for relevant trials (20 July 2021):

Cochrane Vascular Specialised Register (20 July 2021);
Cochrane Central Register of Controlled Trials (20 July 2021) via the Cochrane Register of Studies Online.

See Appendix 1 for details of the search strategy used to search CENTRAL.

The CIS subsequently conducted systematic top‐up searches of the following databases for RCTs and CCTs without language, publication year or publication status restrictions:

Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web) (20 July 2021);
Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Register of Studies Online (20 July 2021);
MEDLINE (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) (20 July 2021);
Embase via Ovid (20 July 2021);
CINAHL via EBSCO (20 July 2021);
AMED via Ovid (20 July 2021);
LILACS (20 July 2021).

The CIS modelled search strategies for the listed databases on the search strategy designed for CENTRAL. Where appropriate, they were combined with adaptations of the Cochrane highly sensitive search strategy for identifying reports of randomised controlled trials and controlled clinical trials (Lefebvre 2011). Search strategies for major databases are provided in Appendix 2.

The Information Specialist also performed searches of the following trials registries on 20 July 2021:

ClinicalTrials.gov (clinicaltrials.gov);
World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch).

Searching other resources

We searched the list of references from relevant studies to identify additional studies.
We contacted pharmaceutical companies for information on any unpublished trials: Kreusller Pharma, Germany (polidocanol); BTG Pharma (polidocanol); LGM Pharma, USA (polidocanol); Shanghai T&W Pharmaceutical Co. Ltd., China (polidocanol); Omega Laboratories Limited, Montreal, Canada (hypertonic saline, polidocanol); Medeva Pharma Limited, Leatherhead, UK (ethanolamine); STD Pharmaceutical, Hereford, UK (STD).
We contacted experts in this area about further unpublished or ongoing trials.

Data collection and analysis

Selection of studies

Two review authors (RAO and VV) independently assessed the search results. First, we screened titles and abstracts (if available). Additional review authors (RR and JCBS) resolved disagreements when necessary. We read the selected, potentially relevant trials in totality to check eligibility with the inclusion criteria. We recorded explanations/justifications for studies excluded at this second phase. If necessary, we contacted study authors for further information. To facilitate transparency, we presented a flow diagram showing the full list of included and excluded studies (PRISMA), as described by Liberati 2009.

Data extraction and management

Two review authors (RAO and VV) extracted data from the included studies. We double‐checked that data were inserted correctly into the form. We used a standard form to collect the following information on study characteristics and outcome data.

Publication details (i.e. year, country, authors)
Study design and methods (inclusion/exclusion criteria, randomisation method, allocation concealment, blinding)
Setting
Population data (i.e. age, the severity of the disease, type of varicose vein)
Details of intervention (i.e. the dose of the sclerosant, technique, duration)
Outcome measures (including effectiveness and adverse effects)
The number of dropouts
Length of follow‐up
Types of data analyses (e.g. intention‐to‐treat, modified intention‐to‐treat)
Any potential risk of bias

We discussed disagreements with the involvement of a third review author (RR or JCBS) until consensus was reached. Two review authors (RAO and VV) entered data into the Review Manager 5.3 software (Review Manager 2014).

Assessment of risk of bias in included studies

We used Cochrane's Risk of bias tool for assessing the risk of bias, by evaluating the following criteria.

Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias (bias due to problems not covered in the other domains)

Two review authors (RAO and VV) independently evaluated the risk of bias for each included study. We resolved disagreements by discussion and consultation with a third review author (RR). We categorised the domains as 'high risk', 'low risk', or 'unclear risk' of bias according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017b). For the domains 'Blinding of participants and personnel,' 'Blinding of outcome assessment' and 'Incomplete outcome data,' we judged each outcome separately. Where studies did not report on an outcome, this section remained blank in the risk of bias table.

We considered the overall methodological quality of the studies as low risk if the sequence generation, allocation concealment and blinding (participants and personnel, and assessors) domains were all at low risk of bias. We considered the overall methodological quality of the studies as moderate if one of these domains was judged as being at unclear risk. Finally, we considered the overall methodological quality as 'high risk' if at least one of these domains was judged as 'high risk' of bias.

In any case of 'unclear risk' of bias, we emailed the study contact author and asked to clarify any questions. When no answer was received from the study author, the judgement was assessed as 'unclear risk' of bias.

Measures of treatment effect

We reported the results as risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes. For continuous outcomes, we expressed the results as mean differences (MDs) with 95% CIs or as the standardised mean difference (SMD) with 95% CIs if different assessment tools were used by the included studies to report the same outcome.

Unit of analysis issues

The unit of randomisation analysed in the included studies was likely to be the individual patient. In some studies, for outcomes such as complications, residual varicose veins, recurrent varicose veins, for which bilateral procedures are possible, each treated limb or varicose vein was considered as an individual unit of analysis. We presented the data for such studies only where the disparity between the units of analysis and number of randomised participants was small. If we pooled data, we performed a sensitivity analysis to examine the effects of excluding any trials with analyses that had not been corrected for this unit of analysis issue. We avoided unit of analysis issues related to repeated observations of the same outcome, such as results presented for several periods of follow‐up. If encountered, we planned to evaluate each outcome at different follow‐up periods: at the end of the treatment, at short‐term and at long‐term follow‐up (Deeks 2017).

Dealing with missing data

We emailed the study authors for additional information when there were missing, incomplete or unavailable data. We performed a search for protocols and/or further articles related to the included trials. When relevant data were unavailable, we presented and discussed the results in the main text of the review. In the case of missing data or dropouts, intention‐to‐treat analyses were conducted by imputing data which considered the worst‐case scenario for dichotomous data. We also undertook an intention‐to‐treat analysis for continuous outcomes, by imputing the 'last‐observation‐carried‐forward'. This action is justified due to the balanced loss of follow‐up that did not change results with data imputation tested by sensitivity analyses. We followed the methods described in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions using the average of two units greater than the observed data in the intervention arm and decreasing two units in the control arm (Higgins 2017a). We did not find discrepancies in the trend of effect direction. Standard deviation imputation was used in one study (King 2015) using data from another included study (Todd 2014) since there was no other source for data imputation.

Assessment of heterogeneity

We considered heterogeneity using the Chi² test and the I² statistic, which indicates the degree of variation across studies related to heterogeneity rather than related to chance. We considered an I² value greater than 50% as substantial heterogeneity (Deeks 2017). We explored clinical and methodological differences as potential causes of heterogeneity.

Assessment of reporting biases

We planned to use funnel plots to explore possible reporting biases only if there were 10 or more included studies.

Data synthesis

We synthesised data using Review Manager 5.3 software (Review Manager 2014). Varicose vein conditions are heterogeneous by nature. Considering the heterogeneity of the disease and interventions used, we have used a random‐effects model for all meta‐analyses in the review. When a meta‐analysis was not possible, data were reported to measure effect size whenever possible. In all cases, we did a descriptive analysis of the study.

As there is considerable variation in the time point measures of outcomes, a stratification into three time intervals was used to conduct a meta‐analysis. We considered a short‐term period from the intervention to up to one month, an intermediate‐term period from one month to three months, and a long‐term period that included any outcome measured after three months. This alternative was considered because some outcomes could not be appropriately measured at the short‐term period (for instance, staining) and others continued to be a risk (for instance, risks of pulmonary embolism (PE) in people with deep vein thrombosis (DVT) and superficial thrombophlebitis) (Kearon 2016).

We intended to present the results from the following comparisons:

Sclerotherapy versus no intervention or no active intervention (placebo)
Sclerotherapy versus sclerotherapy (sclerosant versus different sclerosant/formulation/dose/technique)
Sclerotherapy versus different conservative treatment (including pharmacological therapy and/or graduated compression stockings when sclerotherapy was the intervention being tested). We excluded studies investigating compression sclerotherapy after treatment.

Subgroup analysis and investigation of heterogeneity

We planned to evaluate the following subgroups if sufficient data had been available.

CEAP classification: CEAP C2 (varicose veins with no oedema or staining), CEAP C3 (varicose veins with oedema and no staining), and CEAP C4 (a limb with skin and subcutaneous changes (including pigmentation or eczema, and lipodermatosclerosis or atrophie blanche) related to venous disease) (Eklöf 2004), since we expected worse results for the higher categories.
Presence or absence of truncal incompetence: superficial venous incompetence demonstrated on Duplex ultrasound scanning, (i.e. great saphenous vein, short saphenous vein, and thigh and calf vein perforators (veins connecting superficial and deep venous systems)) and varicose veins with no evidence of superficial venous incompetence, since there is different prognosis and we expect different effects for bigger diameters.
The depth of the vein analysed assessed by Duplex ultrasound scanning: veins below 5 mm deep, and veins more than 5 mm deep, since we expected less pigmentation in deeper veins.
Symptomatic versus nonsymptomatic participants, since we expected fewer symptoms after treatment.
Sclerosant concentration for truncal incompetence (e.g. polidocanol 1% and 3%), since we expected to define the best concentration to use.
Comparison of the gas used when foam sclerotherapy (e.g. CO₂ versus ambient air), since we expected to assess if a gas was better than another one.
Previous complications (thrombophlebitis, DVT), since we expected different clinical evolution in participants with previous complications.

Sensitivity analysis

We planned the following sensitivity analyses to investigate the robustness of our findings by:

excluding studies with high risk of bias. The high risk of bias studies were defined as those presenting at least one of the following domains classified as 'high risk': selection, performance or detection;
excluding studies funded by pharmaceuticals;
excluding studies with data imputation (analysing by per‐protocol analysis).

Summary of findings and assessment of the certainty of the evidence

We created Summary of findings (SoF) tables to present the main findings of this review using GRADEpro GDT software (GRADEpro GDT 2015). We used the five GRADE criteria (risk of bias, inconsistency, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence as it related to the outcomes that contributed to the meta‐analyses. We used the methods and recommendations described in Section 8.5 (Higgins 2017b) and Chapter 12 (Schünemann 2017) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017a). We explained all judgements to downgrade the certainty of the evidence in the footnotes, and we added comments to help readers understand the judgements of the review if necessary. We included the outcomes considered to be most clinically relevant in the Summary of findings tables.

Cosmetic appearance
Thromboembolic complications
Residual varicose veins
Quality of life
Persistence of symptoms
Recurrent varicose veins

We considered the following comparisons to be of the most clinical relevance and created a SoF table for each where data were available.

Foam sclerotherapy (polidocanol 1%) versus placebo for treating varicose veins (summary of findings Table 1)
Foam sclerotherapy (polidocanol 3%) versus foam sclerotherapy (polidocanol 1%) for treating varicose veins (summary of findings Table 2)
Foam sclerotherapy versus liquid sclerotherapy for treating varicose veins (summary of findings Table 3)
Sclerotherapy with STS 1% versus sclerotherapy with polidocanol 1% for treating varicose veins (summary of findings Table 4)

Results

Description of studies

Please see Figure 1 for the search results.

Figure 1

Study flow diagram.

Results of the search

We assessed the reports identified by the searches and cross‐checked these with the reports provided by BTG Pharma. No additional studies were identified in the reports provided by BTG Pharma.

We reassessed the included and excluded studies from the previous version (Tisi 2006), as changes have been made to the inclusion criteria. See Differences between protocol and review. Four studies excluded in the previous version of the review are now included as they met the inclusion criteria (Martimbeau 2003a; Martimbeau 2003b; Wright 2006; Zeh 2003). Studies which were included in the previous version but which compared sclerotherapy with open surgery (e.g. stripping) or investigated compression after sclerotherapy were reassessed as not relevant for this update.

Included studies

We identified 23 new studies for this update (Alos 2006; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Gibson 2010; Hamel‐Desnos 2007; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Santos 2019; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009; Zhang 2014). This review includes a total of 28 RCTs (43 records), and they are described in the Characteristics of included studies tables (Abramowitz 1973; Alos 2006; Belcaro 2003b; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Gibson 2010; Goldman 2002; Hamel‐Desnos 2007; Kahle 2004; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Santos 2019; Schadeck 1995a; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009; Zhang 2014). These studies have the following characteristics.

Design: all included studies were randomised controlled trials (RCTs) with a parallel‐design intervention.
Setting
- Location of participants
  - Inpatients: seven RCTs (Abramowitz 1973; Belcaro 2003b; Chleir 1997; Demagny 2002; Kahle 2004; Wright 2006; Zhang 2014);
  - Outpatients: 10 RCTs (Alos 2006; Ceulen 2007; Goldman 2002; Hamel‐Desnos 2007; King 2015; Ouvry 2008; Rabe 2008; Santos 2019; Todd 2014; Ukritmanoroat 2011);
  - Not specified: 11 RCTs (Blaise 2010; Gibson 2010; Martimbeau 2003a; Martimbeau 2003b; Ragg 2015; Rao 2005; Schadeck 1995a; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009).
Country
- Brazil: one RCT (Santos 2019);
- Chile: one RCT (Zeh 2003);
- China: two RCTs (Zhang 2009; Zhang 2014);
- France: six RCTs (Blaise 2010; Chleir 1997; Demagny 2002; Hamel‐Desnos 2007; Ouvry 2008; Schadeck 1995a);
- Germany: three RCTs (Kahle 2004; Rabe 2008; Ragg 2015);
- Japan: two RCTs (Yamaki 2009; Yamaki 2012);
- South Africa: one RCT (Abramowitz 1973);
- Spain: one RCT (Alos 2006);
- Thailand: one RCT (Ukritmanoroat 2011);
- The Netherlands: one RCT (Ceulen 2007);
- United States of America: seven RCTs (Gibson 2010; Goldman 2002; King 2015; Martimbeau 2003a; Martimbeau 2003b; Rao 2005; Todd 2014);
- Multicentre trials involving Belgium, France, Greece, Italy, South Africa, Sweden, The Netherlands, and United Kingdom: two RCTs (Belcaro 2003b; Wright 2006).
Study duration (calculated by adding the time from start of recruitment to follow‐up duration), when described, ranged from 12 months (Yamaki 2012) to 10 years (Belcaro 2003b). The follow‐up ranged from three minutes (Schadeck 1995a) to 10 years (Belcaro 2003b).
Characteristics of the participants:
- Age
  - Nine studies did not state the age of the participants (Abramowitz 1973; Goldman 2002; Kahle 2004; Martimbeau 2003a; Martimbeau 2003b; Rao 2005; Schadeck 1995a; Zeh 2003; Zhang 2009);
  - Six described the mean age ranging from 41.9 to 59 years of age (Alos 2006; Belcaro 2003b; Chleir 1997; Demagny 2002; Gibson 2010; Ukritmanoroat 2011);
  - Twelve studies described the mean age for each intervention and control group, ranging from a minimum of 28 years to a maximum of 72 years of age (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007; King 2015; Ouvry 2008; Rabe 2008; Todd 2014; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2014);
  - One study included people older than 18 years (group A: 44.8 (SD ± 11.33), group B: 47.5 (SD ± 13.47)) (Santos 2019).
- Gender
  - Nine studies did not state the gender of the participants (Chleir 1997; Gibson 2010; Goldman 2002; Kahle 2004; Martimbeau 2003a; Martimbeau 2003b; Schadeck 1995a; Zeh 2003; Zhang 2009);
  - One study included only women (Abramowitz 1973);
  - All other studies had groups with higher proportions of women than men. The lowest proportion of women included was 60% in two groups (Ragg 2015; Zhang 2014), and the highest was 95% (Rao 2005).
- CEAP classification
  - Two studies were published before or up to the first CEAP publication (Abramowitz 1973; Schadeck 1995a). As the description of the studies matched with CEAP C2 or C3, both studies were included.
  - 13 studies did not clearly state the CEAP classification (Alos 2006; Belcaro 2003b; Chleir 1997; Demagny 2002; Gibson 2010; Goldman 2002; Kahle 2004; Martimbeau 2003a; Martimbeau 2003b; Ragg 2015; Rao 2005; Ukritmanoroat 2011; Zeh 2003). All of these studies suggested the inclusion of people with CEAP C2 and/or C3 and so were included in the review.
  - 12 studies stated the CEAP classification without discriminating between subgroups ranging from C1 to C6 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007; King 2015; Ouvry 2008; Rabe 2008; Todd 2014; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2009; Zhang 2014).
  - Two studies also allocated people with CEAP C1 (Ceulen 2007; Zhang 2009), one study included people with CEAP C2 to C5 (Ceulen 2007), and one study included people with CEAP C2 (Zhang 2009).
  - One study included only people with CEAP C3 (Santos 2019).
  - Three studies included people with CEAP C2 to C4 (Wright 2006; Yamaki 2009; Yamaki 2012).
  - The remaining seven studies included people in CEAP groups C2 to C5 or C6 (Blaise 2010; Hamel‐Desnos 2007; King 2015; Ouvry 2008; Rabe 2008; Todd 2014; Zhang 2014).
- Sample size ranged from 10 participants (Chleir 1997) to 877 participants (Belcaro 2003b).
Unit of analysis:
- 23 studies considered the individual as the unit of analysis (Abramowitz 1973; Belcaro 2003b; Blaise 2010; Gibson 2010; Goldman 2002; Hamel‐Desnos 2007; Kahle 2004; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Santos 2019; Schadeck 1995a; Todd 2014; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009; Zhang 2014);
- Two considered the lower leg (Ceulen 2007; Chleir 1997);
- Three considered the vein as the unit of analysis (Alos 2006; Demagny 2002; Ukritmanoroat 2011).
Characteristics of the interventions/comparator and comparisons:
- Injection technique: different techniques were used to inject the sclerosant. Most of them were described as traditional injection sclerotherapy where a traditional needle and syringe is used to inject the intravenous medicine. One study described the technique as one injection sclerotherapy (Gibson 2010), and four studies used a catheter to deliver the medicine (Ceulen 2007; Ragg 2015; Santos 2019; Zhang 2014). We do not believe this intervention can be considered pharmacomechanical treatment since the catheter had the sole function to deliver the drug in this case.
- Interventions and comparisons:
  - Sclerotherapy versus compression: one RCT (Abramowitz 1973);
  - Sclerosant versus placebo: five RCTs (Gibson 2010; Kahle 2004; King 2015; Todd 2014; Zhang 2009);
  - Sclerosant versus sclerosant: 23 RCTs (Alos 2006; Belcaro 2003b; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Goldman 2002; Hamel‐Desnos 2007; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Schadeck 1995a; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2014). Two of these studies (King 2015; Todd 2014) also compared sclerosant to placebo and were included in both comparator groups;
  - Foam versus liquid sclerotherapy: six RCTs (Alos 2006; Demagny 2002; Martimbeau 2003a; Ouvry 2008; Rabe 2008; Ukritmanoroat 2011);
  - Sodium tetradecyl sulphate (STS) liquid versus liquid plus foam: one RCT (Belcaro 2003b);
  - Polidocanol foam in different concentrations: five RCTs (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007; King 2015; Todd 2014);
  - Polidocanol foam 1% versus any other sclerosant liquid or foam in any concentration: one RCT (Wright 2006);
  - Single versus fractionated injection for sclerotherapy: two RCTs (Chleir 1997; Yamaki 2009);
  - Ultrasound‐guided foam sclerotherapy versus visual‐foam sclerotherapy: one RCT (Yamaki 2012);
  - Catheter directed sclerotherapy using antegrade versus retrograde approach to inject sclerosant: one RCT (Zhang 2014);
  - Injection by needle versus microcatheter and catheter: one RCT (Ragg 2015);
  - Injection by needle versus catheter deliver of the foam associated with tumescent technique:one RCT (Santos 2019);
  - STS versus polidocanol: three RCTs (Goldman 2002; Rao 2005; Schadeck 1995a);
  - Addition of perfluropropane‐filled albumin microspheres of foam STS with air filled foam STS versus polidocanol foam sclerotherapy alone: one RCT (Martimbeau 2003b);
  - Addition of low molecular weight synthetic protein (Gelufusine) to polidocanol foam versus polidocanol foam sclerotherapy alone: one RCT (Zeh 2003).
- Sclerotherapy agent and dose:
  - Four studies described the sclerotherapy agent but not the volume of sclerosant administered using polidocanol (Ceulen 2007; Zhang 2009), or polidocanol and/or STS (Goldman 2002; Schadeck 1995a);
  - 19 studies described the use of polidocanol (Alos 2006; Blaise 2010; Ceulen 2007; Gibson 2010; Hamel‐Desnos 2007; Kahle 2004; King 2015; Ouvry 2008; Rabe 2008; Ragg 2015; Santos 2019, Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009; Zhang 2014) ranging from 0.5 mL liquid (Alos 2006; Yamaki 2009), to 60 mL foam sclerotherapy (Wright 2006);
  - Seven studies used STS (Abramowitz 1973; Belcaro 2003b; Chleir 1997; Demagny 2002; Goldman 2002; Martimbeau 2003a; Martimbeau 2003b) ranging from 0.5 mL liquid (Abramowitz 1973) to up to 6 mL of foam (Belcaro 2003b);
  - One study (Rao 2005) described the use of 1 mL from the liquid form of polidocanol or STS to produce the foam in a ratio 1 to 4 to be injected.
Outcomes ‐ time points used were variable depending on the outcome to be measured. These ranged from three minutes for venous spasm (Schadeck 1995a) to 10 years for recurrent varicose veins (Belcaro 2003b). Outcomes measured are described:
- Cosmetic appearance was assessed in seven RCTs (Abramowitz 1973; Alos 2006; Ceulen 2007; Goldman 2002; King 2015; Rao 2005; Todd 2014). Abramowitz 1973 described combined outcomes of symptomatic improvement and cosmetic results quoted as good, fair, and poor results. Alos 2006 described cosmetic appearance as patient satisfaction using a scale from zero (minimum satisfaction) to ten (maximum satisfaction). Ceulen 2007 described cosmetic appearance as cosmetic improvement described by participants. Goldman 2002 and Rao 2005 described cosmetic appearance as disappearance scale and satisfaction scale ranging from 1 (worse than before treatment) to 5 (complete disappearance). Rao 2005 pooled results as tolerability and satisfaction. King 2015 and Todd 2014 described by IPR‐V (Independent photography review: Visible Varicose veins; scale: 0 to 4; 0 being the best appearance (0: none, 1: mild, 2: moderate, 3: severe, 4: very severe)) and PA‐V (patient self‐assessment of visible varicose veins);
- At least one complication was described in 23 studies (Abramowitz 1973; Alos 2006; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Goldman 2002; Hamel‐Desnos 2007; Kahle 2004; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Santos 2019; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2014);
- Residual varicose veins were assessed in 25 studies (Alos 2006; Belcaro 2003b; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Gibson 2010; Hamel‐Desnos 2007; Kahle 2004; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Santos 2019; Schadeck 1995a; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009; Zhang 2014);
- Recurrent varicose veins were described in six studies (Belcaro 2003b; Blaise 2010; Martimbeau 2003a; Martimbeau 2003b; Yamaki 2009; Yamaki 2012);
- Quality of life (QoL) was measured in six studies (Blaise 2010; Gibson 2010; King 2015; Rabe 2008; Santos 2019; Todd 2014). Blaise 2010 and Rabe 2008 used the CIVIQ questionnaire (using a five‐point Likert scale in the items) to score QoL. Gibson 2010 used the modified venous insufficiency epidemiological and economic study QoL/symptoms (m‐VEINES‐QOL/Sym), Heavy legs, Achy legs, Swelling, Throbbing, and Itching (HASTI) questionnaire, and the chronic venous insufficiency questionnaire 2 (CIVIQ‐2). King 2015 used the modified venous insufficiency epidemiological and economic study QoL/symptoms (m‐VEINES‐QOL/Sym). Todd 2014 used the venous insufficiency epidemiological and economic study score (VEINES‐QOL). Santos 2019 used Aberdeen Varicose Vein Questionnaire (AVVQ);
- Persistence of symptoms were described in seven studies (Abramowitz 1973; Ceulen 2007; Chleir 1997; Gibson 2010; King 2015; Todd 2014; Yamaki 2012). King 2015, Todd 2014 and Yamaki 2012 used venous clinical severity score (VCSS). Gibson 2010 used Veines‐QOL/Sym and Abramowitz 1973, Ceulen 2007 and Chleir 1997 reported this as 'clinical improvements'; and
- 18 other studies described sclerosis or occlusion or venous shrinkage or venous spasm (Alos 2006; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Gibson 2010; Hamel‐Desnos 2007; Kahle 2004; Ouvry 2008; Rabe 2008; Ragg 2015; Schadeck 1995a; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2014). The outcomes were evaluated by duplex ultrasound.

