TITLE: Foam Sclerotherapy for Treatment of Varicose Veins ... · of work days.1,2 If left untreated, varicose veins can progress to chronic venous insufficiency, which increases the

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TITLE: Foam Sclerotherapy for Treatment of Varicose Veins: A Review of the Clinical Effectiveness, Safety, Cost-Effectiveness, and Guidelines

DATE: 12 February 2015 CONTEXT AND POLICY ISSUES Varicose veins are dilated tortuous superficial veins, at least 3mm in diameter, that usually affect the great (GSV) and small (SSV) saphenous veins of the lower limbs.1,2 Varicose veins are caused by decreased elasticity in the vein walls and poorly functioning valves, resulting in blood pooling in the veins and vein enlargement.2 Risk factors for people with varicose veins are unclear although prevalence increases with age and pregnancy.3 Symptoms of varicose veins can range in severity from occasional discomfort to severe ulceration of the skin.1,2 Approximately 10 to 40% of Western populations have varicose veins, and varicosities can cause considerable disability, resulting in decreased quality of life and loss of work days.1,2 If left untreated, varicose veins can progress to chronic venous insufficiency, which increases the likelihood of tissue damage and development of venous ulcers.1

The therapeutic spectrum for varicose veins spans from conservative to interventional methods. Surgery, including saphenous vein ligation and stripping, have traditionally been the treatment standards.3-5 Surgery, however, is invasive and may be associated with a greater incidence of complications and slower recovery relative to newer approaches to treatments.6 Less invasive approaches, either by thermal or chemical means, have become increasingly widespread given potentially faster recovery times, reduced resource use and greater improvement to quality of life.7 Endovascular thermal ablation, which includes laser (EVLT) and radiofrequency ablation (RFA), involves heating a vein from inside to irreversibly damage the vein and its linings in order to close it off. A previous Rapid Response report by CADTH8 has evaluated the clinical, safety and cost-effectiveness of endovascular thermal ablation and found that these less-invasive procedures were non-inferior to surgery with respect to clinical effectiveness and further offered benefits in terms of time to return to normal activity and cost-effectiveness. Another minimally invasive therapeutic option is sclerotherapy. This percutaneous technique involves the targeted chemical ablation of varicose veins. Intravenous injection of either a liquid

Foam Sclerotherapy for Treatment of Varicose Veins 2

or a foamed sclerosing agent destroys the endothelial tissues, exposing the subendothelial collagen fibers and irreversibly forming a fibrotic obstruction to close unwanted veins. Several sclerosants are available including sodium tetradecyl sulfate, polidocanol, and chromated glycerin; each associated with varying efficacies, potencies, side effect profiles, and costs.9 In particular, foamed preparation of sclerosing agents (i.e., a mixture of liquid sclerosant with air and other gases) have been increasingly popular as it has been suggested to increase the surface area of exposure, thereby achieving longer and undiluted contact with the venous endothelium and permitting greater intimal damage at a lower dose.10 Foam sclerotherapy (FS) is typically conducted under ultrasound guidance with local anesthesia in an outpatient setting.7 Constant evolution in techniques to treat varicose veins has been driven by the need for: better patient comfort, reduced side effects and the desire for better and longer-lasting clinical results. New developments towards FS warrant questions regarding their clinical and economic evidence. The purpose of this review is therefore to compare the available evidence on FS for patient with varicose veins compared with alternative treatment modalities (i.e., surgery, endovascular thermal ablation, or liquid sclerotherapy) in terms of their comparative clinical effectiveness, safety, cost-effectiveness, and evidence-based guidelines. RESEARCH QUESTIONS

1. What the clinical effectiveness and safety of foam sclerotherapy for varicose veins?

2. What is the cost-effectiveness of foam sclerotherapy for varicose veins?

3. What are the evidence-based guidelines regarding the use of foam sclerotherapy for varicose veins?

KEY FINDINGS Current evidence suggests that foam sclerotherapy (FS) may be more clinically effective than conventional liquid sclerotherapy. FS is non-inferior to surgery or endovascular laser therapy on most clinical outcomes although a few long-term studies do suggest lower occlusion rates in patients receiving FS. However, FS is associated with shorter procedure duration, lower pain, and faster return to work compared to surgery. Although the majority of studies were not adequately powered to detect safety complications, the overall rates of adverse events were low for all varicose vein treatment modalities. Few cost-effectiveness studies have been conducted to assess the economic value of these treatment modalities. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2015, Issue 1), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2010 and January 15, 2015.


Selection Criteria and Methods One reviewer screened the literature search results to identify relevant publications, including: health technology assessments (HTAs); systematic reviews (SRs) and meta-analyses (MA); randomized controlled trials (RCTs); non-randomized studies; economic evaluations; and clinical practice guidelines (CPGs). The initial screen was based on publication title and abstract, and was followed by a full-text screen. Studies considered for inclusion were based on the selection criteria presented in Table 1. Studies on combined treatment for varicose veins in which FS was one of the treatment modalities were included. If a study generated multiple publications, reports were included if different outcomes were presented.

Table 1: Selection Criteria

Population Patients with varicose veins

Intervention Foam sclerotherapy (alone, or as a combination therapy with a surgical or endovascular thermal ablation modality)

Comparator Other treatments for varicose veins: - Endovascular thermal ablation (includes endovascular laser

therapy and radio frequency ablation) - Surgery - Regular sclerotherapy

Outcomes Clinical benefits, clinical harms, cost-effectiveness, guidelines and recommendations

Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, nonrandomized studies, economic evaluations, clinical practice guidelines

Exclusion Criteria Articles were excluded if there were a duplicate report of the same study; if they were already included in a selected SR or HTA; if they were published prior to 2010; or if they did not meet the specified inclusion criteria. In the case of duplicate reports, the study with the greatest level of detail was selected. Critical Appraisal of Individual Studies HTAs and SRs were appraised using the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist.11 Items considered in the AMSTAR checklist include: a priori design of the review; duplicate independent reviewers; a priori defined eligibility criteria; comprehensive search of information sources; transparent reporting of study selection; clear presentation of study characteristics; assessment of studies’ quality; scientifically-sound interpretation of the results; appropriate methods to combine data from studies; assessment of publication bias; and reporting of funding sources.11 Randomized and non-randomized controlled trials were appraised using the Downs and Black checklist.12 Concepts evaluated within this 27-item checklist included: reporting; external validity; internal validity (separated into bias and confounding) and; power.12


Cost-effectiveness studies were appraised using the Drummond Checklist.13 Items evaluated include: study design; data collection; and analysis and interpretation of results (such as: pre-defined research question; transparent reporting of data sources (e.g. effectiveness, health valuation; resource consumption; costs); relevant and clear description of comparators; application of discounting).13 Guidelines were appraised using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument.14 The items included in the AGREE instrument include: scope and purpose of the guideline; stakeholder involvement; rigor of development; clarity and presentation; applicability; and editorial independence.14 In conducting the critical appraisal, an overall numeric score was not calculated for each study. Instead, the selected instrument was used to identify the strengths and limitations that were subsequently reviewed narratively for the studies and guidelines that met our inclusion criteria. SUMMARY OF EVIDENCE Quantity of Research Available A total of 216 citations were identified from the literature search. Following screening of titles and abstracts, 35 potentially relevant reports were selected for full-text review. With the inclusion of one report from grey literature sources, 19 publications were found to have met the inclusion criteria and were included in this report. Of the studies included, one was an HTA,15 four were SRs,6,16-18 seven were RCTs,19-25 two were cohort studies,26,27 one was an economic evaluation28 and four were CPGs.2,3,9,29 Appendix 1 presents the PRISMA flowchart30 detailing the study selection. Summary of Study Characteristics A summary of the study characteristics table is provided in Appendix 2. Comparative clinical effectiveness and safety of foam sclerotherapy versus other treatments for varicose veins A total of 13 studies addressed either the comparative clinical effectiveness or safety of FS against other treatment modalities, such as surgery, endovascular thermal ablation or conventional liquid sclerotherapy. Of these publications, one was a HTA,15 four were SRs,6,16,18,29 seven were RCTs19-25 and two were cohort studies.26,27 All HTA, RCTs and observational studies reported on both the outcomes of effectiveness and safety. Of the SRs, two focused on both safety and effectiveness6,17 while one each focused on only safety16 or on clinical effectiveness.18 The nine observational studies and RCTs represent eight unique trials as one trial published different outcomes across two different time periods.20,22 Country of Origin The HTA was conducted in the United Kingdom (UK),15 while most SRs were from the United States16-18 with the exception of one from the UK.6 The RCTs predominantly originated from


