Abstract
Objective
This report summarizes the findings of the consensus panel based on the results of the comprehensive questionnaire of US American College of Phlebology annual congress attendees and results of the systematic meta-analysis of the literature and provides quality improvement guidelines for the use of endovenous foam sclerotherapy (EFS) for the treatment of venous disorders, as well as identifies areas of needed research.
Methods
Based on the above data, quality improvement guidelines were developed and reviewed by the ten US consensus panel members and approved by their respective societies.
Results
EFS is effective for the treatment of truncal and tributary varicose veins, both as primary treatment and for treatment of recurrence. It may improve the signs and symptoms associated with varicose veins including pain and swelling. EFS is contraindicated in patients who have experienced an allergic reaction to previous treatment with foam or liquid sclerosant, and in patients with acute venous thrombosis events secondary to EFS.
Conclusion
These guidelines for the use of EFS in the treatment of venous disorders provide an initial framework for the safe and efficacious use of this therapy, and the impetus to promote the evaluation of the questions remaining regarding the use of EFS through well-designed randomized and cohort studies.
Introduction/background
Endovenous foam sclerotherapy (EFS) is used widely in the USA. However, EFS is considered off-label since currently no commercial preformulated preparation is available. No standards of care or quality improvement guidelines in the USA exist for the use of EFS for the treatment of venous disorders. With this recognition, a multidisciplinary consensus panel of US experts was convened in 2009 with three purposes: (1) To conduct a comprehensive questionnaire of those performing foam sclerotherapy in the USA to describe practice patterns and identify areas of common usage and methodology. (2) To conduct a systematic review of the published literature with the goal of summarizing safety and efficacy for the performance of EFS and providing quality improvement guidelines where sufficient evidence exists. (3) To identify important areas of needed research where there is lack of evidence.
This report summarizes the findings of the consensus panel based on the results of the comprehensive questionnaire of US American College of Phlebology (ACP) annual congress attendees and results of the systematic meta-analysis of the literature and provides quality improvement guidelines for the use of EFS, as well as identifies areas of needed research.
Summary of findings: questionnaire and meta-analysis
In 2009, a comprehensive questionnaire was developed to target key areas in the performance of EFS for the treatment of venous disorders. 1 These areas included demographic information, practice specialty and site, indications for sclerotherapy, type of sclerosant used, method of foam preparation, method of foam injection, postprocedural care and follow up and measurements of efficacy and patient safety. Participation was solicited from US attendees at the time of registration on site at the 2009 annual meeting of the American College of Phlebology and was voluntary and anonymous. Participants were asked to complete a five-page questionnaire consisting of 30 finite answer questions. Of 776 questionnaires distributed, 239 were completed (31%). The majority of respondents (87%) reported using EFS for the treatment of venous disorders. Foam sclerotherapy was used by a wide variety of specialists in every census region of the USA. The most common indication was sclerosis of recurrent truncal or tributary veins of the leg, although it was also used as primary therapy. Non-users of EFS most commonly indicated that they were uncertain of the efficacy or safety of EFS. It was clear that the risk and benefit profile and criteria for patient selection have not been well documented and further research was needed in this area.
The second initiative sought to thoroughly evaluate the published literature to determine the efficacy and safety of EFS for the treatment of venous disorders. 2 The databases searched included Medline (January 1948–April 2010), EMBASE (January 1980–April 2010) and Evidence-Based Medicine Reviews (through April 2010): Cochrane database of systematic reviews, American College of Physicians Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment and NHS Economic Evaluation Database using the OVID database search interface. The references cited in the selected publications were manually searched for other relevant manuscripts. Abstracts from four professional meetings were also searched including: Phlebolymphology 2003–2010, American College of Phlebology 2004–2009, American Venous Forum 2005–2010 and Society of Interventional Radiology 2002–2010. All English language reports were included as well as non-English reports when English translation was available. A total of 684 published abstracts and manuscripts were screened for eligibility with 104 meeting criteria for eligibility for further review and data extraction. More than 50% of studies were published recently between 2004 and 2008.
Key findings from the meta-analysis included that the pooled anatomic great saphenous vein (GSV), small saphenous vein (SSV) and tributary closure rate of EFS in 101 foam treatment groups evaluated was 85% (95% CI, 82–88%). Complete cosmetic improvement was reported in 82% of patients (95% CI, 74–88%) based on the pooled estimate. More than 90% of patients (95% CI, 85–96%) reported improvement in symptoms following foam sclerotherapy. Among the 21 studies that reported healing rates of venous ulcers, 88% of patients (95% CI, 82–93%) reported ulcers healed. Among six methodologically variable studies that reported improvement in congenital venous malformations, the pooled anatomic closure rate was 57% (95% CI, 34–78%) and overall cosmetic improvement, reported in one study of 23 patients, was 65% (95% CI, 45–82%).