Excluded studies

We excluded a total of 13 studies from this review update as they investigated sclerotherapy versus an intervention other than nonsurgical interventions (that is, no intervention, conservative treatment including pharmacological therapy and/or graduated compression stockings, or sclerotherapy) (Ariyoshi 1996; Biemans 2013; Brittenden 2015; Lattimer 2012; Leung 2016; Mishra 2016; NCT02462720; Ragg 2015a; Rasmussen 2011; Theivacumar 2008; Vahaaho 2015; Vernermo 2016; Zafarghandi 2017). See the Characteristics of excluded studies tables.

Studies which investigated compression after sclerotherapy or compared sclerotherapy with open surgery (e.g. stripping), other endovascular techniques (endolaser or radiofrequency), and compression therapy were assessed as not relevant as they clearly did not meet the inclusion criteria (Criteria for considering studies for this review).

Ongoing studies

We did not identify any ongoing studies.

Awaiting classification

Five studies were assessed as 'awaiting classification' as in all cases we were unable to contact authors and there was a lack of information to include or exclude them (Labas 2003; Satokawa 2003; Schadeck 1995b; SLCTR/2008/014; Varnagy 1985). In two of these studies, there was limited information (intervention groups were not clear) (Satokawa 2003; Schadeck 1995b). Labas 2003 was included in the previous version of the review, and Schadeck 1995b was excluded in the previous version of the review. On reassessment, we did not find sufficient information to either include or exclude these two studies. We are not sure if one study is a randomised or quasi‐randomised trial (Varnagy 1985). Should further information be provided, we will include these studies in future updates.

Risk of bias in included studies

Two review authors (RAO, VV) independently assessed the included studies for risk of bias following the recommendations in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2017a). Any disagreements were resolved by a third author (RR) in consensus with the group. Details of the risk of bias judgements can be found in the Risk of bias tables, within the Characteristics of included studies tables. A graphical presentation of the risk of bias is shown in Figure 2. For the domains of 'Blinding of participants and personnel', 'Blinding of outcome assessment', and 'Incomplete outcome data' we have also assessed each study by outcome. We have also distinguished between studies comparing intervention versus intervention and intervention versus placebo as we believe this can impact the risk of bias. Not all studies reported on all outcomes and those sections were left blank where appropriate in the tables.

Figure 2

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

Allocation

Random sequence generation

The randomisation sequence generation was rated as low risk in 10 RCTs (Belcaro 2003b; Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007; King 2015; Rabe 2008; Santos 2019; Todd 2014; Yamaki 2009; Yamaki 2012) and unclear risk for 18 RCTs (Abramowitz 1973; Alos 2006; Chleir 1997; Demagny 2002; Gibson 2010; Goldman 2002; Kahle 2004; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Ragg 2015; Rao 2005; Schadeck 1995a; Ukritmanoroat 2011; Wright 2006; Zeh 2003; Zhang 2009; Zhang 2014).

Allocation concealment

One RCT described opening the study randomisation code after deciding the intervention and was judged as having high risk of allocation concealment (Belcaro 2003b). None of the remaining RCTs described allocation concealment, so all were judged as having unclear risk of bias.

Blinding

Performance bias

Cosmetic appearance (assessed by any tool)

Seven RCTs reported on this outcome (Abramowitz 1973; Alos 2006; Ceulen 2007; Goldman 2002; King 2015; Rao 2005; Todd 2014). Four were judged to be at low risk of bias because the blinding of participants and personnel was described and considered appropriate (Goldman 2002; King 2015; Rao 2005; Todd 2014). Two were judged to be at unclear risk because they did not describe the blinding method making judgement impossible (Abramowitz 1973; Ceulen 2007), and one was judged to be at high risk of bias because the nature of the intervention precluded blinding (Alos 2006). Two RCTs compared sclerosant with sclerosant and with placebo (King 2015; Todd 2014). They were considered as being at high risk of bias when any comparison was made with placebo since, due to the nature of the intervention, it was impossible to blind the placebo group (placebos had different physical appearance). We added columns in the Risk of bias table to describe the risk of bias of these RCTs comparing intervention versus intervention and intervention versus placebo.

Complications (at least one of the following complications: haematoma formation, skin pigmentation, ulceration and necrosis, superficial thrombophlebitis, deep vein thrombosis and anaphylactic reaction)

Twenty‐three RCTs reported on this outcome (Abramowitz 1973; Alos 2006; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Goldman 2002; Hamel‐Desnos 2007; Kahle 2004; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Santos 2019; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2014). Seven were judged as being at low risk of bias since blinding of participants and personnel was described, and we judged it as appropriate (Blaise 2010; Goldman 2002; Hamel‐Desnos 2007; Kahle 2004; King 2015; Rao 2005; Todd 2014). Seven RCTs were judged to be at unclear risk of bias because they did not describe the blinding method (Abramowitz 1973; Ceulen 2007; Chleir 1997; Demagny 2002; Martimbeau 2003a; Martimbeau 2003b; Zhang 2014). Nine RCTs were judged as being at high risk of bias as the nature of the intervention precluded blinding (Alos 2006; Ouvry 2008; Rabe 2008; Ragg 2015; Santos 2019; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012). As above, two RCTs were considered as having high risk of bias when any comparison was made with placebo (King 2015; Todd 2014).

Residual varicose veins (veins that failed obliteration, assessed clinically and/or by ultrasound examination)

Twenty‐five RCTs reported on this outcome (Alos 2006; Belcaro 2003b; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Gibson 2010; Hamel‐Desnos 2007; Kahle 2004; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Santos 2019; Schadeck 1995a; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009; Zhang 2014). Five studies described properly the blinding of participants and personnel and were judged to be at low risk of bias (Blaise 2010; Hamel‐Desnos 2007; Kahle 2004; King 2015; Todd 2014). Nine studies were considered to be at unclear risk of bias because they did not describe the blinding method despite it being possible to blind due to the nature of the procedure (Belcaro 2003b; Ceulen 2007; Chleir 1997; Demagny 2002; Martimbeau 2003a; Martimbeau 2003b; Schadeck 1995a; Zeh 2003; Zhang 2014). Eleven RCTs were judged as being at high risk of bias (Alos 2006; Gibson 2010; Ouvry 2008; Rabe 2008; Ragg 2015; Santos 2019; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2009). For ten of these RCTs, it was considered impossible to blind due to the nature of the intervention (Gibson 2010; Ouvry 2008; Rabe 2008; Ragg 2015; Santos 2019; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2009). One RCT was described as blinded but the method was not described. We believe that the nature of the intervention precluded blinding when comparing foam versus liquid sclerotherapy since even a small amount of the sclerosant may flow back to the injection site (Ragg 2015). One RCT described blinding of the patient and ultrasonograph professional. We believe that the nature of the intervention (foam versus liquid) precluded blinding of the interventionist and the ultrasonography professional (Alos 2006). As before, King 2015 and Todd 2014 were considered as being at high risk of bias when any comparison was made with placebo.

Recurrent varicose veins and venous flare formation

Six RCTs reported on this outcome (Belcaro 2003b; Blaise 2010; Martimbeau 2003a; Martimbeau 2003b; Yamaki 2009; Yamaki 2012). One study was judged to be at low risk of bias because it described blinding of participants and personnel and it seemed to be appropriate (Blaise 2010). Three were judged to be at unclear risk of bias because they did not state the blinding method (Belcaro 2003b; Martimbeau 2003a; Martimbeau 2003b). Two RCTs were considered to be at high risk of bias since the nature of the intervention precluded any blinding (Yamaki 2009; Yamaki 2012).

Quality of life (using any specific, validated questionnaire)

Six RCTs reported on this outcome (Blaise 2010; Gibson 2010; King 2015; Rabe 2008; Santos 2019; Todd 2014). Three of them were judged to be at low risk of bias because they described blinding of participants and personnel and it seemed to be appropriate (Blaise 2010; King 2015; Todd 2014). As before, King 2015 and Todd 2014 were considered as being at high risk of bias when any comparison was made with placebo. Three RCTs were considered to be at high risk of bias since it was impossible to blind personnel due to the nature of the procedure (Gibson 2010; Rabe 2008; Santos 2019).

Frequency of persistence of symptoms

Seven RCTs reported on this outcome (Abramowitz 1973; Ceulen 2007; Chleir 1997; Gibson 2010; King 2015; Todd 2014; Yamaki 2012). Two of these studies were considered to be at low risk of bias since blinding of participants and personnel was described and seemed to be appropriate (King 2015; Todd 2014). Three studies were considered to be at unclear risk of bias since they did not state who was blinded or how the blinding was carried out (Abramowitz 1973; Ceulen 2007; Chleir 1997). Two studies were judged to be at high risk of bias due to the nature of the intervention preventing blinding of personnel (Gibson 2010; Yamaki 2012).

Detection bias

Cosmetic appearance (assessed by any tool)

From the seven RCTs reporting on this outcome (Abramowitz 1973; Alos 2006; Ceulen 2007; Goldman 2002; King 2015; Rao 2005; Todd 2014), five RCTs were judged as being at low risk of bias since they described blinding the outcome assessment, and it seemed to be appropriate (Alos 2006; Goldman 2002; King 2015; Rao 2005; Todd 2014). Two RCTs did not describe the blinding of the assessors of the outcomes. We had no data to judge if they did or not. So, we judged the RCTs as having unclear risk of bias (Abramowitz 1973; Ceulen 2007).

Complications (at least one of the following complications: haematoma formation, skin pigmentation, ulceration and necrosis, superficial thrombophlebitis, deep vein thrombosis and anaphylactic reaction)

Twenty‐three RCTs reported on this outcome, and ten studies were judged as having low risk of bias since they described the blinding of the outcome assessment and it seemed to be appropriate (Alos 2006; Blaise 2010; Goldman 2002; Hamel‐Desnos 2007; King 2015; Rao 2005; Todd 2014; Ukritmanoroat 2011; Yamaki 2009; Yamaki 2012). Ten studies were judged as having unclear risk of bias since the authors did not include any text which enabled us to make an assessment. We preferred to judge them as having unclear risk of bias since some studies could have undertaken this task (Abramowitz 1973; Ceulen 2007; Chleir 1997; Demagny 2002; Kahle 2004; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Ragg 2015; Zhang 2014). Three studies were declared as non‐blinded studies and were judged as having high risk of bias (Rabe 2008; Santos 2019; Wright 2006).

Residual varicose veins (veins that failed obliteration, assessed clinically and/or by ultrasound examination)

Twenty‐five studies reported on this outcome. Eight studies were judged as having low risk of bias since they described blinding of the outcome assessment and it seemed to be appropriate (Alos 2006; Blaise 2010; Hamel‐Desnos 2007; King 2015; Todd 2014; Ukritmanoroat 2011; Yamaki 2009; Yamaki 2012). Fourteen studies did not describe any kind of the blinding of assessment (Belcaro 2003b; Ceulen 2007; Chleir 1997; Demagny 2002; Gibson 2010; Kahle 2004; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Ragg 2015; Schadeck 1995a; Zeh 2003; Zhang 2009; Zhang 2014). As we were not sure about the method, we judged these studies as having unclear risk of bias. Three studies were judged as having high risk of bias (Rabe 2008; Santos 2019; Wright 2006). One study stated that it was impossible to perform a 'double‐blind' study (Rabe 2008). The second study was described as an 'open‐label' study (Wright 2006). We decided to judge these as having high risk of bias as we had no response from the authors for further information. One study was reported as an unblinded study for the outcome assessment (Santos 2019).

Recurrent varicose veins and venous flare formation

Six studies reported on this outcome; three studies were judged as having low risk of bias since they described the blinding of outcome assessors and it seemed to be appropriate (Blaise 2010; Yamaki 2009; Yamaki 2012), and three studies were judged as having unclear risk of bias since they did not state any blinding for outcome assessment (Belcaro 2003b; Martimbeau 2003a; Martimbeau 2003b).

Quality of life (using any specific, validated questionnaire)

Six RCTs reported on this outcome. Three studies were judged as having low risk of bias as the authors described assessment blinding, and it seemed to be appropriate (Blaise 2010; King 2015; Todd 2014), and two RCTs were judged as having unclear risk of bias since they did not mention blinding of the assessors of the outcomes (Gibson 2010; Rabe 2008). One study was described as not being able to undertake double‐blinding (Rabe 2008). We believe that, even in this case, the blinding of outcome assessment was possible and we judged it as having high risk of bias. One RCT reported outcome assessors were unblinded and was judged as having high risk of bias (Santos 2019).

Frequency of persistence of symptoms

Seven RCTs reported on this outcome. Three studies were judged as having low risk of bias since the authors described blinding of outcome assessment and it seemed to be appropriate (King 2015; Todd 2014; Yamaki 2012), and four RCTs were judged as having unclear risk of bias since they did not describe any blinding of the assessors (Abramowitz 1973; Ceulen 2007; Chleir 1997; Gibson 2010).

Incomplete outcome data

Cosmetic appearance

Seven studies reported on this outcome (Abramowitz 1973; Alos 2006; Ceulen 2007; Goldman 2002; King 2015; Rao 2005; Todd 2014). Five were judged to be at low risk of bias because they described all proposed outcomes and there was no indication of incomplete outcome data (Alos 2006; Goldman 2002; King 2015; Rao 2005; Todd 2014). One study had 50% of dropouts in the control group and was judged as having unclear risk of bias (Abramowitz 1973). One study was judged to be at unclear risk because there was no description of the dropouts (Ceulen 2007). No study was judged to be at high risk of bias.

Complications

Twenty‐three RCTs reported on this outcome (Abramowitz 1973; Alos 2006; Blaise 2010; Ceulen 2007; Chleir 1997; Demagny 2002; Goldman 2002; Hamel‐Desnos 2007; Kahle 2004; King 2015; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Santos 2019; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2014). Thirteen were considered to be at low risk of bias because they reported all the proposed outcomes, there were a low number of dropouts (less than 20%), and so were considered as appropriate (Alos 2006; Blaise 2010; Chleir 1997; Kahle 2004; King 2015; Ouvry 2008; Rabe 2008; Rao 2005; Santos 2019; Todd 2014; Yamaki 2009; Yamaki 2012; Zhang 2014). Eight RCTs were judged to be at unclear risk of bias due to lack of dropout data to judge (Ceulen 2007; Demagny 2002; Goldman 2002; Hamel‐Desnos 2007; Martimbeau 2003a; Martimbeau 2003b; Ragg 2015; Ukritmanoroat 2011), one RCT had 50% of dropouts in the control group and was judged as having unclear risk of bias (Abramowitz 1973), and one RCT was considered to be at high risk of bias because six participants in the intervention group were removed by the sponsor and reasons for that were not clear to us (Wright 2006).

