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Cost-Effectiveness of Current and Emerging Treatments of Varicose Veins

Open ArchivePublished:March 14, 2018DOI:https://doi.org/10.1016/j.jval.2018.01.012

      Abstract

      Objectives

      To analyze the cost-effectiveness of current technologies (conservative care [CONS], high-ligation surgery [HL/S], ultrasound-guided foam sclerotherapy [UGFS], endovenous laser ablation [EVLA], and radiofrequency ablation [RFA]) and emerging technologies (mechanochemical ablation [MOCA] and cyanoacrylate glue occlusion [CAE]) for treatment of varicose veins over 5 years.

      Methods

      A Markov decision model was constructed. Effectiveness was measured by re-intervention on the truncal vein, re-treatment of residual varicosities, and quality-adjusted life-years (QALYs) over 5 years. Model inputs were estimated from systematic review, the UK National Health Service unit costs, and manufacturers’ list prices. Univariate and probabilistic sensitivity analyses were undertaken.

      Results

      CONS has the lowest overall cost and quality of life per person over 5 years; HL/S, EVLA, RFA, and MOCA have on average similar costs and effectiveness; and CAE has the highest overall cost but is no more effective than other therapies. The incremental cost per QALY of RFA versus CONS was £5,148/QALY. Time to return to work or normal activities was significantly longer after HL/S than after other procedures.

      Conclusions

      At a threshold of £20,000/QALY, RFA was the treatment with highest median rank for net benefit, with MOCA second, EVLA third, HL/S fourth, CAE fifth, and CONS and UGFS sixth. Further evidence on effectiveness and health-related quality of life for MOCA and CAE is needed. At current prices, CAE is not a cost-effective option because it is costlier but has not been shown to be more effective than other options.

      Keywords

      Introduction

      Varicose veins (incompetence of the great saphenous vein [GSV] and its tributaries) carry a considerable burden of disease for patients and health services. Symptoms can be discomforting, painful, and unsightly, and in serious cases can impair mobility and lead to elevated risk of ulcer [
      • Onida S.
      • Lane T.R.A.
      • Davies A.H.
      Varicose veins and their management.
      ]. Reported incidence of varicose veins ranges from 20% to 64% of the total population. Residual varicosities (spider veins), which are in many cases associated with varicose veins, can affect up to 80% of adults.
      Treatment for varicose veins can offer substantial health-related quality-of-life (HRQOL) improvements to patients. The market is characterized by many competing modalities, and innovation continues to be rapid. Established treatments of varicose veins include conservative care (CONS) (such as compression stockings), high-ligation surgery (HL/S) (usually stripping and ligation of the great and small saphenous veins), ultrasound-guided foam sclerotherapy (UGFS), endovenous laser ablation (EVLA), and radiofrequency ablation (RFA) [
      National Clinical Guideline Centre
      Varicose Veins in the Legs.
      ]. To these can be added emerging technologies of mechanochemical ablation (MOCA) [
      • van Eekeren R.R.J.P.
      • Boersma D.
      • Elias S.
      • et al.
      Endovenous mechanochemical ablation of great saphenous vein incompetence using the ClariVein device: a safety study.
      ] and cyanoacrylate glue occlusion (CAE) [
      • Almeida J.I.
      • Javier J.J.
      • Mackay E.
      • et al.
      First human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence.
      ]. Interventional treatments aim to occlude the GSV and in most cases this will relieve the underlying cause of the symptoms. If symptoms do recur, re-intervention may be considered. Residual varicosities may in some cases also be treated during the index treatment or alternatively in a follow-up session [
      • Lane T.R.A.
      • Kelleher D.
      • Shepherd A.C.
      • et al.
      Ambulatory Varicosity avUlsion Later or Synchronized (AVULS).
      ].
      This study develops an economic model of current and emerging technologies for treatment of varicose veins. The model draws together evidence from published literature to estimate the costs of the initial treatments, re-treatments for varicosities and re-interventions for treatment failure, and HRQOL over 5 years. Key input variables for the model are estimated when possible from systematic reviews and meta-analyses of randomized controlled trials (RCTs), conducted according to recognized protocols [

      Higgins J, Green S. Cochrane handbook for systematic reviews of interventions, version 5.1.0. 2011. Available from: www.handbook.cochrane.org. [Accessed October 31, 2017].