There were 102 foam treatment groups with safety data. There was a low pooled rate of neurological events with 1.2% of patients (95% CI, 0.72–1.7%) reporting visual disturbances, and less than 1% reporting epileptic episodes. Among 25 studies, migraine following foam sclerotherapy was found in 3% of patients (95% CI, 1.4–5.4%). Among 35 studies, cerebrovascular events were reported in 0.63% of patients (95% CI, 0.31–1.13%), however, events and outcomes were not independently adjudicated in these reports. The rate of thrombosis following EFS was also low. Less than 1% of patients (95% CI 0.66–1.3%) reported deep vein thrombosis, 0.1% (95% CI, 0–0.21%) reported pulmonary embolism and 11% (95% CI, 7.1–15%) reported thrombophlebitis following treatment. Other minor adverse effects were also found to be rare. It is particularly important to recognize that that the overall study quality was poor with most reports based on retrospective reviews of case series and few published reports from randomized, controlled trials. However, this meta-analysis represented the most comprehensive evaluation of the published literature to date regarding the use of EFS for the treatment of venous disorders, and therefore informs our assessment of effectiveness and safety measures while identifying areas of needed research.
Methods
Based on the above data and additional analyses of the randomized, controlled trials identified through the systematic review, with an updated literature search conducted through April 2011, quality improvement guidelines were developed by the principal investigator and biostatisticians and sent for review by the additional seven US consensus panel members who provided suggested edits and approved the final manuscript. To address concerns regarding poor study quality and the potential for confounding factors to impact between-study comparisons, results from the identified randomized controlled clinical trials are emphasized. The quality guidelines were then submitted to the American College of Phlebology (ACP), Society for Vascular Medicine (SVM), Society for Interventional Radiology (SIR) and American Venous Forum (AVF) for review and approval. At ACP, the document was reviewed by the research committee and approved by the Board of Directors. At SVM, the communications committee reviewed the document with approval by the Board of Directors. At SIR, the operations committee reviewed the document. The draft underwent two sets of revisions followed by Board approval. At AVF, the document was reviewed with approval by the Board at the in-person annual meeting in February 2012.
Recommendations (Table 1)
Indications for EFS
Quality improvement guidelines
GSV, great saphenous vein; SSV, small saphenous vein; EFS, endovenous foam sclerotherapy; DVT, deep vein thrombosis; PFO, patent foramen ovale; US, ultrasound
EFS is effective for the treatment of GSV, SSV and tributary varicose veins, both as primary treatment and for treatment of recurrence. It may improve the signs and symptoms associated with varicose veins including pain and swelling. Since there were no randomized controlled trials included in the meta-analysis comparing EFS to thermal ablation for treatment of truncal veins, no recommendation can be made regarding the comparative efficacy or safety. EFS may be used for treatment of venous ulcers if more conservative therapies have failed. EFS may be used to reduce the size or improve the cosmetic appearance of congenital venous malformations when used by the experienced provider. However, this treatment may be less effective for congenital malformations than for the treatment of varicose veins.
Data have not been published investigating the association between CEAP (clinical, aetiological, anatomical and pathological elements) class and the safety and efficacy of foam sclerotherapy which in order to avoid the confounding effect of regimen on the association between CEAP class and outcome, would require a constant sclerotherapy regimen across CEAP class levels. Instead, foam sclerotherapy regimens vary depending on the CEAP classification. Outcomes from subgroups of patients defined by CEAP classification are often either reported in separate publications that utilize varying treatment approaches across subgroups, for example, manuscripts reporting outcomes for a sample of patients with C6 active venous ulcers, or are included in reports of collective outcomes, not stratified by CEAP classification.
Randomized trials comparing type of sclerosant are very limited. Rao et al., 3 when investigating the treatment of varicose and telangiectatic leg veins, has reported an average 83% improvement rate in vein sizes after a single randomized treatment using STS (n = 20 legs) or polidocanol (n = 20 legs) sclerotherapy regimens that vary in concentration (0.25–1.0%) and delivery method (liquid versus foam) according to vein size with no significant difference in adverse event rates between the randomized arms. There have been no randomized trials investigating the effect of the type of gas used to create the foam sclerosant on efficacy and safety outcomes.