Residual varicose veins

Recurrent varicose veins and venous flare formation

Six RCTs reported on this outcome (Belcaro 2003b; Blaise 2010; Martimbeau 2003a; Martimbeau 2003b; Yamaki 2009; Yamaki 2012). Four RCTs were considered to be at low risk of bias since participants were described and reasons for dropouts reported (Belcaro 2003b; Blaise 2010; Yamaki 2009; Yamaki 2012). Two RCTs provided data in pooled percentages, we were not able to use it to determine the impact of data in the study, and they did not describe dropouts, so were considered to be at unclear risk of bias (Martimbeau 2003a; Martimbeau 2003b).

Quality of life

Six RCTs reported on this outcome and all of them were judged as being at low risk of bias because all studies reported numbers and reasons for dropouts (Blaise 2010; Gibson 2010; King 2015; Rabe 2008; Santos 2019; Todd 2014).

Frequency of persistence of symptoms:

Seven RCTs reported on this outcome (Abramowitz 1973; Ceulen 2007; Chleir 1997; Gibson 2010; King 2015; Todd 2014; Yamaki 2012). Five RCTs were considered to be at low risk of bias since they described numbers and reasons for dropouts (Abramowitz 1973; Gibson 2010; King 2015; Todd 2014; Yamaki 2012). Two RCTs were judged to be at high risk of bias because they did not describe dropouts, and we did not know how this could impact results (Ceulen 2007; Chleir 1997).

Selective reporting

Seven RCTs were judged as being at low risk of reporting bias since the protocol was available and reporting was done according to what was planned (Belcaro 2003b; Blaise 2010; Gibson 2010; Hamel‐Desnos 2007; King 2015; Santos 2019; Todd 2014). None of the remaining RCTs provided a protocol. These RCTs were judged as being at unclear risk of bias (Abramowitz 1973; Alos 2006; Ceulen 2007; Chleir 1997; Demagny 2002; Goldman 2002; Kahle 2004; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Rao 2005; Schadeck 1995a; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zeh 2003; Zhang 2009; Zhang 2014).

Other potential sources of bias

It is estimated that an increase of 48% of size effect occurs in RCTs with fewer than 50 participants (Dechartres 2013). So we graded included studies with fewer than 50 participants as having unclear risk of bias since we could not estimate the impact of such studies in a systematic review and a meta‐analysis. We also considered the diameter chosen to be sclerosed. If there was restriction in the vein diameter, external validity would not be applicable to all varicose vein diameters. When there was no imbalance between intervention and control groups and these previous aspects were observed, the studies were judged as having low risk of other bias. Nine RCTs were therefore classified as having low risk (Alos 2006; Belcaro 2003b; Blaise 2010; Hamel‐Desnos 2007; King 2015; Rabe 2008; Todd 2014; Yamaki 2009; Yamaki 2012). All remaining RCTs were judged as having unclear risk as 12 studies had fewer than 50 participants (Abramowitz 1973; Ceulen 2007; Gibson 2010; Goldman 2002; Kahle 2004; Ouvry 2008; Ragg 2015; Rao 2005; Santos 2019; Schadeck 1995a; Zeh 2003; Zhang 2014). Nine RCTs did not describe baseline characteristics (Abramowitz 1973; Chleir 1997; Demagny 2002; Gibson 2010; Goldman 2002; Ragg 2015; Rao 2005; Schadeck 1995a; Ukritmanoroat 2011); one RCT described imbalances between groups (Ceulen 2007); two RCTs provided insufficient data to judge any imbalance between groups (Wright 2006; Zhang 2014); one RCT provided insufficient data to evaluate (Zhang 2009); and two RCTs did not provide any data regarding the baseline characteristics (Martimbeau 2003a; Martimbeau 2003b).

Effects of interventions

See: Summary of findings 1 Foam sclerotherapy versus placebo for treating varicose veins; Summary of findings 2 Foam sclerotherapy versus foam sclerotherapy for treating varicose veins; Summary of findings 3 Foam sclerotherapy versus liquid sclerotherapy for treating varicose veins; Summary of findings 4 Sclerotherapy versus sclerotherapy with different substances for treating varicose veins

Sclerotherapy versus no intervention or placebo

Comparison 1: Sclerotherapy versus no intervention

None of the included RCTs compared sclerotherapy with no intervention.

Comparison 2: Foam sclerotherapy versus placebo

Five RCTs compared sclerosant with placebo (Gibson 2010; Kahle 2004; King 2015; Todd 2014; Zhang 2009). One study did not provide sufficient data regarding the number of participants included in each group or details on the concentration of polidocanol used, so we could not include it in the analysis (Zhang 2009). One study referred to the use of polidocanol 2% or 3% (Kahle 2004). As the concentrations of polidocanol were different from the other studies, the data were not used in meta‐analysis. We have chosen polidocanol 1% foam to compare with placebo because one study considered this concentration to be necessary to achieve good sclerotherapy results (King 2015). We understand this concentration is clinically relevant for foam sclerotherapy. As described in Data synthesis, we decided to use short‐, intermediate‐, and long‐term time periods according to the moment of the outcome measurement (up to one month, one to three months, and after three months, respectively). There were no available data to perform subgroup analysis by CEAP classification, presence or absence of truncal incompetence, depth of the vein, symptomatic versus nonsymptomatic participants, and previous complications (thrombophlebitis, DVT). Subgroup analysis from different foam concentrations was performed in the comparator 'Sclerotherapy versus sclerotherapy' in the subgroup of 'Foam sclerotherapy versus foam sclerotherapy with different concentrations' due to the importance of the issue. Care was taken to prevent double counting. Due to limitations in the blinding due to the nature of the intervention, all studies were at high risk of bias for participants and personnel. See summary of findings Table 1.

Cosmetic appearance

Two RCTs reported on this outcome, both at intermediate‐term periods (King 2015; Todd 2014). Cosmetic appearance was reported using independent photography review ‐ visible varicose veins scores (IPR‐V) or using patient self‐assessment of visible varicose veins scores (PA‐V). In both cases, there was a possible benefit in favour of foam sclerotherapy if polidocanol 1% or 2% foam was used: polidocanol 1%: IPR‐V mean difference (MD) ‐0.76, 95% CI ‐0.91 to ‐0.60; 2 studies, 223 participants; very low‐certainty evidence; polidocanol 2%: IPR‐V MD ‐0.90, 95% CI ‐1.11 to ‐0.69; 1 study, 119 participants; (Analysis 1.1); polidocanol 1%: PA‐V MD ‐1.46, 95% CI ‐1.72 to ‐1.20; 2 studies, 223 participants; and polidocanol 2%: PA‐V MD ‐1.60, 95% CI ‐1.95 to ‐1.25; 1 study, 119 participants; (Analysis 1.2) (see summary of findings Table 1). We have chosen IPR for grading the evidence since it is independent of participants and personnel. We downgraded the certainty of the evidence due to risk of bias concerns and indirectness (Todd 2014 included 8.8% CEAP C5 and C6 participants in the placebo group compared to 3.4% CEAP C5 and C6 participants in the polidocanol 1% group).

Complications

Four RCTs reported on complications including DVT, phlebitis or thrombophlebitis, haemorrhagic and neurologic complications (Gibson 2010; Kahle 2004; King 2015; Todd 2014). We assessed the outcome of DVT using the GRADE approach due to severity of the conditions related to this event.

Deep vein thrombosis rates may be increased following polidocanol 1% in the short and intermediate term (RR 5.1, 95% CI 1.3 to 20.01; 3 studies, 302 participants; very low‐certainty evidence) (Analysis 1.3). We downgraded the certainty of the evidence due to risk of bias concerns, indirectness, inconsistency and imprecision (see summary of findings Table 1).

Polidocanol foam may increase phlebitis or thrombophlebitis rates. The lowest number of cases of phlebitis or thrombophlebitis were found in the placebo group compared with the polidocanol foam group during the intermediate‐term periods (e.g. for polidocanol ≥ 1% foam: RR 3.12, 95% CI 1.1 to 8.83; 3 studies, 302 participants) (Analysis 1.4; Analysis 1.5).

Haematoma formation was described as a haemorrhagic complication. There were no clear differences in haemorrhagic outcomes between polidocanol foam and placebo in the short term (polidocanol 1%: RR 1.83, 95 CI 0.75 to 4.47; 3 studies, 302 participants) (Analysis 1.6).

There was no evidence of a difference in neurological complication rates between 1% or more concentrated polidocanol foam and placebo at the short term (polidocanol 1%: RR 1.03, 95 CI 0.22 to 4.91; 3 studies, 302 participants) (Analysis 1.7). Gibson 2010 used a different gas mixture (Varithena) in which there is a low proportion of nitrogen aiming to reduce cerebral side effects. A case of transient ischaemic attack was reported on day 13 and could not be related to the intervention. As the gas concentrations were different, we conducted a sensitivity analysis that did not change the effect direction. Aiming to evaluate whether the polidocanol foam concentration could change complication rates, we performed subgroup analysis comparing different concentrations of polidocanol foam (see the comparison 'Sclerotherapy versus sclerotherapy' in the analysis of 'Foam sclerotherapy versus foam sclerotherapy with different concentrations').

Residual varicose veins

Five RCTs reported on this outcome (Gibson 2010; Kahle 2004; King 2015; Todd 2014; Zhang 2009). Residual varicose vein rates may be decreased in the 1% or more polidocanol foam group than in the placebo group (for polidocanol 1% foam: RR 0.19, 95% CI 0.13 to 0.29; 2 studies, 225 participants; very low‐certainty evidence) (Analysis 1.8) at an intermediate‐term period. We downgraded the certainty of the evidence due to risk of bias concerns and indirectness (Todd 2014 included 8.8% CEAP C5 and C6 participants in the placebo group and 3.4% CEAP C5 and C6 participants in the polidocanol 1% group).

Quality of life

Three RCTs reported on this outcome (Gibson 2010; King 2015; Todd 2014). Quality of life (QoL) was measured using QoL adjusted mean change VEINES‐QOL/Sym (Gibson 2010; King 2015; Todd 2014) in polidocanol foam versus placebo (for polidocanol 1%: MD 12.41; 95% CI 9.56 to 15.26; 3 studies, 299 participants; very low‐certainty evidence) (Analysis 1.9), showing a possible improvement in the QoL in the foam group. Although King 2015 did not describe standard deviations, we used standard deviations from Todd 2014 to perform the meta‐analysis following recommendations for standard deviation data imputation from Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017c). The certainty of the evidence was downgraded due to wide confidence intervals, low number of participants, and indirectness (participants with CEAP C5 and C6 included in the studies). Gibson 2010 used a different gas mixture (Varithena) in which there is a low proportion of nitrogen aiming to reduce cerebral side effects. A sensitivity analysis did not show any difference in effect.

Frequency of persistence of symptoms

Three RCTs reported on this outcome (Gibson 2010; King 2015; Todd 2014). Persistence of symptoms was evaluated by Gibson 2010 using the VEINES‐QOL/Sym score to evaluate the patient perspective using polidocanol 1% foam versus placebo. In this case, polidocanol foam was superior to placebo in improving symptoms (MD ‐14.00; 95% CI ‐15.39 to ‐12.61; 1 study, 77 participants) (Analysis 1.10). The remaining two RCTs also evaluated VEINES‐QOL/Sym but we did not have access to sufficient data to conduct a meta‐analysis (missing standard deviations). These RCTs (King 2015; Todd 2014) also described VCSS; we used this outcome to grade the certainty of the evidence. Both studies reported an improvement in symptoms at intermediate‐term periods after sclerotherapy (eight weeks), and pooling the data for polidocanol 1% versus placebo showed: MD ‐3.25, 95% CI ‐3.90 to ‐2.60; 2 studies, 223 participants; low‐certainty evidence (Analysis 1.11). We downgraded the certainty of the evidence due to the low number of participants and indirectness (participants with CEAP C5 and C6 included in the RCTs).

Recurrent varicose veins

None of the RCTs reporting on this comparison described recurrent varicose veins.

Sclerotherapy versus sclerotherapy

Twenty‐two RCTs investigated this comparison. We were able to pool results from the comparison 'foam sclerotherapy versus foam sclerotherapy with different concentrations'; 'Foam versus liquid sclerotherapy'; and from the comparison 'different techniques'. Three RCTs compared 'different substances' (Goldman 2002; Schadeck 1995a; Wright 2006), two RCTs compared addition of substances including perfluropropane‐filled albumin microspheres of foam STS with air‐filled foam STS (Martimbeau 2003b) or a low molecular weight synthetic protein (Gelufusine) to polidocanol foam versus polidocanol foam sclerotherapy alone (Zeh 2003), and we considered it inappropriate to pool results due to indirect comparisons (different concentrations of the substances). Three RCTs did not supply data to measure the size effect (Martimbeau 2003a; Martimbeau 2003b; Zeh 2003).

No RCT compared different time intervals as part of their injection technique.

Comparison 3: Foam sclerotherapy versus foam sclerotherapy with different concentrations

Five RCTs reported on this comparison (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007; King 2015; Todd 2014). Different concentrations of polidocanol foam were used for comparison and they were categorised and described as polidocanol < 1% versus ≥ 1% or the most concentrated polidocanol foam described. We adopted this approach based on data representing an increased efficacy of polidocanol foam to occlude varicose veins at 1% concentration (King 2015).

For polidocanol foam concentrations at 1% to 2%, there was no clear difference in venous occlusion rates (80.4% for polidocanol 1% foam and 82.5% for polidocanol 2% foam) (King 2015). On the other hand, we are not confident that more concentrated foams could show an increase in success rates. So polidocanol 1% was used as a comparator against more concentrated foam preparations whenever there was a possibility to compare in order to investigate if concentrations greater than 1% could improve sclerotherapy effects. When there was an uncertainty of effect size, a subgroup analysis was performed. Care was taken to avoid double counting of participants. Although two authors (King 2015; Todd 2014) used polidocanol 0.125% foam as the smallest concentration permitting a stable foam as a control with other polidocanol concentrations, this sclerosant concentration showed a pharmacologic action, capable of producing objective outcomes (e.g. common femoral vein thrombus extension) as well as subjective outcomes (e.g. QoL improvements); and so is described in this session as an intervention group and not as the inactive placebo group.

We used polidocanol 3% versus 1% to grade the certainty of the evidence and to look for any additional effect with the increase of the concentration of the sclerosant. See summary of findings Table 2.

Cosmetic appearance

Three RCTs reported on this outcome (Ceulen 2007; King 2015; Todd 2014).

One RCT described self‐related cosmetic improvement over a long‐term period (complete cosmetic satisfaction) when comparing polidocanol 3% foam with polidocanol 1% foam (Ceulen 2007). There were no clear differences in cosmetic appearance in this analysis at a short‐term period (RR 1.31, 95% CI 0.81 to 2.12; 1 study, 80 participants) (Analysis 2.1), or at long‐term period (RR 1.11, 95% CI 0.84 to 1.47; 1 study, 80 participants; very low‐certainty evidence) (Analysis 2.2). The certainty of the evidence was downgraded due to concerns over risk of bias, indirectness (study authors included participants with CEAP C1, C5 and C6), and imprecision (low number of participants, wide confidence intervals, and single study).

Two RCTs evaluated the PA‐V (patient‐visible varicose vein instrument) and the IPR‐V (independent expert panel rating scale) of photographs according to Kingsley 2012 (King 2015; Todd 2014). Increased concentrations of polidocanol possibly increased the improvement in cosmetic appearance at intermediate‐term periods as seen with PA‐V: polidocanol 0.125% versus 1% (MD 0.45, 95% CI 0.03 to 0.87; 2 studies, 224 participants). Polidocanol 0.5% versus 1% showed no clear difference (MD 0.06, 95% CI ‐0.21 to 0.32; 2 studies, 221 participants; Analysis 2.3). A similar effect was seen with the IPR‐V (independent expert panel rating scale) of photographs: polidocanol 0.125% versus 1% (MD 0.19, 95% CI ‐0.01 to 0.40; 2 studies, 224 participants); polidocanol 0.5% versus 1% (MD ‐0.04, 95% CI ‐0.19 to 0.12; 2 studies, 221 participants; Analysis 2.4). If the concentration of test polidocanol foam was similar to the comparator (1%), there was no clear difference detected in cosmetic improvement, as is expected. We used the standard deviation from Todd 2014 to perform the meta‐analysis. Data imputation followed recommendations from the Cochrane Handbook to deal with missing data (Higgins 2017c).

Complications

Five RCTs reported on this outcome (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007; King 2015; Todd 2014). Complications were described as DVT, skin pigmentation, phlebitis or thrombophlebitis rates, matting, thromboembolic complications, haemorrhagic complications, and neurologic complications.

Thromboembolic complications (including DVT and PE) were described by three RCTs (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), and there were no clear differences between polidocanol 3% versus 1% in foam (RR 1.47, 95% CI 0.41 to 5.33; 3 studies, 371 participants; very low‐certainty evidence Analysis 2.5). Ceulen 2007 used the lower leg as the unit of analysis and included 11.63% of participants with CEAP C1. Blaise 2010 and Hamel‐Desnos 2007 used the individual as the unit of analysis. A sensitivity analysis was performed and it did not change the effect direction (Analysis 2.6). The certainty of the evidence was downgraded due to indirectness (inclusion of participants with CEAP C1, C5, and C6), and imprecision (low number of events).

From polidocanol 0.125% to 2% foam, there was no evidence of increased DVT for the evaluated subgroups at short or intermediate‐term periods (for polidocanol foam 0.125% versus 2%: RR 1.81, 95% CI 0.17 to 19.43; 1 study, 120 participants) (Analysis 2.7) (for polidocanol 1% versus 2%: RR 0.83, 95% CI 0.12 to 5.66; 1 study, 115 participants) (Analysis 2.7). Analyses were carried out separately to dichotomise polidocanol concentrations lower than 1% versus higher or equal to 1%, and 1% compared to the higher concentrations of polidocanol foam. No differences were detected by the test for subgroup differences (P = 0.73).

Two RCTs (Ceulen 2007; Hamel‐Desnos 2007), investigated the frequency of PE at the short term comparing polidocanol 3% with 1% foam and there was no clear difference seen, with only one case of PE described in the 3% group (RR 3.00, 95% CI 0.13 to 71.51; 2 studies, 228 participants) (Analysis 2.8).

Two RCTs (Blaise 2010; Ceulen 2007) described skin pigmentation at long‐term periods comparing polidocanol 3% with 1% foam and meta‐analysis showed no clear difference in skin pigmentation rates (RR 1.61, 95% CI 0.82 to 3.17; 2 studies, 223 participants) (Analysis 2.9). As Ceulen 2007 used the lower leg as the unit of analysis, a sensitivity analysis was conducted and there were no differences in the overall effect.

A subgroup analysis was carried out to show the results of phlebitis or thrombophlebitis rates in two RCTs with a concentration of polidocanol ranging from 0.125% to 2% (King 2015; Todd 2014); no clear differences in phlebitis and thrombophlebitis rates were seen in any subgroup despite the variation of sclerosant concentrations (polidocanol 0.5% versus 2%: RR 0.77, 95% CI 0.27 to 2.22; 1 study, 114 participants) (Analysis 2.10). No differences were detected by the test for subgroup differences (P = 0.3). Low thrombophlebitis rates were reported with polidocanol 0.125% in the King 2015 study (Analysis 2.10).