UK19,20,22,23 with one each conducted in Netherlands,21 Thailand24 and China.25 The two non-randomized studies were conducted in South Korea26 or Turkey.27 Patient Population The SRs captured a broad range of dates in their literature search. The HTA report and Cochrane SR had the broadest range of dates as they searched the literature spanning from the inception of the databases to July 201115 and January 2014,6 respectively. The SR that reported on only the safety outcomes focused on a narrower search from January 2000 through January 2013. In two studies, the date range - specifically the start date - was unclear.17,18 The number of studies identified from the HTA/SRs varied. Amongst the HTA/SR that were limited to RCTs, a total of 13 6 and 3115 studies were identified. The number of randomized participants in an individual trial ranged from 28 to 71015 with a total of 3,878 participants across all trials.15 In the SR that permitted a broader range of study types (randomized or nonrandomized comparative studies), 9 observational and 30 RCTs were identified in which the number of participants in an individual trial ranged from 28 to 733, with a total of 8,285 captured in the SR.18 In the broader SRs (that permitted study designs from RCTs to non-comparative case series), 3127 and 10417 reports were identified with the sample size of an individual trial varying from 1 to 1200 patients17. A maximum of 11,006 patients were represented in one of these SRs.17 Despite the broad range of study types included in the SR/HTAs, the individual trials mostly shared similar patient demographics. Within the RCTs and observational studies, the mean or median age ranged from 47 to 56,20-22 with the majority of the study population being females (54% to 90%).20,22,24 Most studies included patients with varicose veins associated with the GSV only.20-23,25,27 One study included patients with SSV insufficiency,19 one with primary reticular varices or postoperative varices that did not involve the saphenofemoral junction24 and, in one study, this was not clearly reported.26 Interventions and Comparators One of the identified SR was specific to ultrasound-guided FS (UGFS)6 whereas, the remaining SRs and HTA did not limit the modality for image-guidance. All types of sclerosants were permitted in the SRs/HTA. In terms of comparators, the HTA15 and three of the SRs compared FS against any other form of varicose vein management.17,18,29 The remaining SRs compared FS against two common approaches to endovascular thermal ablation (i.e., EVLT and RFA).16 The majority of the trials involved UGFS20-25,27 although fluoroscopy-guided FS was studied in one instance26 and two studies did not specify their approach.19,27 Two sclerosants have been studied in the identified literature: sodium tetradecyl sulfate19,20,22,23,26 or polidocanol.21,24-27 Foam was prepared by the Tessari method in almost every instance19,21,23-27 although it was unspecified in one trial.20 Four of the trials assessed a combination therapy of FS with either ligation23,25,27 or EVLT.26 Within the identified RCTs and observational studies, FS - by itself or in combination - was compared in five studies against surgical approaches;19,21,23,25,27 four studies against EVLT (individually19,21 or in combination with phlebectomy)20,22 and twice against liquid sclerotherapy (with26 or without EVLT).24 The surgical approaches varied across studies and involved stripping and ligation with19,23,25 or without phlebectomy.21,27 Years of Publications Given the pre-specified inclusion criteria, the publication dates ranged from 2011 to 2014.


Comparative cost-effectiveness of foam sclerotherapy versus other treatments for varicose veins The economic value of foam sclerotherapy was addressed in two publications. The first was an HTA15 conducted on behalf of the UK’s National Health Services (NHS). It involved both a SR of all economic studies published on non-invasive varicose vein treatments, up to September 2012, and the author’s own construction of an exploratory economic model. Although four economic analyses were identified from the SR, only one included FS as a study arm. In that study, FS was compared to RFA, EVLT or surgery over a five year period. Developed as a Markov model, assumptions were made on the utility values of certain health states (i.e., residual varicosities and incomplete occlusion) and on the modelling of recurrence.15 The authors of the HTA report further built their own cost-utility model to simulate the experiences of patients undergoing varicose vein treatment over a ten year time horizon.15 Employing a discrete event simulation, treatments compared included surgery, UGFS, EVLT and RFA. Treatments were assumed to solely provide symptomatic relief with no impact on mortality. Further assumptions include the subsequent treatments necessary to manage recurrence or treatment failure. A NHS perspective was adopted with the initial procedure costs, additional treatment (i.e., top-up sclerotherapy) costs, and costs of recurrence captured. All costs and benefits were discounted at a rate of 3.5%.15 A separate economic evaluation was conducted under the perspective of the UK’s NHS to assess the cost-utility of UGFS against surgery or EVLT across a five year time horizon.28 The Markov model combined short-term trial data from a pre-existing RCT19 with long-term data extrapolated from SRs and network meta-analyses.3 Similarly, costs of the initial procedure, additional treatment (i.e., top-up FS) and retreatment (i.e., due to recurrence) were captured. Assumptions surrounding the modelling of clinical recurrence were similarly required (e.g., impact on utilities, proportion requiring retreatment). Patients with secondary clinical recurrence were further assumed to not pursue additional treatments. Discounting was not mentioned in this study.28 Evidence-based guidelines and recommendations for foam sclerotherapy versus other treatments for varicose veins Country of Origin Four CPGs were found: the first from the National Institute for Health and Care Excellence (NICE) in the UK;3 the second jointly endorsed by the American College of Phlebology, Society for Vascular Medicine, American Venous Forum and Society for Interventional Radiology;29 the third was another joint guideline endorsed by the Society for Vascular Surgery and the American Venous Forum;9 and the last was unendorsed by a particular group or clinical society but was produced in the UK.2 Population All CPGs were specific for an adult population with varicose veins. One CPG also provided specific recommendations for the management of pregnant women with varicose veins.3


Interventions One of the CPGs was specific to only FS29 whereas the remainder were generic evidence-based guidelines that reviewed a broader set of interventions for varicose vein including surgery, endovenous thermal ablation, and compression therapy.2,3,9 Years of Publications The guidelines were published between 20112,9 and 2013.3 Grading of Recommendations Two of the guidelines2,9 provided recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to appraise the quality of the evidence. The remaining guidelines did not specify how recommendations were graded.3,29