Contraindications
EFS is contraindicated in patients who have experienced an allergic reaction to previous treatment with foam or liquid sclerosant, and in patients with acute venous thrombosis events secondary to EFS including deep vein thrombosis and pulmonary embolism. EFS should be avoided in patients who have had prior EFS-induced symptomatic superficial thrombophlebitis requiring medical or surgical therapy. EFS should be avoided in patients who have previously experienced a neurological event temporally related to EFS including visual disturbances, migraine headache, aphasia or other localizing motor or sensory event. There is insufficient data to make recommendations regarding contraindication of EFS in patients with underlying hypercoagulability syndromes, or whether prophylactic use of anticoagulant therapy is effective for avoidance of venous thromboembolic complications.
Data regarding patients with patent foramen ovale (PFO) is limited to several case reports4–6 and two studies with a larger sample of patients with PFO, samples of size seven 7 and 13. 8 Among the seven patients with PFO reported by Ceulen et al. 7 using a single injection of 5 mL of 1% polidocanol foam (air-to-liquid ratio, 4:1), neurological complications of transient scotomas (n = 1) and a migraine attack (n = 1), resulting in an overall neurological complication rate of 29%, were observed. Hansen et al. 8 reported outcome data for 13 patients with PFO following treatment with 1% polidocanol foam mixed with air or carbon dioxide, among whom the following events were reported: migraine (n = 5), visual disturbance (n = 2), cough (n = 2), light headedness (n = 1), sore throat (n = 1), dizziness (n = 1), chest tightness (n = 1) and possible transient ischaemic attack (n = 1). There is insufficient data to make a conclusive recommendation regarding the use of EFS in patients with known patent foramen ovale. Similarly, there is insufficient data to make recommendation regarding the preprocedural evaluation of patients including echocardiogram, and maximal safe volume of foam to reduce risk of neurological events. However, EFS should be avoided in patients with known PFO who have experienced previous localizing neurological events following EFS. For any patient with known PFO, caution should be exercised in deciding whether to perform and in performing EFS. Specifically, the risks and benefits of EFS relative to other treatment modalities should be carefully weighed and discussed with the patient.
Injection technique
Foam can be injected directly into the vein to be treated. The use of ultrasound-guidance to assist the provider will depend on the size, depth and location of the vein. However, it is recommended that for varicose veins that lie directly adjacent to named arteries, ultrasound guided injection be employed to avoid injection of foam into the artery. Although risk of infection has not been formally evaluated in studies, the use of sterile technique is generally recommended when injecting foam into varicose veins. This includes the use of sterile ultrasound gel and barrier protection to the ultrasound probe.
Several randomized controlled trials have investigated the effect of varying doses or injections of foam sclerosant.9–11 Among randomized controlled clinical trials comparing 1% (n = 172 patients) versus 3% (n = 173 patients) polidocanol foam for the treatment of GSV, the pooled relative occlusion rate was 1.04 for 3 versus 1% (95% CI: 0.92–1.18) suggesting that there is no significant difference in the occlusion rate between the 1% and 3% dose levels.3,13,14 Yamaki et al. 12 have reported a relative occlusion rate of 0.88 for multiple injections of <0.5 mg 1% polidocanol foam (n = 54 patients) versus few injections of >0.5 mL 1% polidocanol foam (n = 53 patients) (95% CI: 0.63–1.23) for the treatment of superficial venous incompetence suggesting that there is no significant difference in the occlusion rate between the regimens (P = 0.45). Polidoconal 3% is currently not available in the USA.
Hamel-Desnos et al. 13 reported safety and efficacy data for patients with incompetent GSV or small saphenous veins who were randomized to receive foam sclerotherapy (2–8 mL of polidocanol, 1–2% depending on vein diameter) with (n = 31) or without (n = 29) compression using graduated elastic stockings. The stockings were 15–20 mm Hg compression and were to be worn during the day for three weeks. On day 28, both groups demonstrated an occlusion rate of 100% with equivalent symptom and quality-of-life measures compared with pretreatment assessments. Side-effects were few, with no significant differences between groups. O'Hare et al. 14 reported data from a randomized clinical trial investigating the effect of foam sclerotherapy with compression bandaging for 24 hours (n = 61 legs) versus foam sclerotherapy with compression bandaging for five days (n = 63 legs) among patients with primary uncomplicated varicose veins. Sodium tetradecyl sulphate (3%, 0.5 mL) was mixed with 1.5 mL room air and injected in 2 mL aliquots. A maximum of 14 mL of foam was injected in a single session. At the completion of the injection, a compression bandage was applied to the full length of the leg and patients were instructed to remove the bandage after 24 hours or five days. After removing the bandage, patients were instructed to wear thrombo embolic deterrent stockings for the remainder of the two-week postprocedure period. At the six-week follow-up assessment (n = 121 legs, 98%), the occlusion percentages were similar between the 24-hour (90%) and the five-day (89%) groups (P = 0.84). There were no significant differences between groups in phlebitis scores at two weeks (P = 0.45) or skin discolouration after six weeks (46% versus 40%, P = 0.55) for the 24-hour and five-day bandaging groups, respectively. Also, there were no significant differences between groups in the change in the Aberdeen Varicose Vein Severity Score or the Burford pain scores at two or six weeks and no significant difference in the change in the Short Form 36 score from baseline to six weeks. Patients may benefit from compression with wrapping and/or hose after EFS, however, the optimal duration of use of these garments is unknown.