      ,
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ]. The economic analyses are conducted according to guidelines for evaluation of health care programs [
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.
      ]. The structure of the article is as follows. In the Methods section, we first describe the model structure and justify re-interventions and re-treatments as the principal measures of effectiveness. Next, we present the methods and results of the systematic review and evidence synthesis to obtain each of the key inputs used in the model. In the Results section, we show the 5-year predictions of costs and quality-adjusted life-years (QALYs) from the base-case model and sensitivity analyses. Finally, we discuss the implications for current practice and further research.

      Methods

      Overview

      This study evaluates the cost-effectiveness of therapeutic options for varicose veins in adult patients requiring treatment in the upper leg for incompetence of the GSV (the “truncal” vein). Health outcomes are measured in QALYs, and the cost perspective is that of the UK National Health Service (NHS) and the social care system at 2015 prices. The time horizon of the decision model is 5 years. This is considered to be the maximum time over which recurrence of index symptoms is likely to occur, and is the longest follow-up of any published RCT in this area [
      • Rasmussen L.
      • Lawaetz M.
      • Bjoern L.
      • et al.
      Randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years.
      ,
      • Lawaetz M.
      • Serup J.
      • Lawaetz B.
      • et al.
      Comparison of endovenous ablation techniques, foam sclerotherapy and surgical stripping for great saphenous varicose veins: extended 5-year follow-up of a RCT.
      ,
      • Flessenkamper I.
      • Hartmann M.
      • Stenger D.
      • Roll S.
      Endovenous laser ablation with and without high ligation compared with high ligation and stripping in the treatment of great saphenous varicose veins: initial results of a multicentre randomized controlled trial.
      ]. Costs and QALYs are discounted at 3.5% per year [
      National Institute for Health and Care Excellence
      Guide to the Methods of Technology Appraisal.
      ]. The treatments compared are CONS, HL/S, EVLA, RFA, UGFS, MOCA, and CAE.
      The key outcome data used to inform the decision model are re-interventions, operative time, HRQOL, and time off work. These are based as far as possible on the synthesis of RCT data obtained from systematic review. Because this is a multiple technology appraisal, network meta-analysis (NMA) should be considered when appropriate [
      • Jansen J.P.
      • Fleurence R.
      • Devine B.
      • et al.
      Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices, Part 1.
      ]. The main assumption of NMA, in addition to those used in conventional random-effects meta-analysis, is consistency of treatment effects [
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ]. That is, for any three treatments A, B, and C, the treatment effect (on an appropriate linear scale) of B versus C is the same as that of A versus C minus the effect of A versus B. Consistency can be assessed statistically by observing whether the direct and indirect evidence agree with one another [
      • White I.R.
      Network meta-analysis.
      ,
      • Lu G.
      • Ades A.E.
      Assessing evidence inconsistency in mixed treatment comparisons.
      ]. The network is more likely to be consistent if the distributions of patient characteristics (potential effect modifiers) are similar in all the studies [
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ]. The standard random-effects NMA model also assumes that studies are exchangeable; that is, between-study variance is the same for all treatment comparisons [
      • White I.R.
      Network meta-analysis.
      ]. In this study, for outcomes for which these assumptions appear valid, we estimate model parameters from the RCT data using mixed treatment effects, and for outcomes for which an NMA appears inappropriate, we estimate model parameters from direct treatment effects using conventional random-effects meta-analysis.

      Model Structure

      The decision model is a Markov structure (Fig. 1). The principal measure of effectiveness of the treatments is re-intervention. Broadly, there are two reasons for a re-intervention. The first is the re-treatment of painful or unsightly varicose veins in the tributaries of the GSV at or near the surface, known as residual varicosities. It is assumed that these will be treated shortly after the first 6-week follow-up. The second is the re-intervention on the truncal vein. These re-interventions can occur if the index treatment has failed or symptoms have recurred and will take place between 6 months and 5 years after the index treatment. Varicose veins can be a painful and debilitating condition, but not life-threatening. Hence, mortality is not an outcome in the model.
      Fig. 1
      Fig. 1Structure of Markov model. Residual varicosities are re-treated at 6 weeks and re-interventions can occur up to 5 years after index procedure. GSV, great saphenous vein.