Summary of Critical Appraisal A summary of the results of the critical appraisal are presented in Appendix 3. Comparative clinical effectiveness and safety of foam sclerotherapy versus other treatments for varicose veins The SR within the HTA report was overall well conducted.15 An a priori research question was defined and a well-described research methodology was followed. However, publication bias was not addressed and potential conflicts of interest were not disclosed.15 The critical appraisal by the report authors found that the majority of the selected studies were deemed at high risk of selection or attrition bias due to inadequate randomization, allocation concealment and intention-to-treat analysis. Furthermore, as few studies involved blinded assessment, the authors warned against potential detection bias. Additional factors identified that may confound the SR results included: differences in the level of the surgeon’s experience, non-comparability of groups at baseline and non-identical care programs post intervention. Most SRs identified in this rapid response were generally well conducted: all involved a priori design; had clearly described and comprehensive literature search strategies (that included electronic databases and grey literature); and provided the characteristics of the included studies. With the exception of Dermody et al.,27 the remaining SRs involved duplicate study selection, employed appropriate methods to pool study results quantitatively in their meta-analysis and provided a flowchart detailing the process of study inclusion/exclusion. In the two SRs6,18 that did perform a critical appraisal of their included studies, both agreed that the majority of the trials had adequate allocation concealment but were lacking blinding. One SR further noted concerns of inadequate or poorly reported randomization and non-identical post-intervention care programs between studies.6 However, trials had a low risk of attrition and reporting bias.6 Concerns remained with the three SRs that included non-randomized studies as it was unclear how confounders and differing study quality were factored into the meta-analysis.17,18,31 Furthermore, the SR by Dermody et al.27 did not address heterogeneity when pooling the studies’ results. Few SRs addressed publication bias with the exception of Nesbitt et al.6


All RCTs clearly described their patient populations, the interventions and the outcomes of interest. However, in one of the studies, it was unclear why the outcome of anatomic success was defined differently between the surgical and less-invasive modalities (i.e., UGFS and EVLT).21 The risk of attrition bias was low as dropouts were few and balanced between groups, except in one long-term study where patient follow-up remained unclear.23 Despite their randomized design, the baseline characteristics between treatment groups appeared imbalanced in two studies.19,21 Few of the RCTs conducted a sample size calculation and, amongst the studies that did perform such a calculation,19-21 only one achieved their original sample size requirements.20 Performance bias was likely as none of the blinded the patient or the caregiver although this would be expected given the nature of the interventions being studied. However one trial did manage to blind their outcome assessors to limit the impact of detection bias.24 Although few studies followed principles of intention-to-treat,19,21,24 the potential bias from missing data may be marginal given the low number of dropouts found in most studies. The quality of the observational studies was poor.26,27 Both studies employed convenience sampling which would be vulnerable to selection bias and would limit the overall generalizability of these studies. Baseline patient characteristics between treatment groups were not reported nor was any statistical analysis reported to adjust for such differences. The potential impact of confounders may be high and was not addressed in either study. Performance and detection bias may be likely given the lack of blinding. Furthermore, attrition bias was an issue as one study had a dropout rate calculated to be greater than 75%26 while another did not describe dropouts.27 Furthermore, neither study reported the variability surrounding the point estimate results.26,27 Comparative cost-effectiveness of foam sclerotherapy versus other treatments for varicose veins The SR from the HTA report by Carroll and colleagues was overall well conducted with an a priori research question and clearly-described methods. A single economic study was identified and critical appraisal of this model highlighted concerns with how certain assumptions were made (i.e., treatment success and recurrence) and whether they were justified/ tested in sensitivity analysis.15 Some of the studies incorporated into this model were also considered of poorer quality.15 The remaining two economic models were overall well conducted as an explicit research question was defined and the treatment options were clearly described. Clinical outcomes were derived from SRs and/or network meta-analysis while direct costs were based either from two single-centre UK trials15 or from a single multi-center UK trial.28 Extensive sensitivity analyses were performed on both models although the reporting quality was overall better in the model by Carroll et al. Resource utilization was presented separately by them15 whereas Tassie et al.28 did not present to this level of detail. Discrepancies in the conclusions drawn between these models emerged and may be due to differences in their assumptions of how recurrence was handled and their costing data sources. The models differed in what data sources were used to model recurrence rates; the modality and proportion of retreatments; and the utilities associated with treatment failure. Another potential reason for differences between these two models was the fact that cost-effectiveness in both models was highly sensitive to the relative cost differences between the treatment modalities. Carroll et al.15 derived the cost of EVLT by approximating it against the cost of RFA.


Since RFA was conducted under general anaesthesia and took longer to perform than surgery, the overall procedural costs for both EVLT and RFA were higher than surgery (i.e., total initial procedure cost: surgery, £1155 vs. EVLT, £2472).15 This resulted in a discounted cost difference between EVLT and UGFS of £1,833. By contrast, the model by Tassie et al.28 obtained the cost of EVLT from a multicenter study where such procedures were performed under local anaesthesia, predominantly in a treatment room rather than an operating room. Furthermore, as EVLT was quicker to perform than surgery, the cost of EVLT was lower than surgery. The discounted cost difference between EVLT and UGFS was £431. With this smaller relative cost difference, EVLT was likely to be cost-effective with an incremental cost-effectiveness ratio (ICER) of £3640/QALY. Nonetheless, as all three models were conducted using UK costs, their generalizability to the Canadian perspective may be problematic. Evidence-based guidelines and recommendations for foam sclerotherapy versus other treatments for varicose veins All CPGs clearly described their scope, purpose and intended target user(s). All were developed with recommendations based on well-described SRs; except, in one instance where it was unclear how the SR was conducted.29 Excluding the guideline by Tisi,22 all other CPGs involved extensive stakeholder involvement, even including patient views and preferences in one instance.3 However, details on an external review were rarely reported.2,3,9 Potential conflict of interest were clearly stated in the majority of the guidelines, with the exception of the CPG byTisi.22 Only NICE3 considered cost-effectiveness when developing its recommendations, although most guidelines did consider potential organization barriers.3,9,29 Two of guidelines rated the quality of the evidence and the strength of their recommendation according to GRADE.2,9 The NICE guidelines provided explicit timelines for updating its guidelines.3 Summary of Findings Main study findings and author conclusions are provided in Appendix 4. Comparative clinical effectiveness and safety of foam sclerotherapy versus other treatments for varicose veins Clinical outcomes: FS versus liquid sclerotherapy Ukritmanoroat24 conducted a cross-over RCT comparing FS against liquid sclerotherapy. All patients underwent one session of sclerotherapy in which both sclerosants were given either in the same region of different limbs or in the different regions of the same limb. Total occlusion rates were significantly higher in FS (92%) than liquid sclerotherapy (76%) (P < 0.002).24 These results align with two SRs that found FS was superior in achieving anatomical closure (relative risk [RR] = 1.86, 95% confidence interval [CI]: 1.18 to 2.94; P = 0.0077),17 had lower residual saphenofemoral or small saphenopopliteal junction incompetence (RR = 0.56, 95% CI: 0.38 to 0.84; P = 0.0055)17 and had lower rates of varicose vein recurrence (8.1% vs. 25%; P = 0.048).18