Phlebitis and thrombophlebitis were also described by two other RCTs comparing polidocanol 3% with polidocanol 1% foam (Blaise 2010; Ceulen 2007). These studies were not included in the subgroup analysis above because we dichotomised data to polidocanol foam concentration less than 1% versus polidocanol foam concentration equal to or more than 1%. We assessed the effect size of the higher polidocanol foam concentration separately. There were no clear differences in thrombophlebitis rates in these foam concentrations (RR 1.46, 95% CI 0.88 to 2.41; 2 studies, 223 participants) (Analysis 2.11).

Haematoma complications were described in two RCTs (King 2015; Todd 2014), and no clear differences were detected between any investigated subgroups. For polidocanol 0.125% versus 1%: RR 0.61, 95% CI 0.20 to 1.83; 2 studies, 228 participants) (test for subgroup differences P = 0.18) (Analysis 2.12).

Neurological complications were described as mild in two RCTs (King 2015; Todd 2014), and no clear differences were detected between any of the polidocanol concentrations investigated (0.125% and 0.5% versus 1% and 2%) (Analysis 2.13); or polidocanol 1% versus 2% (RR 0.28, 95% CI 0.01 to 6.64; 1 study, 115 participants) (Analysis 2.13).

Residual varicose veins

Five RCTs reported on this outcome (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007; King 2015; Todd 2014). Residual varicose veins were described by two studies at an intermediate‐term period (King 2015; Todd 2014), and three RCTs reported at a long‐term period (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007). Subgroup analysis was used to compare concentrations of the foam sclerotherapy agent in reducing residual varicose veins (Analysis 2.14). Increasing the polidocanol foam concentration reduced the number of participants with residual varicose veins (for polidocanol 0.5% versus 2%: RR 2.36, 95% CI 1.26 to 4.42; 1 study, 114 participants) (Analysis 2.14). King 2015 compared polidocanol 1% versus 2% and there was no clear difference in residual varicose vein rates (RR 1.21, 95% CI 0.57 to 2.57; 1 study, 115 participants) (Analysis 2.14). Three studies evaluated higher concentrations of polidocanol foam at a long‐term period (3% versus 1% at 6, 12, and 24 months) (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007). The rate of residual varicose veins may be slightly decreased in the polidocanol 3% foam group from six to 24 months (RR 0.67, 95% CI 0.43 to 1.04; 3 studies, 371 participants; moderate‐certainty evidence) (Analysis 2.15). The effect size was not changed following sensitivity analysis to exclude a study that included participants with CEAP C1(Ceulen 2007; Analysis 2.16).

The evidence was downgraded due to indirectness (inclusion of participants with CEAP C1 (11.63% in Ceulen 2007), C5 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), and C6 (Hamel‐Desnos 2007) but there was no description of the proportion of these participants in the groups). One study used the lower leg as the unit of analysis (Ceulen 2007).

Quality of life

Two RCTs reported on this outcome (King 2015; Todd 2014).

Quality of life analysis was possible with data imputation using the standard deviations from Todd 2014 when using the VEINES‐QOL/Sym scores. The study authors reported a tendency for improvement of quality of life if more concentrated polidocanol foam was used. We were only able to conduct meta‐analysis comparing 0.125%, 0.5%, and 1% polidocanol foam (Analysis 2.17). Our analysis did not find a clear improvement in the quality of life when increasing polidocanol foam concentration up to 1% polidocanol foam (test for subgroup differences P = 0.11).

No study evaluated polidocanol 3% versus 1%, so the certainty of the evidence was not graded.

Frequency of persistence of symptoms

Two RCTs reported the frequency of persistence of symptoms using the VCSS score (King 2015; Todd 2014). Both reported an improvement in VCSS scores with increasing concentrations of polidocanol foam and this was confirmed by meta‐analysis: polidocanol 0.125% versus 0.5% (MD ‐0.87, 95% CI ‐1.52 to ‐0.21; 2 studies, 225 participants) (Analysis 2.18). Only polidocanol 0.5% versus 1% did not show a difference in VCSS scores (MD 0.10, 95% CI ‐0.56 to 0.75; 2 studies, 221 participants) (test for subgroup differences P = 0.08) (Analysis 2.18).

The certainty of the evidence was not graded since no study compared polidocanol 3% versus 1%.

Recurrent varicose veins and venous flare formation

One RCT reported on this outcome (Hamel‐Desnos 2007). There was no clear difference in the number of recurrent varicose veins when comparing polidocanol 3% versus 1% foam concentrations at a long‐term period (RR 0.91, 95% CI 0.62 to 1.32; 1 study, 148 participants; low‐certainty evidence) (Analysis 2.19).

The certainty of the evidence was graded as low since data were from a single study with an indirect population (participants with CEAP C5 and C6).

Comparison 4: Foam sclerotherapy versus liquid sclerotherapy

Nine RCTs reported on this comparison (Alos 2006; Belcaro 2003b; Demagny 2002; Martimbeau 2003a; Martimbeau 2003b; Rabe 2008; Ouvry 2008; Ukritmanoroat 2011; Zeh 2003). Three studies did not provide any usable data (Martimbeau 2003a; Martimbeau 2003b; Zeh 2003). One RCT used an ultrasound contrast agent to produce a foam (Belcaro 2003b). As this is not a standard way to produce a foam sclerotherapy agent, we believe it cannot be compared to any conventional foam in which the medicine is agitated with a gas. To grade the certainty of the evidence, we have tried to use similar or equal foam concentrations since it is not known if there is an ideal concentration. Using the same concentration will be more useful for clinicians. See summary of findings Table 3.

Cosmetic appearance

One RCT reported on this outcome. Long‐term cosmetic appearance was reported by Alos 2006 as patient satisfaction and there was no difference when using polidocanol 0.75% to 1.25% foam versus polidocanol 1.5% to 2.5% liquid (MD 0.20, 95% CI ‐0.27 to 0.67; 1 study, 126 participants; very low‐certainty evidence) (Analysis 3.1). The unit of analysis was the vein. No other RCT included in this comparison reported on this outcome and there were differences in the concentrations compared. We downgraded the certainty of the evidence to very low due to risk of bias concerns, and indirectness (different concentrations of the polidocanol used). As the authors did not use similar or equal concentrations of sclerosant, we undertook a descriptive analysis and used this study to grade the certainty of the evidence in summary of findings Table 3.

Complications

Seven RCTs reported on this outcome (Alos 2006; Demagny 2002; Martimbeau 2003a; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ukritmanoroat 2011). Two studies did not report complications as an outcome (Belcaro 2003b; Zeh 2003). There was a lack of reported information and interest in adverse events and complications, including thromboembolic events. Overall, complications were described as mild, and these included pain, phlebitis, haematomas, and skin pigmentation. One study described a case of allergy in the liquid intervention group and five cases of amaurosis in the foam intervention group using STS sclerosant agent (Demagny 2002). Ouvry 2008 described complications as pooled results including an event of vaso‐vagal response, one of sensation of heat in the mouth immediately after injection, persistent inflammation in the thigh, two cases of bruising, two of thrombophlebitis of the leg, one of asthenia, one patient with headache, and two cases of pain in the thigh and knee; with the study authors reporting that there was no difference between the two treatment groups. Alos 2006 described four participants in the foam group as having severe pain as well as 25.3% of the participants from the foam group and 9.5% from the liquid group with local inflammation at 15 days post‐treatment. The RCT also described a greater number of pigmentations in the foam group (33%) compared to the liquid group (6.3%) at one year. However, this RCT included participants with CEAP C1 and we were unable to access individual patient data. Also, the sclerosant concentration was stratified for subgroups of vein diameter. For veins with 1 mm to 2 mm diameter, 1% liquid polidocanol or 0.5% for the foam group was used; veins with 1 mm to 3 mm used 1.25% liquid polidocanol versus 0.5% for foam; varicose veins with 3.1 mm to 4 mm used 1.5% liquid polidocanol and 0.75% for foam; 4.1 mm to 5 mm in diameter varicose veins used 2% liquid polidocanol versus 1% for foam; 5.1 mm to 6 mm in diameter veins used 2.5% liquid polidocanol versus 1.25% for foam sclerotherapy. As we had no access to subgroups of the participants, we decided not to calculate the effect size because it could result in bias. Rabe 2008 and Ukritmanoroat 2011 described skin pigmentation as mild or moderate, with no clear difference detected between the foam and liquid sclerotherapy intervention groups (RR 1.75, 95% CI 0.81 to 3.80; 2 studies, 208 participants) (Analysis 3.2). One RCT described 0.2% of side effects for the foam group versus 2.4% for the liquid group but the study authors did not describe which side effects occurred (Martimbeau 2003a). One RCT described an increase in phlebitis rates in the air‐filled foam compared to microspheres filled (P = 0.01) (Martimbeau 2003b).

Residual varicose veins

Six RCTs reported on this outcome (Alos 2006; Belcaro 2003b; Demagny 2002; Ouvry 2008; Rabe 2008; Ukritmanoroat 2011). One study investigated the use of a tensioactive substance to produce a foam with STS 2% or 3% (Belcaro 2003b). The authors presented results as the reduction of ambulatory venous pressure, refilling time, and number of major sites of incompetence on duplex ultrasound, and using the duplex ultrasound demonstrated no differences in residual varicose veins after 10 years of follow‐up (1.1 points of major site incompetence in each treatment option). As the RCT used different medicine concentrations, different outcome measures, and time points to report the outcomes, we decided not to include it in the analysis. There was a benefit for the use of foam seen in all RCTs for occluding the varicose veins over a long time (Analysis 3.3). We did not think it was appropriate to pool overall, as different concentrations and sclerosants were used, so data have been presented as a subgroup analysis (Analysis 3.3). As Alos 2006 used different concentrations of sclerosant, a sensitivity analysis was conducted and it did not change the effect direction. We decided to report and assess results from polidocanol 3%, as this was most clinically relevant. For polidocanol 3%, there was an RR of 0.51 (95% CI 0.41 to 0.65; 2 studies, 203 participants; very low‐certainty evidence) (Analysis 3.3). Two sclerotherapy products were included in this analysis: polidocanol and STS. There was also heterogeneity in the population due to differences in varicose vein diameter, type of vein treated (saphenous or collaterals), number of sessions necessary to treat, and the CEAP inclusion. Some of these data were difficult or impossible to recover and there were differences in results between different centres of the same RCTs (Rabe 2008). Despite these limitations, sensitivity analysis showed a consistent benefit for the foam groups over the liquid groups. The certainty of the evidence was downgraded due to risk of bias concerns and indirectness: Ouvry 2008 included participants with CEAP C2 to C6 without discriminating between them; Rabe 2008 included one participant with CEAP C5 in the foam group (1.9%) and four participants with CEAP C5 in the liquid group (7.7%).

Residual varicose veins were also investigated following STS 3%, and at a long‐term period showed a benefit of foam over liquid sclerotherapy (RR: 0.63, 95% CI 0.48 to 0.82; 1 study, 130 participants) (Analysis 3.4).

Quality of life

None of the RCTs reporting on this comparison reported QoL.

Frequency of persistence of symptoms

None of the RCTs reporting on this comparison reported persistence of symptoms.

Recurrent varicose veins

Two RCTs reported on recurrent varicose veins (Belcaro 2003b; Martimbeau 2003a). Martimbeau 2003a did not provide any data, but described no difference in recurrent varicose veins at 12 months (1.2% in foam group and 1.7% in liquid group). Belcaro 2003b evaluated this outcome at five years comparing STS foam with liquid and reported recurrence as similar in both groups (RR 1.1, 95% CI 0.86 to 1.42; 1 study, 286 participants; very low‐certainty evidence) (Analysis 3.5).

The certainty of the evidence was downgraded due to the risk of bias (intervention probably impossible to blind due to the nature of the intervention), imprecision (single study), and indirectness (did not describe CEAP of the participants and used a tensioactive substance to produce foam ‐ not the standard way to use gas or room air). The study author described the participants as people with varicose veins with diameters larger than 3 mm.

Comparison 5: Sclerotherapy versus sclerotherapy with different substances

Four RCTs compared sclerotherapy versus sclerotherapy with any other substance (Goldman 2002; Rao 2005; Schadeck 1995a; Wright 2006). These studies investigated a range of concentrations, formulations, and drug volumes, so we were unable to pool all the data. Goldman 2002 studied STS 1.5% versus polidocanol 3%. The same substances were investigated by Rao 2005 but using STS 0.5% versus polidocanol 1%, and Schadeck 1995a with STS 3% versus polidocanol 4%. Wright 2006 compared polidocanol 1% with any market sclerosant in any presentation or concentration. Although we had planned to present a SoF table for the comparison sclerotherapy with STS 1% versus sclerotherapy with polidocanol 1% (see Methods section), no included RCT considered this comparison. See summary of findings Table 4.

Cosmetic appearance

Two RCTs reported on this outcome (Goldman 2002; Rao 2005). Cosmetic appearance was described by Goldman 2002 as the disappearance of the varicose veins after treating the veins (diameter between 3 mm and 6 mm) using polidocanol 3% versus STS 1.5%. The scale to describe disappearance of the varicose veins ranged from 1 to 5: 1 = worse than before treatment; 2 = no change; 3 = minor disappearance; 4 = moderate disappearance; 5 = complete disappearance (MD 0.20, 95% CI ‐0.01 to 0.41; 1 study, 54 participants) (Analysis 4.1). As different polidocanol and STS concentrations were used, we were not able to draw conclusions about the benefit of one product over the other. Rao 2005 described outcomes as clearance scores, tolerability, and patient satisfaction. It was not possible to estimate the effect size from Rao 2005 since there were pooled data from CEAP C1 and C2 and different interventions (STS 0.25% or polidocanol 0.5% solution for vein diameters lower than 1 mm; STS 0.5% or polidocanol 1% solution for 1 mm to 3 mm veins, and STS 0.5% or polidocanol 1% foam for veins with diameter between 3 mm and 6 mm). We believe a sclerosant could reach veins with small or larger diameters once injected in a varicose vein, since reflux could drive sclerosant agent to that site, adding a confounding factor to analysis. We did not pool results to grade the certainty of the evidence. We decided not to grade the certainty of the evidence due to discrepancy in concentration of sclerosants and no discrimination of CEAP population.

Complications

Two RCTs reported on complications but we were unable to pool the data due to differences in sclerosant concentrations used (Goldman 2002; Wright 2006). One RCT compared a commercial polidocanol 1% foam (Varisolve) versus any market sclerosant liquid or foam and reported on skin pigmentation, DVT and haematoma at short‐ or intermediate‐term periods (Wright 2006). No differences were seen in the occurrence of DVT (RR 0.97, 95% CI 0.09 to 10.54; 1 study, 384 participants) (Analysis 4.2); skin pigmentation (RR 1.01, 95% CI 0.80 to 1.27; 1 study, 384 participants; Analysis 4.3); or haematoma formation (RR 1.56, 95% CI 0.76 to 3.18; 1 study, 384 participants) (Analysis 4.4). Goldman 2002 described complications without discriminating between participants with CEAP C1 and C2. Otherwise, intervention and control groups appeared to be balanced. The number of skin pigmentation events were not different between STS 1.5% versus polidocanol 3% (RR 1.21, 95% CI 0.95 to 1.55; 1 study, 167 participants) (Analysis 4.5). Skin necrosis numbers were not clearly different in the STS 1.5% group and in the polidocanol 3% group but no events were reported in the polidocanol 3% group resulting in a very wide CI (RR 14.12, 95% CI 0.81 to 246.76; 1 study, 167 participants) (Analysis 4.6). Goldman 2002 also described thrombosis of the vein, probably related to thrombophlebitis or venous occlusion (superficial venous system). As the RCT compared different sclerosant concentrations, we considered it inappropriate to present the data in a SOF table. We decided not to grade the certainty of the evidence due to discrepancy in concentrations of sclerosants and no discrimination of CEAP population.

Frequency of residual varicose veins

Wright 2006 investigated polidocanol 1% (Varisolve) versus any market sclerosant liquid or foam. We considered the veins that had no occlusion or elimination of reflux as residual varicose veins. At 12 months, the rates of residual varicose veins were greater in any market sclerosant than in the intervention group (RR 0.64, 95% CI 0.42 to 0.97; 1 study, 373 participants) (Analysis 4.7). As the comparators were so discrepant (any concentrations and forms of liquid or foam), we decided not to grade the certainty of the evidence.

Quality of life

None of the RCTs reporting on this comparison reported QoL.

Frequency of persistence of symptoms

None of the RCTs reporting on this comparison reported on persistence of symptoms.

Frequency of recurrent varicose veins and venous flare formation

Goldman 2002 investigated matting and there was no clinical difference in the STS 1.5% intervention group compared to polidocanol 3% (RR 1.53, 95% CI 0.58 to 4.02; 1 study, 167 participants) (Analysis 4.8). We did not grade the certainty of the evidence due to the different sclerosant concentrations. We believe that this concentration comparison does not represent a relevant clinical situation.

Comparison 6: Sclerotherapy versus sclerotherapy with different techniques

Six RCTs evaluated different techniques for injection sclerotherapy (Chleir 1997; Ragg 2015; Santos 2019; Yamaki 2009; Yamaki 2012; Zhang 2014). There was important heterogeneity between comparisons due to the use of different interventions and time points assessed. These techniques included single versus multiple injections (with the same product and the same volume) (Chleir 1997); polidocanol 1% to 3% foam injected in few injections versus in multiple injections (Yamaki 2009); and ultrasound‐guided foam sclerotherapy with visual foam sclerotherapy using polidocanol 1% foam (Yamaki 2012); polidocanol 1% foam sclerotherapy injected by a needle compared to polidocanol 1% foam catheter‐directed sclerotherapy, and with polidocanol 1% foam microcatheter‐directed sclerotherapy (Ragg 2015); polidocanol 3% foam injected by needle versus delivered by a catheter associated with tumescent technique (Santos 2019); and antegrade versus retrograde technique with polidocanol 1% foam (Zhang 2014).

Cosmetic appearance

None of the RCTs reporting on this comparison reported cosmetic appearance.

Complications

Zhang 2014 compared antegrade versus retrograde techniques using polidocanol 1% foam and no DVT events were reported in either group. Similarly, no clear differences were detected in short‐term period thrombophlebitis rates (RR 2.00, 95% CI 0.54 to 7.45; 1 study, 80 participants) (Analysis 5.1); or long‐term period skin pigmentation rates (RR 1.5, 95% CI 0.26 to 8.50; 1 study, 80 participants) (Analysis 5.2); or in thrombophlebitis rates using catheter versus needle injection (RR 1.00, 95% CI 0.07 to 15.12; 1 study, 50 participants) (Analysis 5.3).

There was more foam agent detected in the deep venous system by ultrasound when using fewer injections compared to more injections in Yamaki 2012 (RR 2.12, 95% CI 1.36 to 3.30; 1 study, 112 participants) (Analysis 5.4). Chleir 1997 reported seven participants with pain, nine with phlebitis (described as "venulites"), and two with oedema. Ragg 2015 reported no adverse reaction, especially bleeding. Yamaki 2009 described two cases of migraine in the few injections group, two cases of superficial thrombophlebitis in each group, and one case of pain in each group. Yamaki 2012 reported one case of thrombophlebitis in each group, and one case of migraine in the visual foam sclerotherapy group. One RCT reported skin irritation in two participants, one case of migraine in the catheter foam‐delivered group, and hyperpigmentation in eight participants from the needle injection group, compared to four participants from the catheter group (Santos 2019). As there was a co‐intervention (tumescent technique), we did not include these data in a meta‐analysis.