Follow-up/surveillance
It is recommended that patients be seen post EFS and undergo duplex ultrasound for evaluation of anatomic closure and for deep vein thrombosis (DVT), especially if signs and symptoms of DVT are present, since this is an adverse event with considerable morbidity. There is no recommendation to provide repeated EFS treatments if the patient's primary symptoms or signs are resolved despite residual vein patency.
Safety
The rate of major adverse events associated with EFS is low. Major adverse effects of DVT and pulmonary embolism are extremely rare. Patients who may have a history of venous thrombosis, are relatively sedentary or are at otherwise high risk should be identified and counseled appropriately. However, there is insufficient data to make any recommendations regarding the use of preventive anticoagulation in these patients. Symptomatic superficial thrombophlebitis and/or sequestered coagulum may occur in a larger proportion of patients. Because thrombus from the area of superficial thrombophlebitis may extend to the deep veins, patients should be followed closely. The prescription of anticoagulant medication or the drainage of coagulum should be determined by the treating provider. Hyperpigmentation following EFS is common. Patients should be informed of this potential adverse effect and reassured that it will generally fade within a few months. Currently, there is no validated method for reducing or treating hyperpigmentation. It is commonly held that evacuation of sequestered coagulum will reduce the risk of hyperpigmentation, but data are lacking. Practitioners performing EFS should have procedures and protocols in place for the patients who rarely may require emergency care that could include availability of a cardiac resuscitation cart, and expedient transfer to an emergency room if warranted.
Patient consent/information
Patients should be consented by the treating healthcare provider who is employing EFS for treatment of venous disorders. This includes verbal and written notification of the off-label use of sclerosant, common minor and rare major adverse effects, as well as strategies to minimize these events. Patients should be given the opportunity to ask questions and choose alternate therapies if deemed appropriate after discussing with their provider.
Research
There are numerous questions that need to be answered regarding the use of EFS, and many areas where recommendations could not be made due to lack of data. Assessment strategies for the identification of patients who would most benefit from EFS and who might be at particularly high risk from EFS should be developed. Factors that may be included in this assessment include age, weight, biomarkers, previous treatment profile, gender, factors suggestive of thrombophilia and co-morbidities including cardiac and pulmonary disease and severity of signs and symptoms of venous disease using validated assessment tools. There is additional research needed to standardize foam preparation and injection techniques while commercial microfoam is in development. Investigation into reduction of both major adverse events including neurological events, and especially minor side-effects including thrombophlebitis and hyperpigmentation should be supported. Further, options for postprocedure surveillance and care including the use of compression are needed. Finally, the comparative efficacy and safety with other endovascular techniques should be evaluated in a prospective, randomized fashion especially for the treatment of larger, axial veins.
Quality of life is an increasingly important area of investigation as we recognize that anatomic occlusion rates may not directly correlate with improvement in patients’ signs and symptoms. Since EFS may be performed in the outpatient office setting, cost-effectiveness analyses are needed incorporating the perceived versus actual requirement for repeated procedures.
Most importantly, standards should be developed for training and certification in the performance of EFS, especially since providers from many disciplines are involved in the care of venous disease.
Discussion and conclusions
These guidelines for the use of EFS in the treatment of venous disorders provide an initial framework for the safe and efficacious use of this therapy. In contrast to previous guidelines that have been published, most notably the European guidelines on the performance of EFS, 15 these guidelines have been derived solely from analysis of the literature rather than expert opinion and therefore differ in format and content. These guidelines are thus not comprehensive, do not give definitive recommendations on all aspects of EFS and are not binding, but are fluid with anticipated revision as techniques are refined and more research becomes available. These guidelines are not intended to provide recommendations on comparative efficacy for decisions regarding modality of choice for specific venous disorders, but rather give guidance to those who have already chosen to use EFS for treatment of specifically identified patients. Most importantly, they provide the impetus to promote the evaluation of the questions remaining regarding the use of EFS through well-designed randomized and cohort studies. The findings of this essential research will ultimately be the determining factor in the overall and evolving role of EFS for the treatment of venous disorders.
Footnotes
Acknowledgement
Funding provided by the American College of Phlebology Foundation.