An observational study compared FS or liquid sclerotherapy in combination with EVLT. Although no significant differences were observed in terms of complete closure of saphenous vein (97.9% [FS + EVLT] vs. 95.7% [liquid sclerotherapy + EVLT]), complete sclerosis of the varicose tributaries were higher in the FS-based modality (92.7%) than the liquid sclerotherapy-based modality (71.8%) (P = 0.014).26 Clinical outcomes: FS versus surgery Individual RCTs found no difference between FS and surgery in terms of clinical (i.e., improvement in disease severity, number of residual varicose veins) and quality of life improvement.19,21 However, both reported treatment differences in terms of anatomical success. Higher rates of complete ablation of the GSV were reported in surgery (84.4%) compared to FS (54.6%) (P < 0.001).19 A similar trend in occlusion rates was observed in the long term study (72.7% [FS] vs. 88.2% [surgery], P < 0.02).21 Less consistency was observed amongst the SRs which may likely reflect the fact that few overlapping studies were included between SRs. One found no significant difference between treatment groups in occlusion rates.18 Although another, which combined data meta-analytically, observed the contrary: surgery had statistically better anatomical closure rates (RR = 0.92, 95% CI 0.86 to 0.97) with no difference in the residual saphenofemoral incompetence rate (RR = 0.92, 95% CI 0.56 to 1.51).17 In terms of recanalization and neovascularization, a significant difference was observed (neovascularization: Odds Ratio (OR) 0.05, 95% CI 0.00 to 0.94, favoring FS; recanalization: OR 5.05, 95% CI 1.67 to 15.28, favoring surgery) although both outcomes must be interpreted cautiously given that they were based on a single study.6 The network meta-analysis on the outcome of technical recurrence found that FS was not significantly different than stripping in the first (1-year hazard rates [HR] 1.02, 95% credible interval [CrI] 0.49 to 1.85) and second year post-treatment (2-year HR 0.92, 95% CrI 0.43 to 1.60).15 This was supported by another meta-analysis.6 With respect to pain, a network meta-analysis found no difference between treatment groups15 whereas, a SR noted the contrary with a statistically significant difference favoring FS (P < 0.001).6 Two studies found that clinical severity was significantly more improved in the FS group (venous clinical severity score: (VCSS) median difference -1.63, 95% CrI: -2.90 to -0.4215; median reduction in VCSS 5 to 1 in the sclerotherapy group vs. 7 to 3 in the surgery group [P < 0.001]18). This observation was, however, not supported in another SR as, despite improvements in VCSS in both treatment groups, no between-group differences were reported.6 Two RCTs 23,25 and one observational study 27 compared FS + ligation against conventional surgery (i.e., stripping + ligation ± phlebectomy). No treatment-group differences were observed in the improvement of disease severity and rates of obliteration.23,25,27 Indeed, five-year symptom-free survival rates were 51% in the FS group and 46% in the surgical group (P = 0.69).27 FS was, however, associated with statistically significantly shorter treatment times (median: 43 vs. 65 min), less post-operative analgesic use (proportion reporting any analgesia use: 28% vs. 80%) and faster time-to-return-to-work (median: 3 vs. 6 days) (P < 0.01 for all outcomes).25 Uncertainty remained on the impact of treatment in quality of life. One RCT suggested median scores on the Aberdeen Vein Questionnaire (AVVQ) decreased by 40% in the FS group compared to 37% in the surgical group between the pre-operative and post-operative period (P < 0.01)25 whereas another RCT reported no between-group differences in the AVVQ at 3 and 5 years post-procedure.23


Clinical outcomes: FS vs. endovascular thermal ablation Both RCTs found no statistical difference between FS and EVLT on several of the clinical outcomes (i.e., disease severity, number of residual varicose veins).19,21 Differences exist, however, on anatomical success as higher rates of complete GSV ablation were reported in EVLT than FS (83.0% vs. 54.6%, P < 0.001).19 A similar trend was observed in a longer duration study (occlusion rates: 72.7% [FS] vs. 88.5% [EVLT], P < 0.02).21 A meta-analysis however concluded that residual incompetence rates (RR = 1.52, 95% CI 0.19 to 12.45) and closure rates (RR = 1.02, 95% CI 0.82 to 1.28) were not statistically different between treatment groups.17 One trial found no between-group differences in quality of life improvement on both the disease-specific Chronic Venous Insufficiency Quality-of-Life Questionnaire and the generic EuroQoL-5D.21 However, another reported that, in a post-hoc analysis, FS patients had lower SF-36 mental health score compared to EVLT patients, indicative of poorer quality of life.19 One trial compared FS against EVLT + phlebectomies.20,22 Short term (i.e., 3 months) clinical outcomes were similar between treatment groups (i.e. AVVQ, VCSS, venous filing index, GSV occlusion rate).22 FS was associated with significantly shorter treatment duration (median: 35 min (FS) vs. 85 min (EVLT), P 0.2 for each outcome).17 An observational study reported no statistically significant differences in procedure-related complications between FS or liquid sclerotherapy when performed in conjunct with EVLT.26 Safety: FS versus surgery The frequency of complications was low and did not differ between surgery and FS.19,21 Indeed, the frequency of procedural complications reported in one of the studies was 6% for FS and 7% for surgery with a similar incidence of serious adverse events (i.e., approximately 3% in both groups).19 Two of the SRs narratively concluded that rates of DVT and pulmonary embolism were low, with the most common complications being bruising, skin discoloration, hematoma, paresthesia, infection, and phlebitis.15 A meta-analysis found that the incidence of DVT, skin pigmentation,


and paresthesia were not statistically different between treatment groups (P > 0.1 for both outcomes). However, another study reported that superficial thrombophlebitis was higher in FS compared to surgery (RR = 16.85, 95% CI 2.27 to 124.74) while ecchymosis was higher in surgery compared to FS (RR = 0.40, 95% CI 0.25 to 0.64).17 No serious adverse events were observed between FS + ligation vs. conventional surgery (i.e., stripping + ligation ± phlebectomy). Reports of complications were overall infrequent.23,25,27 The FS group had more reports of pigmentation and superficial thrombophlebitis whereas the surgical group had higher reports of surgery-related complications such as temporary saphenous nerve injury,23,25,27 urinary retention, hematoma and skin ulcers.23,25 Safety: Foam sclerotherapy vs. endovascular thermal ablation RCTs comparing FS and EVLT found no significant differences between the groups in terms of the number of serious adverse events.19 Incidence of any procedure-related complications was lower in the laser group (1%) than in the foam group (6.2%) (P < 0.001) in one study,19 although another reported no differences (7.4% [FS] vs. 9.0% [EVLT], P = 0.64).21 The SRs suggested that there is no statistical difference between treatment modalities (i.e., FS, RFA, EVLT) in terms of the incidence of thromboembolic complications,27 skin pigmentation, paresthesia and ecchymosis.17 The only complication more likely to be observed in patients treated with FS compared to EVLT was superficial thrombophlebitis (RR = 2.03, 95% CI 1.11 to 3.73).17 In the trial that compared FS against EVLT + phlebectomies, no serious complications were observed.20,22 Complications of thrombosis and procedure-related headaches, coughs and dizziness were more common in the FS group; whereas hematoma, dermal thermal injury and severe pain were more commonly reported in the EVLT + phlebectomies group.22 Comparative cost-effectiveness of foam sclerotherapy versus other treatments for varicose veins Overall, all the economic evaluations identified have been conducted under the perspective of UK’s NHS. In the single cost-effectiveness study identified from the literature review within the HTA report,15 the probabilities of a treatment being cost-effective at a willingness-to-pay threshold of £20,000/QALY ranged from: EVLT with local anesthesia (35%), day case surgery (29%) and RFA with local anesthesia (24%). Given that the expected net monetary benefits for different treatment approaches were similar, this highlights that there is little difference in the expected benefits between the different treatment modalities for varicose vein. However, this model was highly sensitive to uncertainty in its assumptions.15 In the economic model constructed by the HTA report authors, FS was found to be less costly and marginally more effective than stripping (i.e., surgery is dominated by FS).15 The ICER for EVLT compared to FS was £518,462/QALY while RFA was found to be extendedly dominated. Between willingness-to-pay thresholds of £20,000 to £50,000/QALY, FS was found to be the most cost-effective treatment in over 90% of the cases although the base-case results were found to be sensitive to the model’s time horizon. The authors thus conclude that, from both an NHS and societal perspective, FS was the most cost-effective option.15 In the last economic evaluation, the cost-effectiveness of UGFS against EVLT or surgery was compared.28 At six months, the mean health services cost savings for UGFS and EVLT compared to surgery was £902 and £392, respectively. In extrapolating to five years, surgery