Frequency of residual varicose veins

Six studies reported on this outcome but we were not able to pool data due to heterogeneity (Chleir 1997; Ragg 2015; Santos 2019; Yamaki 2009; Yamaki 2012; Zhang 2014). Yamaki 2012 compared visual foam sclerotherapy with ultrasound‐guided foam sclerotherapy using polidocanol 1% foam and there were no clear differences in residual varicose vein rates in the long‐term period (RR 1.05, 95% CI 0.75 to 1.48; 1 study, 103 participants) (Analysis 5.5). Two studies reported on this outcome questioning if an increase in puncture number could impact residual varicose vein rates (Chleir 1997; Yamaki 2009). Chleir 1997 evaluated STS 3% injected in fractionated versus single injections with no differences detected in residual varicose vein rates (RR 1.08, 95% CI 0.79 to 1.49; 1 study, 150 participants) (Analysis 5.6). Yamaki 2009 compared polidocanol 1% or 3% foam in multiple injections versus few injections showing no differences in the residual varicose vein rates (RR 1.17, CI 0.78 to 1.78; 1 study, 112 participants) (Analysis 5.6). The injection technique (retrograde versus antegrade) made no difference to the number of residual varicose veins at the intermediate‐term period (Zhang 2014) (RR 1.80, 95% CI 0.66 to 4.90; 1 study, 80 participants) (Analysis 5.7).

Ragg 2015 compared polidocanol 1% foam sclerotherapy injected by a needle with polidocanol 1% foam catheter‐directed sclerotherapy, and with polidocanol 1% foam microcatheter‐directed sclerotherapy. There were low numbers of participants in each group (10), and there was no difference in residual varicose veins at the intermediate‐term period between all comparable groups: microcatheter versus catheter (RR 5.00, 95% CI 0.27 to 92.62; 1 study, 20 participants; Analysis 5.8); or needle versus catheter with zero events in the catheter group leading to very wide CIs (RR 9.00, 95% CI 0.55 to 147.95; 1 study, 20 participants; Analysis 5.9); and needle sclerotherapy versus microcatheter (RR 2.00, 95% CI 0.47 to 8.56; 1 study, 20 participants; Analysis 5.10). Santos 2019 compared polidocanol 3% foam injected by a catheter associated with tumescent technique versus needle and reported lower rates of residual varicose veins in the catheter‐delivered group at a short‐term period (RR 0.31, 95% CI 0.14 to 0.72; 1 study, 50 participants; Analysis 5.11). At a long‐term period, both groups had a similar number of participants requiring retreatments (RR 0.92, 95% CI 0.50 to 1.67; 1 study, 50 participants; Analysis 5.12).

Frequency of recurrent varicose veins and venous flare formation

None of the RCTs reporting on this comparison reported on recurrent varicose veins and venous flare formation.

Quality of life

One RCT reported QoL in this comparison (Santos 2019). The authors reported an improvement in QoL without inter‐group differences but with intra‐group differences before and after six months of follow‐up. They used AVVQ (Aberdeen Varicose Vein Questionnaire) with the most favourable result being the lowest score. Our analysis did not show a clear improvement for either catheter‐directed or ultrasound‐guided sclerotherapy (MD ‐2.71, 95% CI ‐9.33 to 3.91; 1 study, 50 participants; Analysis 5.13).

Frequency of persistence of symptoms

One RCT reported on this outcome. Yamaki 2012 did not find clinical differences in VCSS in the long‐term period (MD 0.00, 95% CI ‐0.77 to 0.77; 1 study, 103 participants; Analysis 5.14).

Sclerotherapy versus different conservative treatment

Comparison 7: Sclerotherapy versus pharmacological therapy

No study compared sclerotherapy with any pharmacological therapy.

Comparison 8: Sclerotherapy versus conservative compression treatment

One study compared sclerotherapy versus conservative management at six months to two years of follow‐up (Abramowitz 1973). This study was conducted in pregnant women and reported a benefit with injection sclerotherapy compared to conservative management (compression) on the outcome of symptomatic improvement and cosmetic appearance (RR 7.96, 95% CI 3.38 to 18.76; 1 study, 101 participants) (Analysis 6.1). However, an increased number of ulcers were reported after sclerotherapy (RR 13.63, 95% CI 0.77 to 240.13; 1 study, 101 participants) (Analysis 6.2). It is also important to note that the outcomes, cosmetic appearance and symptomatic improvement, were described as pooled data and we were unable to discriminate data for each outcome. There were no other outcomes evaluated by the RCT.

Sensitivity analysis

We performed a sensitivity analysis excluding studies which had data imputation. As the lost of follow‐up was balanced in all groups, this action did not change the effect direction. We preferred to present results using intention‐to‐treat analysis.

Fourteen RCTs were judged as being at high risk of bias for at least one of the following domains: selection, performance, or detection (Alos 2006; Belcaro 2003b; Gibson 2010; King 2015; Martimbeau 2003b; Ouvry 2008; Rabe 2008; Ragg 2015; Todd 2014; Ukritmanoroat 2011; Wright 2006; Yamaki 2009; Yamaki 2012; Zhang 2009). Two of these RCTs (King 2015; Todd 2014) were considered as having high risk of bias when placebo was the comparator, as it was impossible to blind placebo due to the nature of the intervention. Belcaro 2003b declared that investigators opened the randomisation code after randomisation. Martimbeau 2003b did not describe the outcome assessment. All other studies were deemed as being at high risk of detection bias as it was not possible to blind participants and personnel. As planned, we conducted a sensitivity analysis

any of these studies were included in a meta‐analysis. High risk of bias studies were combined in most meta‐analyses (e.g. foam versus placebo). One meta‐analysis evaluated residual varicose veins at a long‐term period comparing foam versus liquid sclerotherapy (Analysis 3.3). Only one RCT was not judged as being at high risk of bias (Demagny 2002). A sensitivity analysis was performed and the effect direction was not changed (RR 0.63, 95% CI 0.48 to 0.82; 1 study, 300 participants; Analysis 3.4). To perform this analysis we evaluated only great saphenous veins (300 included, and 50% in each group) and considered recanalisation as residual varicose veins, since a duplex ultrasound image was presented in the paper showing the recanalised vein as an unresolved varicose vein, with sinals of thrombus in the lumen. So, with sensitivity analysis, foam appeared better than liquid to avoid residual varicose veins. Another analysis compared sclerotherapy versus sclerotherapy with different techniques and two studies in a subgroup analysis had different judgements for the risk of bias (Analysis 5.6). There was no change in the effect direction following sensitivity analysis, indicating residual varicose veins were not different with single versus fractionated doses of injection sclerotherapy.

Six RCTs were funded by pharmaceutical companies (Blaise 2010; Gibson 2010; King 2015; Rabe 2008; Todd 2014; Wright 2006). These RCTs were involved in six meta‐analyses (Analysis 2.5; Analysis 2.6; Analysis 2.9; Analysis 2.11; Analysis 2.15; Analysis 3.3). We performed a sensitivity analysis for all of these analyses and we did not find changes in the direction of the effect for any of the meta‐analyses. So, RCTs funded by industry did not appear to change the effect of the intervention.

We expected to find the participant as the unit of analysis. However, in five RCTs, the unit of analysis was the vein (Alos 2006; Demagny 2002; Rao 2005; Ukritmanoroat 2011; Zhang 2014) and, in four RCTs, the lower leg (Ceulen 2007; Chleir 1997; Yamaki 2009; Yamaki 2012). In these cases, whenever a meta‐analysis was performed, we did a sensitivity analysis. We did not find any change in effect direction in any of the analyses evaluated (Analysis 2.5; Analysis 2.8; Analysis 2.9; Analysis 2.11; Analysis 2.12; Analysis 3.2; Analysis 3.3; Analysis 5.6).

Subgroup analysis

Planned subgroup analysis was not possible for CEAP clinical classes since we did not have data to discriminate participants from each clinical class. No RCT cited the depth of the vein or discriminated between symptomatic versus asymptomatic participants.

RCTs comparing foam versus foam sclerotherapy evaluated only truncal incompetence, precluding subgroup analysis.

Previous complications (e.g. thrombophlebitis) were exclusion criteria of the included studies, making subgroup analysis impossible.

We used many comparators in the foam versus foam sclerotherapy dealing with subgroups. So, the 'Foam versus foam sclerotherapy' comparison was presented as subgroup analysis. King 2015 demonstrated that the best foam concentration to reduce residual varicose veins was at least polidocanol 1%. But polidocanol 3% foam was more effective at reducing residual varicose veins than 1% foam (RR 0.67, 95% CI 0.43 to 1.04; 3 studies, 371 participants; moderate‐certainty evidence) (Analysis 2.15). Polidocanol 1% foam versus 3% did not change cosmetic appearance, complications, QoL or symptoms (low‐ to moderate‐certainty evidence).

Four RCTs investigated different gases (called physiologic gases including O₂ and CO₂ in Varithena and Varisolve) in the foam preparation (Gibson 2010; King 2015; Todd 2014; Wright 2006). The study authors compared Varisolve with any market sclerosant liquid or foam (Wright 2006), precluding subgroup analysis. Gibson 2010 compared foam sclerotherapy with placebo. The other proposed subgroup analysis involved the other three studies in the same meta‐analysis.

We also performed subgroup analyses of the different sclerosant concentrations to simplify the data interpretation (Analysis 1.1; Analysis 1.2; Analysis 1.4; Analysis 1.5; Analysis 1.3; Analysis 1.6; Analysis 1.7; Analysis 1.8; Analysis 1.9; Analysis 1.11; Analysis 2.3; Analysis 2.4; Analysis 2.7; Analysis 2.9; Analysis 2.10; Analysis 2.12; Analysis 2.13; Analysis 2.14; Analysis 2.17; Analysis 2.18; Analysis 3.2; Analysis 3.3; Analysis 5.6).

Discussion

Summary of main results

We included 28 RCTs involving 4278 participants. The studies varied in the interventions and comparisons used.

Sclerotherapy versus no intervention or placebo

Comparison 1: Sclerotherapy versus no intervention

The review did not find any RCT comparing sclerotherapy with no intervention. This lack of information highlights the continuance of the disappointing gap of knowledge for this comparison, mainly for CEAP C2 varicose veins.

Comparison 2: Sclerotherapy versus placebo

summary of findings Table 1

Foam sclerotherapy may improve cosmetic appearance compared to placebo (polidocanol 1%: independent photography review ‐ visible varicose veins scores (IPR‐V) mean difference (MD) ‐0.76, 95% CI ‐0.91 to ‐0.60; 2 studies, 223 participants; very low‐certainty evidence (Analysis 1.1)).

Mild to moderate rates of complications were higher in the sclerotherapy group, including deep vein thrombosis (DVT) rates (polidocanol 1% foam: RR 5.10, CI 1.30 to 20.01; 3 studies, 302 participants; very low‐certainty evidence) (Analysis 1.3); and thrombophlebitis (polidocanol 1% foam: RR 3.12, 95% CI 1.10 to 8.83; 3 studies, 302 participants) (Analysis 1.5). DVT occurrence is rare in sclerotherapy and can also occur in other modalities of treatment (Jacobs 2014; Paravastu 2016). In this case, the occurrence of DVT is derived from usually small asymptomatic thrombus, and did not cause an increased rate in pulmonary embolism (PE) in most participants (no symptomatic PE events in any of the three studies were included in meta‐analysis) (Gibson 2010; King 2015; Todd 2014). Most thrombi originated in the saphenous veins and extended to the femoral vein and there were no participants with signs or symptoms of DVT (King 2015).

Sclerotherapy did not increase the rates of haemorrhagic (polidocanol 1%: RR 1.83, 95 CI 0.75 to 4.47; 3 studies, 302 participants) (Analysis 1.6) or neurologic complications (polidocanol 1%: RR 1.03, 95 CI 0.22 to 4.91; 3 studies, 302 participants) (Analysis 1.7).

Sclerotherapy may reduce the rate of residual varicose veins (polidocanol 1% foam: RR 0.19, 95% CI 0.13 to 0.29; 2 studies, 225 participants; very low‐certainty evidence) (Analysis 1.8); may improve quality of life (polidocanol 1%: MD 12.41, 95% CI 9.56 to 15.26; 2 studies, 222 participants; low‐certainty evidence) (Analysis 1.9); and may reduce varicose vein symptoms (MD ‐3.25, 95% CI ‐3.90 to ‐2.60; 2 studies, 223 participants; low‐certainty evidence) (Analysis 1.11).

Sclerotherapy versus sclerotherapy

Twenty‐two RCTs investigated sclerotherapy versus sclerotherapy, with four comparisons involved:

Foam versus foam sclerotherapy with different concentrations
Foam versus liquid sclerotherapy
Sclerotherapy versus sclerotherapy with different substances
Sclerotherapy versus sclerotherapy with different techniques

Comparison 3: Foam sclerotherapy versus foam sclerotherapy with different concentrations

Five RCTs reported on this comparison. See summary of findings Table 2.

Increasing concentrations of polidocanol foam to 3% showed no clear differences in cosmetic appearance compared to polidocanol 1% foam in a single study at one month (RR 1.31, 95% CI 0.81 to 2.12; 1 study, 80 participants; Analysis 2.1); or one year (RR 1.11, 95% CI 0.84 to 1.47; 1 study, 80 participants; very low‐certainty evidence; Analysis 2.2). Lower concentrations of polidocanol foam sclerotherapy (0.125%) had a similar effect to placebo. Higher concentrations of polidocanol possibly increased the improvement in cosmetic appearance as assessed by the adjusted mean for patient visible varicose vein instrument (PA‐V) (polidocanol 0.125% versus 1% (MD 0.45, 95% CI 0.03 to 0.87; 2 studies, 224 participants).Polidocanol 0.5% versus 1% showed no clear difference (MD 0.06, 95% CI ‐0.21 to 0.32; 2 studies, 221 participants; Analysis 2.3). A similar effect was seen with IPR‐V (independent expert panel rating scale) of photographs:polidocanol 0.125% versus 1% (MD 0.19, 95% CI ‐0.01 to 0.40; 2 studies, 221 participants); polidocanol 0.5% versus 1% (MD ‐0.04, 95% CI ‐0.20 to 0.12; 2 studies, 224 participants; Analysis 2.4). However, improvement in cosmetic appearance was still uncertain for concentrations higher than 1%.

No clear differences in the rates of thromboembolic complications were detected between polidocanol 3% and 1% (RR 1.47, 95% CI 0.41 to 5.33; 3 studies, 371 participants; very low‐certainty evidence; Analysis 2.5). Whenever there was a thrombus detected, it was clinically well manageable, and there were no severe clinical endpoints described after the event (Todd 2014). Pulmonary embolism was diagnosed despite no detection of DVT in one study (Ceulen 2007). It was impossible to predict if the embolus could have derived from the superficial or deep venous system. No deaths or cardiac complications were described in the pooled studies. However, the number of events was small, with a need for more studies to better answer this concern. There was still imprecision due to the low number of events and participants. Skin pigmentation also impacts on worsening cosmetic appearance. Skin pigmentation rates did not increase when using polidocanol foam 3% compared to 1% (Analysis 2.9). Aspects associated with the relationship between the vein and the skin still need to be studied (vein depth, for example). We are not sure if the depth of the vein correlates with more pigmentation rates.

One RCT demonstrated that a concentration of at least 1% polidocanol foam is necessary to reach the best effect for occluding veins (King 2015). There was no other similar finding for any other sclerotherapy agent, and the ideal polidocanol foam concentration is still not established. If the concentration of polidocanol foam was increased, the residual varicose vein rates may decrease (RR 0.67, 95% CI 0.43 to 1.04; 3 studies, 371 participants; moderate‐certainty evidence) (Analysis 2.15).

Two RCTs investigated the improvements in QoL (King 2015; Todd 2014), and no clear improvement was detected when increasing polidocanol foam concentration up to 1% polidocanol foam (Analysis 2.17).

Increasing the foam concentration for sclerotherapy improved symptoms measured using change in VCSS from baseline (polidocanol 0.125% versus 0.5%, MD ‐0.87, 95% CI ‐1.52 to ‐0.21; 2 studies, 225 participants; Analysis 2.18). When polidocanol 0.5% foam was compared to 1% foam, there was no improvement in symptoms. There is a reasonable chance to improve the effect with increasing foam concentration if symptoms could be attributed to varicose vein disease. Therefore, there is a need to define which symptoms we could attribute to the varicose veins and which symptoms cannot be attributed to varicose veins.

Only one RCT investigated the recurrence of varicose vein rates (Hamel‐Desnos 2007). No differences were detected (RR 0.91, 95% CI 0.62 to 1.32; 1 study, 148 participants; low‐certainty evidence; Analysis 2.19). Despite the low number of participants, recurrent varicose veins could have other factors driving the formation of new varicose veins. The recanalisation rate is another important issue to be studied. As described by Hamel‐Desnos 2007, the recanalisation event in sclerotherapy evolves into a smaller vein diameter. Those recanalised veins were successfully treated with a new sclerotherapy session. It is not clear if the recanalisation and reflux into a smaller vein diameter is a disease capable of producing chronic venous insufficiency in the long run since fibrous tissues in venous walls could limit newer diameter increments. Labropoulos 1995 demonstrated that saphenous veins were developing reflux after a working day in normal medical subjects (Labropoulos 1995). Maybe, in this case, reflux is not the best outcome to be evaluated. The possible confusion sources drove the authors to consider technical success as occluded, fibrotic, or reabsorbed veins.

Comparison 4: Foam sclerotherapy versus liquid sclerotherapy

Nine RCTs reported on this comparison. See summary of findings Table 3.

The use of liquid or foam sclerotherapy for better cosmetic appearance results still needs to be answered since there were conflicting data due to the heterogeneity of sclerosant concentrations (polidocanol liquid concentrations ranged from 0.75% to 1.25% versus polidocanol foam 1.5% to 2.5%). In one study in the long‐term period, there was no difference in patient satisfaction (MD 0.20, 95% CI ‐0.27 to 0.67; 1 study, 126 participants; very low‐certainty evidence) (Analysis 3.1). It is necessary to consider that a liquid volume is converted to a higher volume in foam presentation, possibly being more efficient to occupy vessel lumen and to sclerose varicose veins using a smaller overall volume of sclerosant agent (Pollak 2008). Gas also causes floating phenomena that boost foam to the top part of the target vessels. In a lying patient, this floating phenomenon could cause damage only in the top portion of the venous lumen. These factors could explain more spasm in foam than in liquid intervention (Ouvry 2008), but it could drive sclerotherapy results in any effect direction since it can produce recanalisation with no success of occluding the varicose veins.

Complications were described again as mild to moderate in foam versus liquid sclerotherapy and there were no DVTs described in the participants treated. An active search for DVT was not reported by the included studies. There were no differences in skin pigmentation rates between both interventions (RR 1.75, 95% CI 0.81 to 3.80; 2 studies, 208 participants) (Analysis 3.2).

There was a consistent reduction in residual varicose vein rates at a long‐term period in the foam intervention group. We did not think it was appropriate to pool overall as different concentrations and sclerosants were used, so data have been presented as subgroup analyses. We decided to report and assess results from polidocanol 3% foam versus 3% liquid as this is the most clinically relevant: RR 0.51, 95% CI 0.41 to 0.65; 2 studies, 203 participants; very low‐certainty evidence (Analysis 3.3), indicating foam is more effective than liquid sclerotherapy in resolving residual varicose veins.

No RCT reported on quality of life or persistence of symptoms.

One additional RCT reported similar recurrence rates between the foam and liquid groups (Belcaro 2003b) (RR 1.10, 95% CI 0.86 to 1.42; 1 study, 286 participants; very low‐certainty evidence, Analysis 3.5). Differently from conventional foams, the foam produced in this RCT used a tensioactive substance to enhance ultrasound vision (ultrasound contrast agent). Otherwise, factors that drive recurrence are related to the formation of new varicose veins and maybe not be influenced by the sclerosant used.