was extendedly dominated by EVLT. UGFS was found to be less costly but also less effective to EVLT and the ICER for EVLT was £3640/QALY. At a willingness-to-pay threshold of £20,000/QALY, the probabilities that a treatment was cost-effective, in decreasing order, were: endovenous laser ablation (78.7%), UGFS (16.8%) and surgery (4.5%). These results were similarly sensitive to the model’s time horizon and the utilities values.28 Despite differences in the recommendation on which technology is most cost-effective, all three studies consistently found that the QALYs differences between treatments tended to be very small. Differences existed between models on how health states were defined, the approach to costing the surgical technique and where effectiveness data was gathered from. Evidence-based guidelines and recommendations for foam sclerotherapy versus other treatments for varicose veins Within the general disease guidelines, NICE3 recommends the following treatment hierarchy for the treatment of varicose veins: RFA > EVLT > UGFS > surgery based on the benefits and harms of the interventions while taking into account the quality of the underpinning evidence. Pregnant women were however recommended to receive compression hosiery instead of interventional therapy.3 In the joint guidelines by the American Venous Forum and the Society for Vascular Surgery, sclerotherapy is mainly recommended for telangiectasia, reticular veins and varicose veins (GRADE 1B).9 Endovenous thermal ablation is recommended over chemical ablation although FS may be appropriate for the treatment of incompetent saphenous vein (GRADE 1B).9 Tisi2 however suggests a different treatment hierarchy: surgery > sclerotherapy > compression after considering the evidence on the comparative clinical effectiveness. The authors provide no recommendations on endovenous thermal ablation as they note a lack of comparative clinical data comparing endovenous thermal ablation (these guidelines were also the least current). The authors mention that newer treatments (i.e., FS, RFA and EVLT) may be challenging this hierarchy whereby surgery is first-line therapy. In the intervention-specific guideline endorsed by the American College of Phlebology and several other American medical societies, FS was recommended as effective for the treatment of GSV, SSV and tributary varicose veins both as primary treatment and for treatment of recurrence. Furthermore, they state that it may be used for treatment of venous ulcer upon failure of more conservative therapies and potentially to reduce the size or improve the cosmetic appearance of congenital venous malformations. However, FS is contraindicated in patients who developed allergies or experienced temporary neurological events during previous sclerotherapy, or in patients with acute venous thrombotic events. Limitations In terms of the clinical and safety evidence, given the nature of the interventions involved in this comparison, blinding was not possible. Indeed, one study had a decreased percentage of enrolment in the surgery group compared to the less-invasive groups which may be a reflection of selection bias.21 One study however attempted to reduce detection bias by blinding the outcome assessor.24 Only one of the RCTs was adequately powered to detect any significant differences between the treatment groups.20 Variations in outcome reporting and non-identical post-intervention care programs may limit the meaningfulness of the meta-analyses.6,15 The most common outcome, clinical recurrence, is often defined as an incomplete occlusion of the GSV. However, Lattimer et al.20 demonstrated an unclear relationship between incomplete occlusion of the GSV and reflux abolishment / symptomatic recurrence that are more clinically


relevant outcomes. The observational studies, which were included in this analysis since they primarily provided a comparison on the efficacy and safety of combination therapies, suffered overall from poor reporting and are at high-risk of multiple sources of bias (e.g., selection bias, confounding, performance bias, detection bias, attrition bias). So far, most of the included trials have discussed statistical significance although it is unclear what the minimally clinically important difference would be for the outcome measures studied. Existing economic models have produced conflicting results on which treatment is most cost-effective (i.e., endovenous laser ablation or UGFS).15,28 Furthermore, the cost-effectiveness of varicose vein treatment is likely to vary depending on local costs structures and the settings in which the procedures are performed. As this will differ across different jurisdictions and there are no published Canadian economic evaluations that have assessed the potential cost-effectiveness of FS as an intervention for varicose veins compared to other treatment modalities, there is uncertainty which treatment modality would be the most cost-effective in Canada. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING This review assessed the comparative clinical, safety, cost-effectiveness of FS against other treatment modalities for varicose veins. Few reports were identified that have compared FS against RFA and the quality of evidence surrounding combination therapy remains poor. However, the evidence on single interventions includes more and better-quality RCTs, HTAs and SRs. Nonetheless, given the nature of these interventions, all of the present trials have been open-labeled studies which may limit the strength of the available evidence. Existing evidence comparing FS against conventional liquid sclerotherapy has consistently found that FS may be equally or more effective than liquid sclerotherapy in terms of occlusion of the varicose vein and closure of the varicose tributaries. FS may provide benefits compared to surgery in terms of shorter procedure duration, lower pain and faster return-to-work, although the comparative clinical efficacy of FS is uncertain. At best, FS is non-inferior to surgery or EVLT on most clinical outcomes; although, a few long-term studies have emerged suggesting worse occlusion rates for FS compared to these alternative treatment modalities. Trials and SRs have further provided conflicting reports on the impact of treatment on patient-important outcomes such as quality of life and technical recurrence. It is difficult to answer with certainty which treatment modality would be most cost-effective, especially given the lack of Canadian-based economic evaluations. The existing models, albeit well-constructed, have reached different conclusions on which treatment would be considered most cost-effective in the UK setting due to differences in how recurrence is handled and the costing data sources. As the generalizability of procedure costs from UK to Canada is expected to be low, there is limited transferability in these models’ findings. In conclusion, current evidence suggests that FS may be more clinically effective than conventional liquid sclerotherapy. FS is non-inferior to surgery or EVLT on most clinical outcomes although a few long-term studies do suggest lower occlusion rates in patients receiving FS. However, FS is associated with shorter procedure duration, lower pain and faster return-to-work compared to surgery. Although the majority of studies were not adequately powered to detect safety complications, the overall rates of adverse events were low for all varicose vein treatment modalities. Few cost-effectiveness studies have been conducted to assess the economic value of these treatment modalities.


PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


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26. Park SW, Yun IJ, Hwang JJ, Lee SA, Kim JS, Chee HK, et al. Fluoroscopy-guided endovenous sclerotherapy using a microcatheter prior to endovenous laser ablation: comparison between liquid and foam sclerotherapy for varicose tributaries. Korean J Radiol [Internet]. 2014 Jul [cited 2015 Jan 19];15(4):481-7. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105811

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28. Tassie E, Scotland G, Brittenden J, Cotton SC, Elders A, Campbell MK, et al. Cost-effectiveness of ultrasound-guided foam sclerotherapy, endovenous laser ablation or surgery as treatment for primary varicose veins from the randomized CLASS trial. Br J Surg. 2014 Nov;101(12):1532-40.

29. Rathbun S, Norris A, Morrison N, Gibson K, Raymond-Martimbeau P, Worthington-Kirsch R, et al. Performance of endovenous foam sclerotherapy in the USA for the treatment of venous disorders: ACP/SVM/AVF/SIR quality improvement guidelines. Phlebology. 2014 Mar;29(2):76-82.

30. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34.

31. Shadid N, Ceulen R, Nelemans P, Dirksen C, Veraart J, Schurink GW, et al. Randomized clinical trial of ultrasound-guided foam sclerotherapy versus surgery for the incompetent great saphenous vein. Br J Surg. 2012 Aug;99(8):1062-70.

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APPENDIX 1: Selection of Included Studies

181 citations excluded

35 potentially relevant articles retrieved for scrutiny (full text, if

available)

1 relevant report retrieved from other

sources (grey literature, hand

search)

36 potentially relevant reports

17 reports excluded: - irrelevant or missing comparator (3) - already included in at least one of the selected systematic reviews or health technology assessments (4) - other (review articles, editorials) (9) - duplicate publication (1)

19 reports included in review

216 citations identified from electronic literature search and

screened


APPENDIX 2: Characteristics of Included Publications

First Author, Publication Year, Country

Study design, Length of Follow-up

Patients Characteristics, Sample Size (n)

Intervention Comparator(s) Outcomes

Health Technology Assessment

NHS (Carroll et al.), 2013,15 United Kingdom

HTA, consisting of:

Clinical SR/MA of RCTs published up to July 2011. No language restriction. No minimal duration of follow-up.

Economic SR of full economic evaluation (i.e., CEA, CUA, CBA). published up to Sept 2012. No language restriction. No minimal duration of follow-up.

Economic model: DES, 10 y duration

Clinical SR: 31 studies, 3,873 patients. 13 on FS vs. alternative management of VV. Sample size ranged from 28 to 710 patients, more females, patients ≥ 16 y of age.

Economic SR SR: 4 studies, 2 trial-based economic evaluations, 2 model-based economic evaluations, patients ≥ 16 y of age.

Economic model: UK NHS perspective

SR: EVLT, RFA, UGFS, transilluminated-powered phlebectomy

Economic model: EVLT, RFA, FS

SR: Any form of VV management (e.g., surgical, conservative, phlebectomy, alternative minimally invasive techniques)

Economic model: stripping

Clinical: - Technical

failure - Recurrence - Severity of

clinical symptoms (VCSS)

- Pain - Time to

return to work or normal activity

- Post-operative complications

Economic SR assumptions: Some effectiveness parameters based on two SRs. Others (e.g, rate and time-to recurrence) based on single sources.

Economic model assumptions: Efficacy data based on SR, network meta-analysis and, in some cases, single studies (e.g., probability of adverse

events).






Systematic Reviews

Nesbitt, 2014,6 United Kingdom

SR/MA of RCTs on the treatment of GSV varices. Update of a 2011 Cochrane review, included literature up to January 2014. No language restriction.

13 studies, 3081 patients. 3 studies compared UGFS vs surgery. Sample size ranged from 33 to 500 patients, more females within all studies, age ranged from 18 to 79.

EVLT, RFA, UGFS

Ligation + stripping

- Recurrence or recanalisation - Neovascularisation - Technical failure - QoL - Severity of clinical symptoms (VCSS) - Post-operative complications - Procedure length - Length of hospital stay - Procedure costs

Dermody, 2014,16 United States

SR of RCTs and case series published from January 2000 to January 2013 on thromboembolic complications following treatment for GSV insufficiency. Uncertain on language restriction and follow-up duration.

31 studies (12 RCTs, 19 case series). 10 studies on FS. More females within all studies, age ranged from 48 to 56.

FS RFA; EVLT - Post-operative complications (i.e., DVT, PE)

Rathbun, 2011,17 United States

SR/MA of literature (i.e., RCTs and observational studies) published up to April 2010 on endovenous FS. English or English-translated publications. No

104 studies (20 RCTs, 82 observational studies, 2 unclassified). Sample size ranged from 1 to 1200 patients, percentage of female ranged from

FS Any form of VV management (e.g., surgery, LS, EVTA).

- Anatomical closure rate - Residual incompetence - Post-operative complications






minimal duration of follow-up.

0% to 100%, age ranged from 5 mo to 95 y.

Murad, 2011,18 United States

SR/MA of RCTs and comparative cohort studies on the treatment of VV. Uncertain on last search date. No language restriction. No minimal duration of follow-up.

39 studies (30 RCTs, 9 observational studies), 8285 patients. One study on FS vs. LS, two studies on FS vs. surgery. Mean sample size of 225, 70% female mean age of 49.

FS Any form of VV management (e.g., surgery, LS).

- Occlusion - Recurrence - Severity (VCSS) - Pain - Return to work - Costs

Randomized Controlled Trials

Brittenden, 2014,19 United Kingdom

RCT, open-label, multi-center, Length of follow-up: 6 mo

FS (n=286), 56.6% female, mean age: 49.0 Surgery (n=289), 56.4% female, mean age: 49.2 EVLT (n=210), 57.1% female, mean age: 49.7 Inclusion criteria: ≥18 years, unilateral or bilateral primary symptomatic VV (≥C2 on CEAP) and reflux of GSV/SSV >1s on duplex ultrasonography

FS Stripping + Ligation + phlebectomy; EVLT

- Clinical success - Severity (VCSS) - Ablation rates of the main trunks of SV - QoL (AVVQ, EQ-5D, SF-36) - Post-operative complications

Biemans, 2013,21 Netherlands

RCT, open-label, single-center, Length of follow-up: 12 mo

UGFS (n=77), 67.5% female, mean age: 56 Surgery (n=68), 67.6% female, mean age: 52

UGFS Stripping + ligation; EVLT

- Anatomical success (defined as no flow or reflux; absence of GSV) - Neovascularization






EVLT (n=78), 69.2% female, mean age: 49 Inclusion criteria: adult patients with symptomatic primary incompetent GSV above the knee and incompetent SFJ

- QoL (CIVIQ, EQ-5D) - Post-operative complications

Lattimer, 2013,20 United Kingdom (preliminary 15 mo. results) Lattimer, 2012,22 United Kingdom (preliminary 3 mo. results)

RCT, open-label, single-center, Length of follow-up: up to 15 mo

UGFS (n=46), 54% female, mean age: 50 EVLT + phlebectomy (n=44), 61% female, mean age: 47 Inclusion criteria: symptomatic primary incompetent GSV with SFJ reflux (>0.5s) on duplex ultrasonography

UGFS EVLT + phlebectomy

In both studies: - GSV occlusion - Severity (VCSS, STS) - QoL (AVVQ) - Post-operative complications

In 3 mo follow-up study: - VAS 7-day pain score - Analgesia use - Costs

Kalodiki, 2012,23 United Kingdom

RCT, open-label, Length of follow-up: 5 y

UGFS + ligation (n=43), 74% female, mean age: 49 Stripping + phlebectomy + ligation (n=39), 59% female, mean age: 47 Inclusion criteria: primary symptomatic

UGFS + ligation

Stripping + ligation + phlebectomy

- Occlusion - Recurrence - Severity (VCSS, VSDS) - QoL (AVVQ, SF-36) - Post-operative complications






varicosities involving the GSV without previous treatment

Liu, 2011,25 China

RCT, open-label, single-center, Length of follow-up: 6 mo

UGFS (n=29) Surgery (n=30) Overall: 57% female, median age: 49 Inclusion criteria: symptomatic primary VV with SFJ and GSV reflux. ≥C2 on CEAC scale.

UGFS + ligation

Stripping + ligation + phlebectomy

- Obliteration - Recanalization - QoL (AVVQ) - CEAP - Analgesia use - Post-operative complications - Time-to-return-to-work - Costs

Ukritmanoroat, 2011,24 Thailand

Crossover RCT, open-label, single-center, Length of follow-up: 90 days

UGFS (n= 50), Liquid sclerotherapy (n=50) Overall: 90% female, mean age: 46 Inclusion criteria: symptomatic primary reticular varices or postoperative varices that did not involve SFJ

UGFS Liquid sclerotherapy

- Total occlusion - Pain - Post-operative complications

Non-randomized study designs

Park, 2014,26 South Korea

Cohort, open-label, Length of follow-up:12 mo

FS + EVLT (n=41) LS + EVLT (n=42) Inclusion criteria: VV in unilateral or bilateral lower extremities

FS + EVLT LS + EVLT - Technical success - Clinical Success - Post-operative complications






Islamoglu, 2011,27 Turkey

Nonrandomized cohort, open-label, single-center, Mean length of follow-up: 10.2 mo

FS + ligation (n=156), 60% female, mean age: 48 Stripping (n=216), 56% female, mean age: 49 Inclusion criteria: GSV reflux and C2-6, Epr, As on CEAP score

FS + ligation Stripping + ligation

- Unclear: postoperative symptoms, convalescence time, recurrence, thrombosis

Economic Evaluations

Tassie, 2014,28 United Kingdom

Short-term (6 mo): Markov model Type of analysis: cost-utility analysis Perspective: United Kingdom NHS Duration: 5 y

Trial population inclusion criteria: >18 y of age, primary unilateral or bilateral symptomatic varicose veins (CEAP class ≥C2), GSV and/or SSV involvement.