Comparison 5: Sclerotherapy versus sclerotherapy with different substances

Four RCTs compared sclerotherapy versus sclerotherapy with any other substance. See summary of findings Table 4.

Cosmetic appearance was evaluated by two RCTs but it was not possible to draw conclusions as different polidocanol and STS concentrations were used (Goldman 2002), and different vein diameters for different concentrations compared (Rao 2005), so we were not able to draw conclusions about the benefit of one product over the other (Analysis 4.1). No other sclerosant was investigated, so, the best sclerotherapy agent still needs to be determined.

King 2015 and Todd 2014 described rare neurologic events as mild and completely recovered with observation in all participants using foam with room air or with CO₂ and O₂ gas mixture (Varisolve) (Wright 2006); but there was insufficient information to indicate any ideal gas mixture for sclerotherapy. The same RCT lacked congruency since comparison was with any market sclerosant liquid or foam and did not discriminate between participants with CEAP C1 and C2 (Wright 2006). However, the RCTs found no differences in the occurrence of DVT (RR 0.97, 95% CI 0.09 to 10.54; 1 study, 384 participants; Analysis 4.2), skin pigmentation (RR 1.01, 95% CI 0.80 to 1.27; 1 study, 384 participants; Analysis 4.3), or haematoma formation (RR 1.56, 95% CI 0.76 to 3.18; 1 study, 384 participants; Analysis 4.4). Goldman 2002 found no differences in skin pigmentation rates (RR 1.21, 95% CI 0.95 to 1.55; 1 study, 167 participants) (Analysis 4.5) and skin necrosis numbers (RR 14.12, 95% CI 0.81 to 246.76; 1 study, 167 participants) (Analysis 4.6). The study also described thrombosis of the vein, probably related to thrombophlebitis or venous occlusion (superficial venous system) and did not describe DVT.

Wright 2006 also investigated the rates of residual varicose veins at 12 months and found higher rates in any market sclerosant (RR 0.64, 95% CI 0.42 to 0.97; 1 study, 373 participants; Analysis 4.7). The incongruence in the comparator made it difficult to interpret results.

No RCT investigated quality of life or persistence of symptoms. It is a disappointing finding for the systematic review since varicose vein treatment aims to improve quality of life and to reduce complication rates.

Matting also was investigated by Goldman 2002 and there were no clinical differences in the number of matting rates between the STS 1.5% group compared to polidocanol 3% (RR 1.53, 95% CI 0.58 to 4.02; 1 study, 167 participants; Analysis 4.8). There is also a need for congruency in objectives and outcomes in this comparison since varicose vein disease is probably incurable, and treatment is not directed to the aetiology of the disease (Labas 2003). Many factors that can produce varicose veins will drive the recurrence rates. Mainly, sclerotherapy alone or in association with any other intervention is essential for varicose vein treatment. Sclerotherapy is a unique and effective treatment in any varicose vein and with any diameter (Labas 2003). Sometimes, matting can be confused with a flare formation. Matting is formed by tiny vessels that usually disappear by themselves from weeks to months. As Goldman 2002 described the outcome at 16 weeks, we decided to include these results as residual varicose veins in this section (considering, possibly, a flare formation or a residual telangiectasia).

Comparison 6: Sclerotherapy versus sclerotherapy with different techniques

Six RCTs evaluated different techniques for injection sclerotherapy (Chleir 1997; Ragg 2015; Santos 2019; Yamaki 2009; Yamaki 2012; Zhang 2014).

Surprisingly, no RCT investigated cosmetic appearance using different techniques.

There were no thromboembolic complications detected in the antegrade versus retrograde sclerotherapy comparison (Analysis 5.1) (Zhang 2014). Phlebitis and thrombophlebitis, and skin pigmentation rates were also not different (Analysis 5.1; Analysis 5.2). It is important to report that, in a study comparing few versus multiple injections for sclerotherapy, less foam was detected in the deep veins when using multiple injections (Yamaki 2009) (Analysis 5.4). If an embolus originated from the superficial venous system, there is a better prognosis due to the smaller diameter of the veins (Wu 2017). On the other hand, the deep venous system has the potential to produce a bigger embolus increasing the risk of death to patients. Thromboembolic events were related to a proximal extension of a superficial thrombus usually derived from saphenous veins, or the extension of a perforator vein. DVT can also occur without an extension thrombus from the superficial venous system. So it is essential to investigate if foam in higher concentrations in the deep vein could cause any hazard to patients.

Injection by a catheter associated with tumescent technique reduced residual varicose veins in the short‐term period compared to needle injection (Santos 2019). However, other different sclerotherapy techniques did not show any benefit in reducing residual varicose vein rates, clinical severity scores, and complications (Analysis 5.5; Analysis 5.6; Analysis 5.7; Analysis 5.8; Analysis 5.9; Analysis 5.10; Analysis 5.14). After six months, participants from both groups (catheter‐delivered associated with tumescent technique versus needle‐delivered sclerotherapy) needed retreatment (Santos 2019). The studies need to be more congruent and with a larger number of participants to increase certainty. Despite incongruence, it does not appear that different techniques produce different outcomes. Concerns about outcomes remain related to proximal versus distal technique for sclerotherapy (if treating proximal saphenous vein versus distal saphenous vein).

Sclerotherapy versus different conservative treatment

Comparison 7: Sclerotherapy versus pharmacological therapy

No RCT evaluated sclerotherapy with pharmacological therapy. It is important to note that this comparison involves expensive medication for some people. So, a study including a cost‐effectiveness analysis should be carried out to ensure there are more benefit than harms to patients since varicose veins impact quality of life more than they risk life.

Comparison 8: Sclerotherapy versus conservative compression treatment

Only one RCT reported on this comparison (Abramowitz 1973). The RCT was conducted in 1973 in South Africa and enrolled only pregnant women. It is of some importance since pregnant women are a subgroup of vulnerable patients at risk of complications (phlebitis, deep vein thrombosis, bleeding) (Smyth 2015). In the RCT, there was an improvement of pooled data from symptomatic and cosmetic improvement outcomes (RR 7.96, 95% CI 3.38 to 18.76; 1 study, 101 participants; Analysis 6.1), at the same time, producing more leg ulcer rates in the sclerotherapy group (RR 13.63, 95% CI 0.77 to 240.13; 1 study, 101 participants; Analysis 6.2). Despite the need to treat pregnant women, there are concerns related to the risks of DVT and PE produced by the procedure. As described by Smyth 2015, there is still a paucity of data in the literature. Ethical concerns will drive future research.

Overall completeness and applicability of evidence

Overall, 4278 participants were included in the RCTs, increasing the confidence that the procedure is a safe and an effective treatment. The aim of the review was to include CEAP C2, C3, and C4 criteria varicose veins. Due to differences in the vein diameter, the effects presented in this review are likely not relevant to people with CEAP C1, but possibly some results could also be applied to people with CEAP C5 and C6 (e.g. occlusion rates). Even in the cases of residual varicose veins, new sessions of sclerotherapy are feasible and acceptable procedures while other more invasive methods are related to patients' costs and risks.

RCTs described cosmetic appearance and complications (including staining, DVT and PE). However, there is a lack of consistency between interventions, time points, and outcomes evaluated. There was variability and heterogeneity in participants, drugs, drug concentrations, varicose veins classification, and interventions (e.g. usage or non‐usage of stockings after sclerotherapy). The present systematic review did not investigate the role of co‐interventions.

Overall, varicose veins are heterogeneous and, even when not described, there are likely to be smaller varicose veins (including CEAP C1) associated with the clinical classes described. Sclerosant agents may reach these veins, as noted in clinical practice. So it is important to have similar proportions of participants with C1, C5, and C6 between intervention and control groups. We described these proportions of CEAP C1, C5, and C6 in the footnotes of the meta‐analyses to assist with a critical analysis. It was not possible to estimate if the depth of the vein could result in different ratings of skin pigmentation due to the lack of information provided.

Quality of life and symptoms were poorly reported. Some studies used VCSS to report symptoms; however, for VCSS, there is one attribute for symptoms and eight attributes for signs. So, there is a lack of data to increase confidence in the estimate of the effect. For symptoms, there is a need for establishing a cause‐effect relationship.

It should be taken into account that it is not the aim of this review to evaluate injection sclerotherapy versus varicose vein surgery methods. This subject is the scope of another Cochrane Review. Applicability of the evidence is limited to injection sclerotherapy and their comparators with other types of sclerotherapy including other techniques of performing injection sclerotherapy.

There was no evidence found for three interventions due to a lack of RCTs investigating these.

Sclerotherapy versus no interventions for varicose veins
Sclerotherapy versus sclerotherapy at different time intervals
Sclerotherapy versus pharmacological therapy

Quality of the evidence

Overall, certainty of the evidence was very low to moderate. This is due to the heterogeneity of the interventions and population (including participants with CEAP class C1, C5, and C6 in the studies), variation in concentration of medicines, different time point measures, lack of core outcome set definitions (for instance: recurrent varicose veins and residual varicose veins), some outcomes evaluated by single RCTs, low number of events (e.g. DVT), wide confidence intervals including the line of no effect, most risk of bias domains judged as unclear, and different units of analysis studied. We decided to use the GRADE approach to assess our certainty of the evidence for the outcomes cosmetic appearance, complications (thromboembolic complications), residual varicose veins, quality of life, persistence of symptoms, and recurrent varicose veins. We created a summary of findings table for each of the four main comparisons.

Foam sclerotherapy (1% polidocanol) versus placebo for treating varicose veins (summary of findings Table 1)
Foam sclerotherapy (3% polidocanol) versus foam sclerotherapy (polidocanol 1%) for treating varicose veins (summary of findings Table 2)
Foam sclerotherapy versus liquid sclerotherapy for treating varicose veins (summary of findings Table 3)
Sclerotherapy with STS 1% versus sclerotherapy with polidocanol 1% (summary of findings Table 4)

Foam sclerotherapy (polidocanol 1%) versus placebo

See summary of findings Table 1.

Five RCTs compared polidocanol foam sclerotherapy versus placebo but only three provided results from polidocanol 1% foam versus placebo to grade the certainty of the evidence (Gibson 2010; King 2015; Todd 2014). There was a considerable variation of polidocanol concentration used, ranging from 0.125% (King 2015; Todd 2014) to 2% (King 2015). For grading certainty of the evidence, polidocanol 1% foam was chosen as the interventional group since there is a trend to increase occluded veins rates with up to 1% polidocanol foam (King 2015), and 1% concentration is clinically relevant.

We understand that is impossible to blind personnel and participants for this comparison due to the nature of the intervention but we downgraded two levels for risk of bias concerns.

For cosmetic appearance, the evidence was downgraded to very low‐certainty for risk of bias concerns and indirectness (one RCT (Todd 2014) included 8.8% participants with CEAP C5 and C6 in the placebo group and 3.4% participants with CEAP C5 and C6 in the 1% polidocanol foam group ‐ we planned to include CEAP C2, C3 or C4 participants. As the study authors included participants with other CEAP classes and we were unable to obtain information to exclude these data, we determined the population in the study as an indirect population).

The evidence for thromboembolic complications was downgraded to very low‐certainty for risk of bias concerns and due to the indirectness, imprecision (low number of events, wide confidence intervals), and both clinical heterogeneity among studies (severity of the disease) and statistical heterogeneity (I² = 53%).

The outcome, residual varicose veins, was downgraded to very low‐certainty evidence due to the same limitations observed in the cosmetic appearance outcome.

Quality of life and the persistence of symptoms were both downgraded to very low‐certainty evidence due to indirectness (8.8% of participants in the placebo group had CEAP C5 or C6), imprecision (low number of participants, and wide confidence intervals).

No RCT investigated recurrent varicose veins.

Foam sclerotherapy (polidocanol 3%) versus foam sclerotherapy (polidocanol 1%)

See summary of findings Table 2.

Polidocanol foam 3% versus 1% concentrations were chosen to evaluate the certainty of the evidence due to clinical relevance.

Only Ceulen 2007 evaluated cosmetic appearance. As most of the risk of bias domains were unclear, inclusion of only a single study with a wide confidence interval (imprecision), and a low number of participants (imprecision); the evidence was downgraded to very low‐certainty.

Thromboembolic complications were measured by three RCTs (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007) and the evidence was judged as very low‐certainty due to indirectness (there were participants with CEAP C1 (11.63% in Ceulen 2007), C5 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007) and C6 (Hamel‐Desnos 2007) but the lower legs were equal in each group), imprecision (low number of events) and wide confidence intervals. Ceulen 2007 used the lower leg as the unit of analysis and there was a heterogeneous population (11.64% with CEAP C1), so a sensitivity analysis was carried out (Analysis 2.6). The effect direction was not changed.

Residual varicose veins were evaluated by three RCTs (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), with indirectness (there were participants with CEAP C1 (11.63% in Ceulen 2007), C5 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), and C6 (Hamel‐Desnos 2007) but these were equal in each group). Therefore, the evidence was rated as moderate‐certainty evidence.

No RCT described the quality of life or the persistence of symptoms for this comparison.

Recurrent varicose veins were investigated by one RCT (Hamel‐Desnos 2007). We detected imprecision (single study), and indirectness (participants with CEAP C5 and C6 (Hamel‐Desnos 2007) without describing the proportion of these participants in the study arms). We downgraded by two levels and the evidence was judged as low‐certainty evidence.

Foam sclerotherapy versus liquid sclerotherapy

See summary of findings Table 3.

Ten RCTs reported on the comparison foam versus liquid sclerotherapy. There were outcomes that may not have correlated with clinical implications (immediate spasm after sclerotherapy) (Ouvry 2008) and substantial differences in sclerosant concentrations (ranging from 1.5% to 2.5% in liquid versus 0.75% to 1.25% in the foam group (Alos 2006)), lacking congruency.

For cosmetic appearance, the certainty of the evidence was downgraded to very low due to lack of description of the randomisation method, risk of bias concerns (the RCT probably not blinded due to the nature of the intervention), indirect population, single study, and comparing different concentrations of the same substances in different vein diameters in both arms of the study.

No RCT investigated DVT, quality of life, or persistence of symptoms.

There was a lack of data for the complications outcome, despite some RCTs describing complications such as thrombophlebitis and skin pigmentation as mild. No DVT events were described and we are not sure if the outcome was systematically investigated in the RCTs.

Six RCTs reported on residual varicose veins and two of them compared polidocanol 3% liquid versus foam (Ouvry 2008; Rabe 2008). We assessed this outcome as having very low‐certainty evidence. The quality was downgraded since there was doubt about the randomisation method, the intervention was presumably not blinded due to the nature of the intervention, and one study (Ouvry 2008) included participants from CEAP C2 to C6 without discriminating between then. The other study (Rabe 2008) included one participant with CEAP C5 in the foam group (1.85%) and four participants with CEAP C5 in the liquid group intervention (7.69%).

Recurrent varicose veins and flare formation was investigated by one RCT (Belcaro 2003b). There was some doubt about the randomisation method used. The intervention was presumably not blinded due to the nature of the intervention. There was a single RCT, and the author did not describe CEAP participants. Belcaro 2003b also used a tensioactive substance to enhance ultrasound vision (ultrasound contrast agent) to produce foam, which is not the usual way to produce foam. We judged the evidence as very low‐certainty.

Sclerotherapy with STS 1% versus sclerotherapy with polidocanol 1%

Data were insufficient to allow assessment using the GRADE criteria. See summary of findings Table 4.

Potential biases in the review process

We were unable to carry out a funnel plot analysis to investigate publication bias since there were fewer than 10 RCTs for each meta‐analysis. Due to unavailable data, it was impossible to perform a subgroup analysis between CEAP C2, C3, and C4 groups and symptomatic versus nonsymptomatic participants. Indeed, no RCTs evaluated the depth of the vein as a possible issue influencing pigmentation. Also, previous complications were exclusion criteria for the studies, limiting subgroup analysis.

Authors were contacted to reduce bias in the review process. Most of them did not reply. Some RCTs were old, and others had no contact authors available (Abramowitz 1973; Chleir 1997; Demagny 2002; Ragg 2015; Schadeck 1995a; Zeh 2003; Zhang 2009; Zhang 2014).

Two RCTs had heterogeneous populations including some participants with CEAP C1 (Ceulen 2007; Zhang 2009). It was expected that there would be fewer thromboembolic and pigmentation rates in some of these subgroups. Differences from protocols were noted where participants with CEAP C1 should not be included. Ceulen 2007 included 12.8% of participants with CEAP C1, and Zhang 2009 did not discriminate between the proportions of the C1 class. Given this consideration, we included Ceulen 2007 in the meta‐analysis but Zhang 2009 was not included since the author did not describe the proportion of CEAP C1 included in each group. A sensitivity analysis was conducted to check the robustness of the results. Similarly, other RCTs considered CEAP C5 and C6 inclusions. All of them were described, with the proportions of the non‐proposed clinical classes included in each analysis and taken into consideration when interpreting the results.

Three studies were assessed as 'awaiting classification'; there was a lack of data and we were unable to contact the authors for two of the studies (Labas 2003; Satokawa 2003; Schadeck 1995b); and we were unable to determine if one study was a randomised or quasi‐randomised controlled trial (Varnagy 1985).

Co‐interventions were used during and after injection sclerotherapy (e.g. walking after injection sclerotherapy) (King 2015; Todd 2014). These co‐interventions may have influenced the outcomes and there could be other confounders to consider. One crucial co‐intervention is the use or not of medical stockings after injection sclerotherapy. We suggest that this issue could be better evaluated in a further systematic review to evaluate sclerotherapy versus compression sclerotherapy for varicose veins. Lattimer 2012 described a lack of criteria between side effects and treatment effects, making it difficult to quantify in a meaningful way an effect size in a multi‐ethnic and multicultural population. Lattimer 2012 also concluded that pigmentation, inflammation, pain, and other side effects could be effects from the stockings rather than from sclerotherapy. These arguments contributed to deciding not to include compression stockings in this review. Despite that, the co‐intervention was common in the included studies, and the real effect of compression was not evaluated.

Despite a proposed subgroup analysis to evaluate the different gases for foam sclerotherapy, there was no study comparing them. So, the issue of different gases to reduce incidence of neurological complications is still to be resolved (Gibson 2010).

We considered it important to make a distinction between 'recurrent varicose veins' and 'residual varicose veins' because of the clinical relevance. The previous version of this review considered the time to measure the outcome and 'recurrent varicose veins' was defined as an outcome related to the time of the detection (described as 'long‐term patient follow‐up'). The previous version of the review included 'flare formation' in the same outcome. We believe these outcomes are quite different and they should not be measured together. Differences in definitions used by the study authors led us to consider the long‐term outcome as a 'recurrent varicose vein' and short‐term outcome as 'residual varicose vein'. This definition carries bias but we believe we need to be pragmatic. We will consider the subject again in a future update of this review.

As with many other interventions, age is likely to increase heterogeneity between study groups. Despite balanced groups there could be different results in older and younger patients. This Cochrane review did not address this topic since we did not have data to investigate this. If possible, we will address this concern in a future update.