UGFS EVLT, Stripping + ligation + phlebectomy

Assumptions: Short-term cost and efficacy parameters estimated from multicenter head-to-head RCT. Long-term data extrapolated from SR and network MA.

Clinical Practice Guidelines

NICE clinical guideline 168 [CG168]. Varicose veins in the legs: the diagnosis and management of varicose veins. 2013,3 United Kingdom

CPG

Guideline developed from series of SRs.

All treatments (e.g., conservational, interventional).


- Patient management (i.e., referral, assessment efficacy and safety of treatments)

- Cost-effectiveness






ACP/ SVM/ SIR/ AVF Quality improvement guidelines. 2012,29 United States

CPG Guideline developed from previous MA17 and comprehensive questionnaire of ACP annual congress attendees

FS None - Patient management (i.e., indication, contraindication, injection technique, follow-up surveillance, safety, patient consent)

SVS and AVF. 2011, 9 United States

CPG Guideline developed from previous SR/MAs, consensus documents, reports from summits and symposiums. GRADE criteria applied to guideline development.



- Patient management (i.e., diagnostic evaluation, classification, outcome measure, referral, efficacy and safety of treatments)

Tisi. Clinical evidence. 2011,2 No specific jurisdiction

CPG Guideline developed from SR conducted by author. GRADE criteria applied to guideline development.



- Effectiveness and safety of different interventions.

ACP = American College of Phlebology; AVF = American Venous Forum; AVVQ = Aberdeen varicose veins questionnaire; CBA = cost-benefits analysis; CEA = cost-effectiveness analysis; CEAP = Clinical-Etiology-Anatomy-Pathophysiology; CIVIQ = Chronic Venous Insufficiency Quality-of-Life Questionnaire; CPG = clinical practice guidelines; CUA = cost-utility analysis; DES = discrete event simulation; DVT = deep vein thrombosis; EQ-5D = EuroQoL 5 dimension; EVLT = endovenous laser therapy; EVTA = endovenous thermal ablation; FS = foam sclerotherapy; GSV = great saphenous vein; HTA = health technology assessment; LS = liquid sclerotherapy; MA = meta-analysis; mo = month; NHS = National Health Service (UK); NICE = National Institute for Health and Care Excellence; PE = pulmonary embolism; QoL = quality of life; RCT = randomized controlled trial; RFA = radio frequency ablation; SF-36 = short-form 36; SFJ = saphenofemoral junction; SIR = Society for Interventional Radiology; SR = systematic review; SSV = small saphenous veins SV= saphenous vein; SVM = Society for Vascular Medicine; SVS = Society for Vascular Surgery; UGFS = ultrasound-guided foam sclerotherapy; VAS = visual analogue scale; VCSS = Venous Clinical Severity Score; VSDS = venous segmental disease score; VV = varicose veins; y = year.


APPENDIX 3: Critical Appraisal of Included Publications


Strengths Limitations

HTAs

NHS (Carroll et al.), 2013,15 United Kingdom

SR [clinical and economic]: A priori-designed SR with MAs. Clear description of literature search with duplicate study selection performed. Provides list of included & excluded studies alongside the characteristics of the included studies. Critical appraisal (incl. risk of bias assessment) conducted. Addressed homogeneity in the meta-analysis.

Economic model: Study based on well-defined question, description of the competing treatments and established effectiveness of the therapies. Perspective, time horizon, study design and discounting were stated. Cost and benefits from network meta-analysis and relevant database. Quantities for resource utilization are presented separately. Assumptions to model are clearly reported. Sensitivity analyses (i.e., parameter, structural) were performed. Conclusions appear adequate.

SR [clinical and economic]: Publication bias has not been considered. No declaration of conflict of interest or sources of funding.

Economic model: Major outcomes not presented as a disaggregate form. Only presented as an aggregate. Applicability of costs from United Kingdom to Canada remains uncertain.

SRs

Nesbitt, 2014,6 United Kingdom

A priori-designed SR with MAs. Clear description of literature search, including grey literature, with duplicate

No mention of potential conflict of interest.




study selection performed. Provides list of included & excluded studies alongside the characteristics of the included studies. Critical appraisal (incl. risk of bias assessment) conducted. Addressed homogeneity in the conduct of the meta-analysis. Publication bias considered.

Dermody, 2014,16 United States

A priori-designed SR with MAs. Clear description of literature search, including grey literature. Characteristics of the included studies provided. Mentions potential conflict of interest.

Uncertain whether study selection was performed in duplicate. Missing list of included & excluded studies. No critical appraisal conducted. Methods to combine findings did not factor for heterogeneity. Unclear how randomized and observational study results were pooled. Publication bias not considered.

Rathbun, 2011,17 United States

A priori-designed SR with MAs. Clear description of literature search, including grey literature, with duplicate study selection performed. Provides list of included & excluded studies alongside the characteristics of the included studies. Addressed homogeneity in the conduct of the meta-analysis. Mentions potential conflict of interest.

Although authors mention that study quality was reviewed, no details are provided on how quality was assessed and the outcome of this assessment. Unclear how randomized and observational study results were pooled. Publication bias not considered.

Murad, 2011,18 United States

A priori-designed SR with MAs. Clear description of literature search, including grey literature, with duplicate study selection performed.

Unclear how randomized and observational study results were pooled. Publication bias not considered.




Provides list of included & excluded studies alongside the characteristics of the included studies. Critical appraisal conducted using pre-defined list of criteria. Addressed homogeneity in the meta-analysis. Mentions potential conflict of interest.

RCTs

Brittenden, 2014,19 United Kingdom

Clear description of characteristics of subjects, the interventions studied and standardization of outcome assessment. ITT analysis. Appropriate statistical test employed with adjustment for differences in covariates and baseline scores. Clear explanation of patient disposition with relatively low and balanced rates of dropouts.

Study subjects, clinicians and outcome assessors were not blinded. Sample size calculated (this number was however revised during the study due to better than expected efficacy). Although randomization was conducted with stratification of hospital site, baseline characteristics differed between treatment groups. Did not correct statistically for multiple comparisons. Uncertain how ultrasound examination was performed to assess the primary outcome. If multiple raters were involved, inter-rater reliability was not assessed.

Biemans, 2013,21 Netherlands

Clear description of characteristics of subjects, the interventions studied, and standardization of most of the outcome assessment. Physicians had more than 5 years of experience with the treatment. ITT analysis with sensitivity analysis conducted based on per-protocol. No difference in the results was found. Statistical tests appear appropriate.

Study subjects and clinicians not blinded. Unclear whether outcome assessors were blinded. Although sample size calculated, the calculated sample size per treatment group was not reached. Enrolment in the surgery group was lower than the two other groups. Although randomization was conducted, age significantly differed between treatment groups.




Protocol adapted to include second study site as lower than expected enrolment rate. Subgroup analysis did not show any difference between the two centers. Clear explanation of patient disposition with relatively low and balanced rates of dropouts.

Unclear why primary outcome, anatomic success, was defined differently depending on the treatment group. Uncertain how ultrasound examination was performed to assess the primary outcome. If multiple raters were involved, inter-rater reliability was not assessed.

Lattimer, 2013,20 and Lattimer, 2012,22 United Kingdom

Clear description of characteristics of subjects, the interventions studied, and standardization of outcome assessment. Randomization was conducted and treatment groups appear balanced in the demographic and baseline characteristic. Sample size calculation conducted with adjustment to account for potential loss-to-follow-up. Sample size desired was achieved. Appropriate statistical test employed with adjustment for differences in covariates and baseline scores. Clear explanation of patient disposition with relatively low and balanced rates of dropouts. Ultrasound examination performed by one accredited vascular scientist to assess the primary clinical outcome.

Study subjects, clinicians and outcome assessors unblinded. Statistical analysis done according to per-protocol. Did not correct statistically for multiple comparisons across different time points (i.e., 3 and 15 months).

Kalodiki, 2012,23 United Kingdom

Clear description of characteristics of subjects, the interventions studied, and standardization of outcome assessment. Randomization was conducted and, according to author, the treatment groups were balanced. Ultrasound examination performed by one accredited vascular scientist to assess the primary clinical outcome.

Study subjects and clinicians not blinded. Unclear whether outcome assessors were blinded. No sample size calculation. Enrolment was based on financial resources available to study authors. Number of participants reported in the short-term study does not align with the long-term study. Fewer patients reported in the short-term study.




Uncertain how dropouts handled. Statistical analysis done according to per-protocol. Statistical tests unclear whether adjustment made to account for differences in follow-up time between treatment groups.

Liu, 2011,25 China Clear description of characteristics of subjects, the interventions studied, and standardization of outcome assessment. Randomization was conducted and, according to author, the treatment groups were balanced (data not presented). Clear explanation of patient disposition with relatively low and balanced rates of dropouts.

Study subjects and clinicians not blinded. Unclear whether outcome assessors were blinded. No sample size calculation. Statistical analysis done according to per-protocol. Did not correct statistically for multiple comparisons. Although define protocol for ultrasound examination, multiple raters were involved with no reported assessment of inter-rater reliability.

Ukritmanoroat, 2011,24 Thailand

Clear description of characteristics of subjects, the interventions studied, and standardization of outcome assessment. The same physician performed both treatments on the patient. Given cross-over design, each patient formed its own control. As such, treatment groups were identical. Study subjects and clinicians were not blinded. However, outcome assessors were blinded. No dropouts. As such, study was conducted as ITT.

No sample size calculation. Did not correct statistically for multiple comparisons.

Non-randomized study designs

Park, 2014,26 South Korea

Clear description of interventions studied, and standardization of outcome

Study subjects and clinicians not blinded. Unclear whether outcome




assessment. assessors were blinded. Study not randomized. Furthermore, little transparency on the demographics and baseline characteristics between the two treatment groups to assess whether extent selection bias may impact results observed. No sample size calculation. Convenience sampling, which is highly vulnerable to selection bias. Statistical analysis done according to per-protocol. Unclear explanation of patient disposition. Dropouts high (e.g., >75% attrition rate at one year in LS group). Two year follow-up data only reported for the surgery group. Statistical tests not adjusted to account for differences in baseline characteristics and follow-up time between treatment groups. Did not correct statistically for multiple comparisons. Variability in the point estimates not reported. Potential impact of confounders on study results not acknowledged.

Islamoglu, 2011,27 Turkey

Clear description of characteristics of subjects, the interventions studied, and standardization of outcome assessment.

Study subjects and clinicians not blinded. Unclear whether outcome assessors were blinded. Study not randomized. Patients permitted to select their preferred treatment. However, measured demographics and baseline characteristics between the two groups appear balanced.




No sample size calculation. Convenience sampling, which is highly vulnerable to selection bias. Unclear if statistical analysis based on ITT or per-protocol. Did not report dropsout (i.e., numbers and rational). Statistical tests not adjusted to account for differences in baseline characteristics. Variability in the point estimates not reported. Potential impact of confounders on study results not acknowledged.

Economic Evaluation

Tassie, 2014,28 United Kingdom

Study based on well-defined question, description of the competing treatments and established effectiveness of the therapies.

Perspective, time horizon, study design and discounting were stated.

Analysis of short-term prospectively-collected trial data for costs and effects appropriately conducted. Long-term extrapolation of costs and benefits from network meta-analysis and relevant database. Assumptions to model are clearly reported.

Sensitivity analyses (i.e., parameter, structural) were performed. Conclusions were deemed adequate.

Quantities for resource utilization are not presented separately. Major outcomes not presented as a disaggregate form. Only presented as an aggregate. Applicability of costs from United Kingdom to Canada remains uncertain.

CPGs

NICE. 2013,3 United Kingdom

Clear description of scope and purpose. Guideline development group includes individuals from relevant professional

Not clear on who provided external review.




groups and patient views. Intended target user for guideline clearly defined. Rigorous methodology and development applied to guideline development with balanced consideration of efficacy, safety and cost-effectiveness. Potential organization barrier discussed. Recommendations are clearly presented with different options to management available.

Conflicts of interests have been addressed.

ACP/ SVM/ SIR/ AVF. 2012,29 United States

Clear description of scope and purpose. Guideline development group includes individuals from relevant professional groups. Intended target user for guideline clearly defined. Rigorous development with external review clearly described. Balanced consideration of efficacy and safety. Potential organization/ management issues discussed. Recommendations are clearly presented.


Patient views and preferences were not sought. Although systematic review was conducted, the criteria for selecting the evidence were unclear. No procedure mentioned for updating guideline. Alternative options to management and cost implications were not considered.

SVS and AVF. 2011,9 United States

Clear description of scope and purpose. Guideline development group includes individuals from relevant professional groups. Intended target user for guideline clearly defined. Rigorous methodology and development with balanced consideration of efficacy and safety. Methods to formulate recommendations based on GRADE. Potential organization barriers discussed. Recommendations are clearly presented with different options to management

Not clear on who provided external review. Patient views and preferences were not sought. Although mention revision, details on when such revisions would occur is not mentioned. Cost implications were not considered.




available.


Tisi. 2011,2 No specific jurisdiction

Clear description of scope and purpose. Intended target user for guideline clear. Rigorous methodology and development with balanced consideration of efficacy and safety. Methods to formulate recommendations based on GRADE. Recommendations are clearly presented with different options to management available.

Guideline developed by single individual without involvement of relevant professional groups or an external review. Patient views and preferences were not sought. Organization barriers, monitoring and auditing are not factored in these guidelines. No procedure mentioned for updating guideline. Cost implications were not mentioned. Conflicts of interests not addressed.

ACP = American College of Phlebology; AVF = American Venous Forum; CPG = clinical practice guidelines; EVLT = endovenous laser therapy; FS = foam sclerotherapy; GRADE = Grading of Recommendations, Assessment, Development, and Evaluation; HTA = health technology assessment; ITT = intention-to-treat; LS = liquid sclerotherapy; MA = meta-analysis; NHS = National Health Service; NICE = National Institute for Health and Care Excellence; P = probability value; RCT = randomized controlled trial; RFA = radio frequency ablation; SR = systematic review; SIR = Society for Interventional Radiology; SVM = Society for Vascular Medicine; SVS = Society for Vascular Surgery.


APPENDIX 4: Summary of Main Study Findings and Author’s Conclusions


Main Study Findings Authors’ Conclusions

Health Technology Assessment

Carroll, 2013,15 United Kingdom

Clinical SR: - 31 RCTs comprising 3,873 patients

(range: 28 to 710 patients/trial); mean age ranged from 33 to 54 y; predominantly female (54 to 95%); majority of patients were C2 on CEAP score. 1

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