Agreements and disagreements with other studies or reviews

One systematic review described foam sclerotherapy as an effective and safe procedure similar to the findings of this review (Rathbun 2012). It also described rare serious events like myocardial infarction and death related to sclerotherapy detected in case reports. Our update did not find any of these severe events. Death rates could be a result of the amount of sclerotherapy agent administered as well as anaphylactic reaction and the RCTs were perhaps aware of the injection volume. Rabe 2014 recommended the maximum injection foam volume of 10 mL since complications like thrombosis and neurological symptoms tend to occur in higher volume injections. This updated review considered only randomised clinical trials while Rathbun 2012 considered other study types, including case reports, making it difficult to directly compare findings. However, it is important to report that most neurologic events are described in case reports since they are rare (Sarvananthan 2012; Willemberg 2013). So, systematic reviews involving case reports could find more events than those described in the present update.

A systematic review by Hammel‐Desnos 2009 found foam better than liquid for reducing rates of residual varicose veins. This review update confirmed this finding with very low‐certainty evidence. There is still a need for congruence in comparators and doses.

No other systematic review involved only sclerotherapy, highlighting the importance of this update to answer clinical questions.

Figure 1

Study flow diagram.

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Figure 2

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

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Analysis 1.1

Comparison 1: Foam sclerotherapy versus placebo, Outcome 1: Cosmetic appearance: medical related IPR‐V adjusted mean change from baseline (intermediate term)

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Analysis 1.2

Comparison 1: Foam sclerotherapy versus placebo, Outcome 2: Cosmetic appearance: participant self assessment PA‐V adjusted mean change from baseline (intermediate term)

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Analysis 1.3

Comparison 1: Foam sclerotherapy versus placebo, Outcome 3: DVT (short and intermediate term)

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Analysis 1.4

Comparison 1: Foam sclerotherapy versus placebo, Outcome 4: Phlebitis or thrombophlebitis rates (intermediate term)

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Analysis 1.5

Comparison 1: Foam sclerotherapy versus placebo, Outcome 5: Phlebitis or thrombophlebitis rates (intermediate term)

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Analysis 1.6

Comparison 1: Foam sclerotherapy versus placebo, Outcome 6: Haemorrhagic complications (short term)

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Analysis 1.7

Comparison 1: Foam sclerotherapy versus placebo, Outcome 7: Neurologic complications (dizziness, TIA) (short term)

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Analysis 1.8

Comparison 1: Foam sclerotherapy versus placebo, Outcome 8: Residual varicose veins (intermediate term)

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Analysis 1.9

Comparison 1: Foam sclerotherapy versus placebo, Outcome 9: Quality of life: VEINES‐QOL score change from baseline (intermediate term)

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Analysis 1.10

Comparison 1: Foam sclerotherapy versus placebo, Outcome 10: Persistence of symptoms: absolute change from baseline score for the VVSymQ (total score) (intermediate term)

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Analysis 1.11

Comparison 1: Foam sclerotherapy versus placebo, Outcome 11: Persistence of symptoms: mean change from baseline score for the VCSS (total score) (intermediate term)

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Analysis 2.1

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 1: Cosmetic appearance: number of participants with cosmetic improvement (short term) ‐ polidocanol 3% foam versus polidocanol 1% foam

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Analysis 2.2

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 2: Cosmetic appearance: number of participants with cosmetic improvement (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam

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Analysis 2.3

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 3: Cosmetic appearance: adjusted mean PA‐V (intermediate term) ‐ polidocanol foam versus polidocanol foam

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Analysis 2.4

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 4: Cosmetic appearance: adjusted mean IPR‐V (intermediate term) ‐ polidocanol foam versus polidocanol foam

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Analysis 2.5

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 5: Thromboembolic complications (intermediate term) ‐ polidocanol 3% foam versus polidocanol 1% foam

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Analysis 2.6

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 6: Thromboembolic complications (intermediate term) ‐ polidocanol 3% foam versus polidocanol 1% foam (sensitivity analysis)

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Analysis 2.7

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 7: DVT (short and intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration

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Analysis 2.8

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 8: PE (short term) ‐ polidocanol 1% foam versus polidocanol 3% foam

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Analysis 2.9

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 9: Skin pigmentation rates (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam

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Analysis 2.10

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 10: Phlebitis or thrombophlebitis rates (intermediate term) ‐ polidocanol < 1% foam versus polidocanol ≥ 1% foam

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Analysis 2.11

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 11: Phlebitis or thrombophlebitis ‐ polidocanol 3% foam versus polidocanol 1% foam

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Analysis 2.12

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 12: Haemorrhagic complications (intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration

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Analysis 2.13

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 13: Neurologic complications (dizziness, TIA) (intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration

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Analysis 2.14

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 14: Residual varicose veins (intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration

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Analysis 2.15

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 15: Residual varicose veins (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam

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Analysis 2.16

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 16: Residual varicose veins (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam (sensitivity analysis)

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Analysis 2.17

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 17: Quality of life: adjusted mean change VEINES‐QOL (intermediate term) ‐ polidocanol foam versus polidocanol foam

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Analysis 2.18

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 18: Persistence of symptoms: adjusted mean change from baseline VCSS score (intermediate term) ‐ polidocanol foam versus polidocanol foam

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Analysis 2.19

Comparison 2: Foam sclerotherapy versus foam sclerotherapy with different concentrations, Outcome 19: Recurrent varicose veins (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam

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Analysis 3.1

Comparison 3: Foam sclerotherapy versus liquid sclerotherapy, Outcome 1: Cosmetic appearance: participant satisfaction (long term) ‐ polidocanol foam versus polidocanol liquid

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Analysis 3.2

Comparison 3: Foam sclerotherapy versus liquid sclerotherapy, Outcome 2: Skin pigmentation (long term) ‐ polidocanol foam versus polidocanol liquid

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Analysis 3.3

Comparison 3: Foam sclerotherapy versus liquid sclerotherapy, Outcome 3: Residual varicose veins (long term) ‐ polidocanol foam versus polidocanol liquid

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Analysis 3.4

Comparison 3: Foam sclerotherapy versus liquid sclerotherapy, Outcome 4: Residual varicose veins (long term) ‐ polidocanol foam versus polidocanol liquid (sensitivity analysis)

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Analysis 3.5

Comparison 3: Foam sclerotherapy versus liquid sclerotherapy, Outcome 5: Recurrent varicose veins (long term) ‐ STS 3% liquid versus STS 3% foam

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Analysis 4.1

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 1: Cosmetic appearance: disappearance of varicose veins (long term) ‐ polidocanol 3% versus STS 1.5%

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Analysis 4.2

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 2: DVT (short and intermediate term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam)

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Analysis 4.3

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 3: Skin pigmentation (intermediate term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam)

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Analysis 4.4

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 4: Haematoma (short term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam)

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Analysis 4.5

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 5: Skin pigmentation (long term) ‐ STS 1.5% versus polidocanol 3%

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Analysis 4.6

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 6: Skin necrosis (long term) ‐ STS 1.5% versus polidocanol 3%

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Analysis 4.7

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 7: Residual varicose veins (long term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam)

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Analysis 4.8

Comparison 4: Sclerotherapy versus sclerotherapy with different substances, Outcome 8: Matting (long term) ‐ STS 1.5% versus polidocanol 3%

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Analysis 5.1

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 1: Phlebitis or thrombophlebitis rates (short term) ‐ polidocanol 1% foam ‐ antegrade versus retrograde technique

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Analysis 5.2

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 2: Skin pigmentation rates (long term) ‐ polidocanol 1% foam ‐ antegrade versus retrograde technique

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Analysis 5.3

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 3: Thrombophlebitis rates (short term) ‐ polidocanol 3% foam injected by catheter associated to tumescent technique versus polidocanol 3% foam injected by needle

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Analysis 5.4

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 4: Detection of polidocanol foam in deep veins ‐ few injections versus multiple injections

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Analysis 5.5

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 5: Residual varicose veins (long term) ‐ visual foam sclerotherapy versus ultrasound guided foam + visual foam sclerotherapy

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$Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 6: Residual varicose veins (long term) ‐ multiple/fractionated injections versus few/single injections$

Analysis 5.6

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 6: Residual varicose veins (long term) ‐ multiple/fractionated injections versus few/single injections

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Analysis 5.7

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 7: Residual varicose veins (intermediate term) ‐ polidocanol 1% foam retrograde versus antegrade technique

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Analysis 5.8

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 8: Residual varicose veins (intermediate term) ‐ microcatheter directed foam sclerotherapy versus catheter directed foam sclerotherapy

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Analysis 5.9

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 9: Residual varicose veins (intermediate term) ‐ needle foam sclerotherapy versus catheter directed foam sclerotherapy

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Analysis 5.10

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 10: Residual varicose veins (intermediate term) ‐ needle foam sclerotherapy versus microcatheter directed foam sclerotherapy

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Analysis 5.11

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 11: Residual varicose veins (short term) ‐ polidocanol 3% foam injected by catheter versus polidocanol 3% foam injected by needle

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Analysis 5.12

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 12: Participants not requiring retreatment (long term) ‐ polidocanol 3% foam injected by catheter versus polidocanol 3% foam injected by needle

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Analysis 5.13

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 13: QoL: AVVQ (long term) ‐ catheter‐directed foam sclerotherapy with tumescence versus ultrasound‐guided foam sclerotherapy

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Analysis 5.14

Comparison 5: Sclerotherapy versus sclerotherapy with different techniques, Outcome 14: VCSS (long term) ‐ ultrasound guided foam + visual foam sclerotherapy versus visual foam sclerotherapy

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Analysis 6.1

Comparison 6: Sclerotherapy versus compression conservative treatment, Outcome 1: Cosmetic appearance: good symptomatic improvement and cosmetic result (long term) liquid STS versus compression

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Analysis 6.2

Comparison 6: Sclerotherapy versus compression conservative treatment, Outcome 2: Ulcer (short, intermediate and long term) ‐ liquid STS versus compression

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Summary of findings 1. Foam sclerotherapy versus placebo for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Foam sclerotherapy (polidocanol 1%) compared to placebo for varicose veins
Patient or population: participants with varicose veins^a Setting: clinical or hospital‐based study Intervention: polidocanol 1% foam sclerotherapy Comparison: placebo
Outcomes	Risk with placebo	Risk with polidocanol 1% foam sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance (IPR‐V) (Scale from: 0 to 4; 0 being the best appearance (0: none, 1: mild, 2: moderate, 3: severe, 4: very severe)) follow‐up: 8 weeks	The adjusted mean change from baseline in cosmetic appearance (IPR‐V) was ‐0.04	The MD was 0.76 lower (0.91 lower to 0.6 lower)	‐	223 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c
Complications ‐ DVT follow‐up: 8 weeks	Study population		RR 5.10 (1.30 to 20.01)	302 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e,f
Complications ‐ DVT follow‐up: 8 weeks	13 per 1000	68 per 1000 (17 to 265)	RR 5.10 (1.30 to 20.01)	302 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e,f
Residual varicose veins follow‐up: 8 weeks	Study population		RR 0.19 (0.13 to 0.29)	225 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c
Residual varicose veins follow‐up: 8 weeks	973 per 1000	185 per 1000 (127 to 282)	RR 0.19 (0.13 to 0.29)	225 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c
QoL (VEINES‐QOL/Sym; scale from: 0 to 50 with 0 being the worst and 50 better) follow‐up: 8 weeks	The mean change from baseline in QoL (VEINES‐QOL/Sym score) was 9.60	The MD was 12.41 higher (9.56 higher to 15.26 higher)	‐	299 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^f,g,h
Persistence of symptoms (VCSS) follow‐up: 8 weeks	The mean change from baseline in persistence of symptoms (VCSS score) was ‐1.14	The MD was 3.25 lower (3.9 lower to 2.6 lower)	‐	223 (2 RCTs)	⊕⊕⊝⊝ LOW ^g,h
Recurrent varicose veins	See comment		‐	‐	‐	No study evaluated recurrent varicose veins in this comparison
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT: deep vein thrombosis; IPR‐V: independent photography review ‐ visible varicose veins scores;MD: mean difference; QoL: quality of life; RCT: randomised controlled trial; RR: risk ratio; VCSS: venous clinical severity score; VEINES‐QOL/Sym: disease‐specific QoL instrument for chronic venous disorders of the leg
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^a There were CEAP C1 (11.63% in Ceulen 2007), C5 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), and C6 (Hamel‐Desnos 2007) participants included but there was no description of the proportion of these participants in the groups. Ceulen 2007 used the lower leg as the unit of analysis. In the remaining studies, the participant was the unit of analysis. ^b We downgraded the certainty of the evidence two levels as neither personnel nor participants were blinded (risk of bias concerns). ^c We downgraded one level for indirectness as Todd 2014 included 8.8% CEAP C5 and C6 in the placebo group and 3.4% CEAP C5 and C6 in the polidocanol 1% foam group. ^d We downgraded one level due to inconsistency ‐ clinical heterogeneity among studies (severity of disease). ^e We downgraded one level for imprecision due to low number of events; CI included both 'no difference' and a 'clinically important difference'. ^f We downgraded one level due to a wide CI. ^g We downgraded one level for imprecision ‐ low number of participants. ^h We downgraded one level for indirectness (8.8% CEAP C5 and C6 participants in the placebo group).

Summary of findings 1. Foam sclerotherapy versus placebo for treating varicose veins

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Summary of findings 2. Foam sclerotherapy versus foam sclerotherapy for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Foam sclerotherapy (polidocanol 3%) compared to foam sclerotherapy (polidocanol 1%) for treating varicose veins
Patient or population: participants with varicose veins^a Setting: hospital or clinical setting Intervention: polidocanol 3% foam sclerotherapy Comparison: polidocanol 1% foam sclerotherapy
Outcomes	Risk with polidocanol 1% foam sclerotherapy	Risk with polidocanol 3% foam sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance (self‐described cosmetic improvement) follow‐up: mean 1 year	Study population		RR 1.11 (0.84 to 1.47)	80 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e
	675 per 1000	749 per 1000 (567 to 992)	RR 1.11 (0.84 to 1.47)	80 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^b,c,d,e
Complications ‐ thromboembolic follow‐up: range 3 weeks to 6 months	Study population		RR 1.47 (0.41 to 5.33)	371 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^d,f,g
	16 per 1000	24 per 1000 (7 to 86)	RR 1.47 (0.41 to 5.33)	371 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^d,f,g
Residual varicose veins follow‐up: range 6 months to 2 years	Study population		RR 0.67 (0.43 to 1.04)	371 (3 RCTs)	⊕⊕⊕⊝ MODERATE ^f
	364 per 1000	244 per 1000 (156 to 378)	RR 0.67 (0.43 to 1.04)	371 (3 RCTs)	⊕⊕⊕⊝ MODERATE ^f
QoL	See comment		‐	‐	‐	No study evaluated QoL for this comparison
Persistence of symptoms	See comment		‐	‐	‐	No study evaluated persistence of symptoms for this comparison
Recurrent varicose veins follow‐up: mean 2 years	Study population		RR 0.91 (0.62 to 1.32)	148 (1 RCT)	⊕⊕⊝⊝ LOW ^c,h
Recurrent varicose veins follow‐up: mean 2 years	446 per 1000	406 per 1000 (276 to 589)	RR 0.91 (0.62 to 1.32)	148 (1 RCT)	⊕⊕⊝⊝ LOW ^c,h
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; QoL: quality of life; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aCeulen 2007 included 12.5% C1 participants. The studies included participants from C2 to C6 clinical classes without description of the proportions of C5 and C6 participants. ^b We downgraded by one level as most risk of bias domains were judged as "unclear". ^c We downgraded by one level due to imprecision ‐ single study. ^d We downgraded by one level due to imprecision ‐ wide confidence interval. ^e We downgraded by one level due to imprecision ‐ low number of participants. ^f There were CEAP C1 (11.63% in Ceulen 2007), C5 (Blaise 2010; Ceulen 2007; Hamel‐Desnos 2007), and C6 (Hamel‐Desnos 2007) participants included but there was no description of the proportion of these participants in the groups. Ceulen 2007) used the lower leg as the unit of analysis. In the remaining studies, the participant was the unit of analysis. We downgraded by one level for indirectness. ^g We downgraded by one level due to imprecision ‐ low number of events. ^h There were participants from C5 and C6 clinical classes included (Hamel‐Desnos 2007) but there was no description of the proportion of these participants in the groups. We downgraded by one level for indirectness.

Summary of findings 2. Foam sclerotherapy versus foam sclerotherapy for treating varicose veins

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Summary of findings 3. Foam sclerotherapy versus liquid sclerotherapy for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Foam sclerotherapy compared to liquid sclerotherapy for varicose treating veins
Patient or population: participants with varicose veins^a Setting: hospital or clinic‐based Intervention: foam sclerotherapy using the same agent and concentration of the control Comparison: liquid sclerotherapy using the same agent and concentration of the intervention
Outcomes	Risk with liquid sclerotherapy	Risk with foam sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance (patient satisfaction scale, the higher the better) follow‐up: long‐term (365 days)	The mean cosmetic appearance of the patient satisfaction scale was 7.2	The MD was 0.2 higher (0.27 lower to 0.67 higher)	‐	126 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^a,b,c	Alos 2006 reported no difference when using polidocanol 0.75% to 1.25% foam versus polidocanol 1.5% to 2.5% liquid. Different concentrations and different vein diameters were compared, reducing our confidence in these results
Complications ‐ DVT	See comment		‐	‐	‐	No study evaluated DVT or thromboembolic events for this comparison
Residual varicose veins follow‐up: range 3 months to 2 years	Study population		RR 0.51 (0.41 to 0.65)	203 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d
	842 per 1000	429 per 1000 (345 to 547)	RR 0.51 (0.41 to 0.65)	203 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^b,c,d
QoL	See comment		‐	‐	‐	No study evaluated QoLfor this comparison
Persistence of symptoms	See comment		‐	‐	‐	No study evaluated persistence of symptoms for this comparison
Recurrent varicose veins follow‐up: mean 5 years	Study population		RR 1.10 (0.86 to 1.42)	286 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^a,e,h
Recurrent varicose veins follow‐up: mean 5 years	433 per 1000	477 per 1000 (373 to 615)	RR 1.10 (0.86 to 1.42)	286 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^a,e,h
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT; deep vein thrombosis; MD: mean difference; QoL: quality of life;RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^a Did not describe randomisation method. Due to the nature of the intervention was probably impossible to blind interventionist. We did not find a protocol. Risk of bias concerns ^b Single study. We downgraded by one level for imprecision. ^c Compared different concentration of the same substances for different vein diameter. Used different concentrations of the drug if liquid or foam ^d We downgraded by one level for risk of bias concerns (query about randomisation method). ^e We downgraded by one level for risk of bias concerns (intervention was presumably not blinded (foam vs liquid) due to the nature of the intervention). ^f One study (Ouvry 2008) included participants from CEAP C2 to C6 without discriminating between them. Rabe 2008 included 1 CEAP C5 participant in the foam group (1.85%) and 4 CEAP C5 participants in the liquid group (7.69%). We downgraded by one level for indirectness. ^hBelcaro 2003b used a tensioactive substance (ultrasound contrast agent) to produce foam. This is not a standard way to produce foam. We downgraded by one level for indirectness.

Summary of findings 3. Foam sclerotherapy versus liquid sclerotherapy for treating varicose veins

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Summary of findings 4. Sclerotherapy versus sclerotherapy with different substances for treating varicose veins

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Sclerotherapy with STS 1% compared to sclerotherapy with polidocanol 1%^a
Patient or population: participants with varicose veins^b Setting: clinical or hospital‐based study Intervention: STS 1% sclerotherapy Comparison: polidocanol 1% sclerotherapy
Outcomes	Risk with polidocanol 1% sclerotherapy	Risk with STS 1% sclerotherapy	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cosmetic appearance follow‐up: 12 to 16 weeks	See comment		‐	‐	‐	Two RCTs compared sclerotherapy with sclerotherapy with different substances but used a range of concentrations, formulations and drug volumes. We were unable to pool the data or draw conclusions
Complications ‐ DVT follow‐up: 16 weeks to 12 months	See comment		‐	‐	‐	Two RCTs reported on DVT but we were unable to pool the data or draw conclusions
Residual varicose veins follow‐up: 12 months	See comment		‐	‐	‐	One RCT reported on residual varicose veins but we were unable to draw conclusions
QoL	See comment		‐	‐	‐	No study evaluated QoL in this comparison
Persistence of symptoms	See comment		‐	‐	‐	No study evaluated persistence of symptoms in this comparison
Recurrent varicose veins	See comment		‐	‐	‐	No study evaluated recurrent varicose veins in this comparison
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DVT: deep vein thrombosis; QoL: quality of life; RCT: randomised controlled trial: RR: risk ratio; STS: sodium tetradecyl sulphate
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^a Four RCTs compared sclerotherapy with sclerotherapy with different substances but used a range of concentrations, formulations and drug volumes so we were not able to pool the data (Goldman 2002; Rao 2005; Schadeck 1995a; Wright 2006). None of these compared STS 1% sclerotherapy versus sclerotherapy with polidocanol 1% which we had planned to present in this table. ^b Three studies did not describe CEAP classification of participants (Goldman 2002; Rao 2005; Schadeck 1995a). One study compared Varisolve with polidocanol 1% to any marketed sclerosant at any marketed concentration liquid or foam (Wright 2006)

Summary of findings 4. Sclerotherapy versus sclerotherapy with different substances for treating varicose veins

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Comparison 1. Foam sclerotherapy versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Cosmetic appearance: medical related IPR‐V adjusted mean change from baseline (intermediate term) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1.1 Polidocanol 1% foam versus placebo	2	223	Mean Difference (IV, Random, 95% CI)	‐0.76 [‐0.91, ‐0.60]
1.1.2 Polidocanol 2% foam versus placebo	1	119	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.11, ‐0.69]
1.2 Cosmetic appearance: participant self assessment PA‐V adjusted mean change from baseline (intermediate term) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.2.1 Polidocanol 1% foam versus placebo	2	223	Mean Difference (IV, Random, 95% CI)	‐1.46 [‐1.72, ‐1.20]
1.2.2 Polidocanol 2% foam versus placebo	1	119	Mean Difference (IV, Random, 95% CI)	‐1.60 [‐1.95, ‐1.25]
1.3 DVT (short and intermediate term) Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.3.1 Polidocanol 0.125% foam versus placebo	2	227	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.08, 4.95]
1.3.2 Polidocanol 0.5% foam versus placebo	2	224	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.08, 5.16]
1.3.3 Polidocanol 1% foam versus placebo	3	302	Risk Ratio (M‐H, Random, 95% CI)	5.10 [1.30, 20.01]
1.3.4 Polidocanol 2% foam versus placebo	1	119	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.17, 19.08]
1.4 Phlebitis or thrombophlebitis rates (intermediate term) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.4.1 Polidocanol 0.125% foam versus placebo	2	227	Risk Ratio (M‐H, Random, 95% CI)	4.48 [1.02, 19.63]
1.4.2 Polidocanol 0.5% foam versus placebo	2	224	Risk Ratio (M‐H, Random, 95% CI)	3.26 [1.09, 9.75]
1.5 Phlebitis or thrombophlebitis rates (intermediate term) Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.5.1 Polidocanol 1% foam versus placebo	3	302	Risk Ratio (M‐H, Random, 95% CI)	3.12 [1.10, 8.83]
1.5.2 Polidocanol 2% foam versus placebo	1	119	Risk Ratio (M‐H, Random, 95% CI)	3.56 [0.79, 16.05]
1.6 Haemorrhagic complications (short term) Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.6.1 Polidocanol 0.125% foam versus placebo	2	227	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.42, 5.18]
1.6.2 Polidocanol 0.5% foam versus placebo	2	224	Risk Ratio (M‐H, Random, 95% CI)	2.73 [0.87, 8.53]
1.6.3 Polidocanol 1% foam versus placebo	3	302	Risk Ratio (M‐H, Random, 95% CI)	1.83 [0.75, 4.47]
1.6.4 Polidocanol 2% foam versus placebo	1	119	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.23, 7.69]
1.7 Neurologic complications (dizziness, TIA) (short term) Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.7.1 Polidocanol 0.125% foam versus placebo	2	227	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.08, 4.95]
1.7.2 Polidocanol 0.5% foam versus placebo	2	224	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.16, 7.36]
1.7.3 Polidocanol 1% foam versus placebo	3	302	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.22, 4.91]
1.7.4 Polidocanol 2% foam versus placebo	1	119	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.01, 7.14]
1.8 Residual varicose veins (intermediate term) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.8.1 Polidocanol 0.125% foam versus placebo	2	227	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.34, 0.78]
1.8.2 Polidocanol 0.5% foam versus placebo	2	224	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.11, 0.72]
1.8.3 Polidocanol 1% foam versus placebo	2	225	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.13, 0.29]
1.8.4 Polidocanol 2% foam versus placebo	1	119	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.11, 0.31]
1.9 Quality of life: VEINES‐QOL score change from baseline (intermediate term) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.9.1 Polidocanol 0.125% foam versus placebo	2	227	Mean Difference (IV, Random, 95% CI)	11.16 [6.17, 16.15]
1.9.2 Polidocanol 0.5% foam versus placebo	2	223	Mean Difference (IV, Random, 95% CI)	14.14 [11.02, 17.25]
1.9.3 Polidocanol 1% foam versus placebo	3	299	Mean Difference (IV, Random, 95% CI)	12.41 [9.56, 15.26]
1.10 Persistence of symptoms: absolute change from baseline score for the VVSymQ (total score) (intermediate term) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.10.1 Polidocanol 1% foam versus placebo	1	77	Mean Difference (IV, Random, 95% CI)	‐14.00 [‐15.39, ‐12.61]
1.11 Persistence of symptoms: mean change from baseline score for the VCSS (total score) (intermediate term) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.11.1 Polidocanol 0.125% foam versus placebo	2	227	Mean Difference (IV, Random, 95% CI)	‐2.47 [‐3.12, ‐1.82]
1.11.2 Polidocanol 0.5% foam versus placebo	2	224	Mean Difference (IV, Random, 95% CI)	‐3.35 [‐4.00, ‐2.70]
1.11.3 Polidocanol 1% foam versus placebo	2	223	Mean Difference (IV, Random, 95% CI)	‐3.25 [‐3.90, ‐2.60]

Comparison 1. Foam sclerotherapy versus placebo

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Comparison 2. Foam sclerotherapy versus foam sclerotherapy with different concentrations

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Cosmetic appearance: number of participants with cosmetic improvement (short term) ‐ polidocanol 3% foam versus polidocanol 1% foam Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.2 Cosmetic appearance: number of participants with cosmetic improvement (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.3 Cosmetic appearance: adjusted mean PA‐V (intermediate term) ‐ polidocanol foam versus polidocanol foam Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.3.1 Polidocanol 0.125% foam versus polidocanol 1% foam	2	224	Mean Difference (IV, Random, 95% CI)	0.45 [0.03, 0.87]
2.3.2 Polidocanol 0.5% foam versus polidocanol 1% foam	2	221	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.21, 0.32]
2.4 Cosmetic appearance: adjusted mean IPR‐V (intermediate term) ‐ polidocanol foam versus polidocanol foam Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.4.1 Polidocanol 0.125% foam versus polidocanol 1% foam	2	224	Mean Difference (IV, Random, 95% CI)	0.19 [‐0.01, 0.40]
2.4.2 Polidocanol 0.5% foam versus polidocanol 1% foam	2	221	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.19, 0.12]
2.5 Thromboembolic complications (intermediate term) ‐ polidocanol 3% foam versus polidocanol 1% foam Show forest plot	3	371	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.41, 5.33]

2.6 Thromboembolic complications (intermediate term) ‐ polidocanol 3% foam versus polidocanol 1% foam (sensitivity analysis) Show forest plot	2	291	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.31, 5.22]

2.7 DVT (short and intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.7.1 Polidocanol 0.125% foam versus polidocanol 1% foam	2	226	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.01, 14.53]
2.7.2 Polidocanol 0.125% foam versus polidocanol 2% foam	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.81 [0.17, 19.43]
2.7.3 Polidocanol 0.5% foam versus polidocanol 1% foam	2	223	Risk Ratio (M‐H, Random, 95% CI)	4.71 [0.59, 37.61]
2.7.4 Polidocanol 0.5% foam versus polidocanol 2% foam	1	114	Risk Ratio (M‐H, Random, 95% CI)	1.62 [0.15, 17.35]
2.7.5 Polidocanol 1% foam versus polidocanol 2% foam	1	115	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.12, 5.66]
2.8 PE (short term) ‐ polidocanol 1% foam versus polidocanol 3% foam Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.9 Skin pigmentation rates (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam Show forest plot	2	223	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.82, 3.17]

2.10 Phlebitis or thrombophlebitis rates (intermediate term) ‐ polidocanol < 1% foam versus polidocanol ≥ 1% foam Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.10.1 Polidocanol 0.125% foam versus polidocanol 1% foam	2	226	Risk Ratio (M‐H, Random, 95% CI)	1.67 [0.54, 5.23]
2.10.2 Polidocanol 0.125% foam versus polidocanol 2% foam	1	120	Risk Ratio (M‐H, Random, 95% CI)	2.49 [1.17, 5.27]
2.10.3 Polidocanol 0.5% foam versus polidocanol 1% foam	2	223	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.55, 2.57]
2.10.4 Polidocanol 0.5% foam versus polidocanol 2% foam	1	114	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.27, 2.22]
2.11 Phlebitis or thrombophlebitis ‐ polidocanol 3% foam versus polidocanol 1% foam Show forest plot	2	223	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.88, 2.41]

2.12 Haemorrhagic complications (intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.12.1 Polidocanol 0.125% foam versus polidocanol 1% foam	2	226	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.20, 1.83]
2.12.2 Polidocanol 0.125% foam versus polidocanol 2% foam	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.34, 6.30]
2.12.3 Polidocanol 0.5% foam versus polidocanol 1% foam	2	223	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.53, 2.93]
2.12.4 Polidocanol 0.5% foam versus polidocanol 2% foam	1	114	Risk Ratio (M‐H, Random, 95% CI)	3.29 [0.92, 11.78]
2.12.5 Polidocanol 1% foam versus polidocanol 2% foam	1	115	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.11, 1.57]
2.13 Neurologic complications (dizziness, TIA) (intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.13.1 Polidocanol 0.125% foam versus polidocanol 1% foam	2	226	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.06, 3.57]
2.13.2 Polidocanol 0.5% foam versus polidocanol 1% foam	2	223	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.08, 7.45]
2.13.3 Polidocanol 0.125% foam versus polidocanol 2% foam	1	120	Risk Ratio (M‐H, Random, 95% CI)	3.31 [0.14, 79.67]
2.13.4 Polidocanol 0.5% foam versus polidocanol 2% foam	1	114	Risk Ratio (M‐H, Random, 95% CI)	6.15 [0.30, 125.38]
2.13.5 Polidocanol 1% foam versus polidocanol 2% foam	1	115	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.01, 6.64]
2.14 Residual varicose veins (intermediate term) ‐ polidocanol foam lower concentration versus polidocanol foam higher concentration Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.14.1 Polidocanol 0.125% foam versus polidocanol 1% foam	2	219	Risk Ratio (M‐H, Random, 95% CI)	2.69 [1.76, 4.09]
2.14.2 Polidocanol 0.125% foam versus polidocanol 2% foam	1	120	Risk Ratio (M‐H, Random, 95% CI)	3.42 [1.92, 6.09]
2.14.3 Polidocanol 0.5% foam versus polidocanol 1% foam	2	221	Risk Ratio (M‐H, Random, 95% CI)	1.50 [0.93, 2.43]
2.14.4 Polidocanol 0.5% foam versus polidocanol 2% foam	1	114	Risk Ratio (M‐H, Random, 95% CI)	2.36 [1.26, 4.42]
2.14.5 Polidocanol 1% foam versus polidocanol 2% foam	1	115	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.57, 2.57]
2.15 Residual varicose veins (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam Show forest plot	3	371	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.04]

2.16 Residual varicose veins (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam (sensitivity analysis) Show forest plot	2	291	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.35, 1.28]

2.17 Quality of life: adjusted mean change VEINES‐QOL (intermediate term) ‐ polidocanol foam versus polidocanol foam Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.17.1 Polidocanol 0.125% foam versus polidocanol 0.5% foam	2	225	Mean Difference (IV, Random, 95% CI)	2.86 [‐0.24, 5.97]
2.17.2 Polidocanol 0.125% foam versus polidocanol 1% foam	2	224	Mean Difference (IV, Random, 95% CI)	1.10 [‐2.50, 4.69]
2.17.3 Polidocanol 0.5% foam versus polidocanol 1% foam	2	221	Mean Difference (IV, Random, 95% CI)	‐1.82 [‐4.96, 1.32]
2.18 Persistence of symptoms: adjusted mean change from baseline VCSS score (intermediate term) ‐ polidocanol foam versus polidocanol foam Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.18.1 Polidocanol 0.125% foam versus polidocanol 0.5% foam	2	225	Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.52, ‐0.21]
2.18.2 Polidocanol 0.125% foam versus polidocanol 1% foam	2	224	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.42, ‐0.12]
2.18.3 Polidocanol 0.5% foam versus polidocanol 1% foam	2	221	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.56, 0.75]
2.19 Recurrent varicose veins (long term) ‐ polidocanol 3% foam versus polidocanol 1% foam Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Comparison 2. Foam sclerotherapy versus foam sclerotherapy with different concentrations

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Comparison 3. Foam sclerotherapy versus liquid sclerotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Cosmetic appearance: participant satisfaction (long term) ‐ polidocanol foam versus polidocanol liquid Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

3.2 Skin pigmentation (long term) ‐ polidocanol foam versus polidocanol liquid Show forest plot	2	208	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.81, 3.80]

3.2.1 Polidocanol 3%	1	108	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.34, 4.24]
3.2.2 Polidocanol liquid versus foam (unknown concentration)	1	100	Risk Ratio (M‐H, Random, 95% CI)	2.20 [0.82, 5.87]
3.3 Residual varicose veins (long term) ‐ polidocanol foam versus polidocanol liquid Show forest plot	5	753	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.33, 0.64]

3.3.1 Polidocanol foam (0.75 to 1.25%) versus liquid (1.25 to 2.5%)	1	150	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.06, 0.34]
3.3.2 Polidocanol 3%	2	203	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.41, 0.65]
3.3.3 Polidocanol (unknown concentration)	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.12, 0.96]
3.3.4 STS 3%	1	300	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.48, 0.82]
3.4 Residual varicose veins (long term) ‐ polidocanol foam versus polidocanol liquid (sensitivity analysis) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.4.1 STS 3%	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.5 Recurrent varicose veins (long term) ‐ STS 3% liquid versus STS 3% foam Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 3. Foam sclerotherapy versus liquid sclerotherapy

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Comparison 4. Sclerotherapy versus sclerotherapy with different substances

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Cosmetic appearance: disappearance of varicose veins (long term) ‐ polidocanol 3% versus STS 1.5% Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

4.2 DVT (short and intermediate term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.3 Skin pigmentation (intermediate term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.4 Haematoma (short term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.5 Skin pigmentation (long term) ‐ STS 1.5% versus polidocanol 3% Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.6 Skin necrosis (long term) ‐ STS 1.5% versus polidocanol 3% Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.7 Residual varicose veins (long term) ‐ Varisolve polidocanol foam versus any market sclerosant (liquid or foam) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.8 Matting (long term) ‐ STS 1.5% versus polidocanol 3% Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 4. Sclerotherapy versus sclerotherapy with different substances

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Comparison 5. Sclerotherapy versus sclerotherapy with different techniques

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Phlebitis or thrombophlebitis rates (short term) ‐ polidocanol 1% foam ‐ antegrade versus retrograde technique Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.2 Skin pigmentation rates (long term) ‐ polidocanol 1% foam ‐ antegrade versus retrograde technique Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.3 Thrombophlebitis rates (short term) ‐ polidocanol 3% foam injected by catheter associated to tumescent technique versus polidocanol 3% foam injected by needle Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.4 Detection of polidocanol foam in deep veins ‐ few injections versus multiple injections Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.5 Residual varicose veins (long term) ‐ visual foam sclerotherapy versus ultrasound guided foam + visual foam sclerotherapy Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.6 Residual varicose veins (long term) ‐ multiple/fractionated injections versus few/single injections Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.6.1 STS 3% single versus fractionated injections	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.6.2 Polidocanol 1% or 3% low versus fractionated injections	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.7 Residual varicose veins (intermediate term) ‐ polidocanol 1% foam retrograde versus antegrade technique Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.8 Residual varicose veins (intermediate term) ‐ microcatheter directed foam sclerotherapy versus catheter directed foam sclerotherapy Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.9 Residual varicose veins (intermediate term) ‐ needle foam sclerotherapy versus catheter directed foam sclerotherapy Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.10 Residual varicose veins (intermediate term) ‐ needle foam sclerotherapy versus microcatheter directed foam sclerotherapy Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.11 Residual varicose veins (short term) ‐ polidocanol 3% foam injected by catheter versus polidocanol 3% foam injected by needle Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.12 Participants not requiring retreatment (long term) ‐ polidocanol 3% foam injected by catheter versus polidocanol 3% foam injected by needle Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.13 QoL: AVVQ (long term) ‐ catheter‐directed foam sclerotherapy with tumescence versus ultrasound‐guided foam sclerotherapy Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

5.14 VCSS (long term) ‐ ultrasound guided foam + visual foam sclerotherapy versus visual foam sclerotherapy Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 5. Sclerotherapy versus sclerotherapy with different techniques

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Comparison 6. Sclerotherapy versus compression conservative treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Cosmetic appearance: good symptomatic improvement and cosmetic result (long term) liquid STS versus compression Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.2 Ulcer (short, intermediate and long term) ‐ liquid STS versus compression Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 6. Sclerotherapy versus compression conservative treatment

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Idioma de la Revisión Cochrane

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Resumen

Antecedentes

Objetivos

Métodos de búsqueda

Criterios de selección

Obtención y análisis de los datos

Resultados principales

Conclusiones de los autores

PICO

PICO

Population

Intervention

Comparison

Outcome

Resumen en términos sencillos

Tratamiento con escleroterapia para las varices

Resumen visual

Authors' conclusions

Implications for practice

Implications for research

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

Included studies

Excluded studies

Ongoing studies

Awaiting classification

Risk of bias in included studies

Allocation

Random sequence generation

Allocation concealment

Blinding

Performance bias

Cosmetic appearance (assessed by any tool)

Complications (at least one of the following complications: haematoma formation, skin pigmentation, ulceration and necrosis, superficial thrombophlebitis, deep vein thrombosis and anaphylactic reaction)

Residual varicose veins (veins that failed obliteration, assessed clinically and/or by ultrasound examination)

Recurrent varicose veins and venous flare formation

Quality of life (using any specific, validated questionnaire)

Frequency of persistence of symptoms

Detection bias

Cosmetic appearance (assessed by any tool)

Complications (at least one of the following complications: haematoma formation, skin pigmentation, ulceration and necrosis, superficial thrombophlebitis, deep vein thrombosis and anaphylactic reaction)

Residual varicose veins (veins that failed obliteration, assessed clinically and/or by ultrasound examination)

Recurrent varicose veins and venous flare formation

Quality of life (using any specific, validated questionnaire)

Frequency of persistence of symptoms

Incomplete outcome data