      Re-treatments of residual varicosities

      Residual varicosities are usually unsightly but can also be symptomatic and painful. In most patients, treatment of the GSV will lead these to be significantly less prominent. This leads some practitioners not to treat these during the index procedure, but instead to “wait and see.” Nevertheless, the Ambulatory Varicosity avUlsion Later or Synchronized (AVULS) study found that the most effective course of action (in terms of overall patient quality of life) is to treat the varicosities alongside the truncal treatment during the index procedure [
      • Lane T.R.A.
      • Kelleher D.
      • Shepherd A.C.
      • et al.
      Ambulatory Varicosity avUlsion Later or Synchronized (AVULS).
      ]. It is assumed in our model that concomitant phlebectomy or foam will be used to treat nontruncal varicosities as needed alongside all the surgical treatment options, except in UGFS because it does not use appropriate anesthetics to allow this strategy to be followed. This means that the rate of re-treatment of residual varicosities is greater after UGFS than after other interventional modalities [
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ]. In all treatment modalities, patients are re-assessed at a 6-week follow-up. If residual varicosities are still present and symptomatic, these will be treated by ambulatory foam [
      • Marsden G.
      • Perry M.
      • Bradbury A.
      • et al.
      A cost-effectiveness analysis of surgery, endodermal ablation, ultrasound-guided foam sclerotherapy and compression stockings for symptomatic varicose veins.
      ].

      Re-interventions on the truncal vein

      Re-intervention on the truncal vein is an indicator of the failure of the initial treatment or a recurrence of serious symptoms. In the case of re-intervention, HRQOL is assumed to be impaired from the time of index treatment to the time of re-intervention. Re-intervention in practice might take place between 6 months and 5 years after the initial treatment, and occurs at a roughly constant rate [
      • van den Bos R.
      • Arends L.
      • Kockaert M.
      • et al.
      Endovenous therapies of lower extremity varicosities: a meta-analysis.
      ]. Five years is the maximum time over which symptoms are likely to recur [
      • van der Velden S.K.
      • Biemans A.A.
      • De Maeseneer M.G.
      • et al.
      Five-year results of a randomized clinical trial of conventional surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy in patients with great saphenous varicose veins.
      ], whereas 6 months is the minimum time for recurrent symptoms to develop, be assessed by the clinician, and their appropriate treatment scheduled in a public health system. If there are no re-interventions or re-treatments, the index treatment is assumed to have been fully successful and the patient will be at full health for the whole 5-year period. It is assumed that 42% of patients requiring re-intervention will be treated by UGFS, 46% by EVLA, and 12% by surgery [
      • Marsden G.
      • Perry M.
      • Bradbury A.
      • et al.
      A cost-effectiveness analysis of surgery, endodermal ablation, ultrasound-guided foam sclerotherapy and compression stockings for symptomatic varicose veins.
      ,
      • Tassie E.
      • Scotland G.
      • Brittenden J.
      • 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.
      ]. As assumed in previous models, only one re-intervention on the truncal vein would be considered per patient in the UK NHS [
      • Marsden G.
      • Perry M.
      • Bradbury A.
      • et al.
      A cost-effectiveness analysis of surgery, endodermal ablation, ultrasound-guided foam sclerotherapy and compression stockings for symptomatic varicose veins.
      ,
      • Tassie E.
      • Scotland G.
      • Brittenden J.
      • 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.
      ]. It is assumed in the base-case model that symptoms are successfully resolved after re-intervention. In a sensitivity analysis, it is assumed, as an upper limit, that 25% of patients continue to experience symptoms after re-intervention.

      Systematic Review

      A systematic review of the literature was undertaken to inform operative time, HRQOL (EuroQol five-dimensional questionnaire [EQ-5D]), re-interventions, re-treatments, and time to return to work or normal activities. MEDLINE was searched for articles in English describing RCTs published between 1974 and July 2017 that compared the treatment options discussed in this article. Reference lists of other reviews were examined. The search terms are listed in Appendix 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012. Risk of bias for each RCT was assessed using the Cochrane checklist [

      Higgins J, Green S. Cochrane handbook for systematic reviews of interventions, version 5.1.0. 2011. Available from: www.handbook.cochrane.org. [Accessed October 31, 2017].

      ]. The protocol was registered in PROSPERO (CRD42015029618).
      The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart for study selection is given in Appendix 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012. A Cochrane review carried out in 2014 found 13 studies that were cross-checked [
      • Nesbitt C.
      • Bedenis R.
      • Bhattacharya V.
      • Stansby G.
      Endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus open surgery for great saphenous vein varices.
      ]. Thirty-eight publications met our inclusion criteria [
      • Rasmussen L.
      • Lawaetz M.
      • Bjoern L.
      • et al.
      Randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years.
      ,
      • Lawaetz M.
      • Serup J.
      • Lawaetz B.
      • et al.
      Comparison of endovenous ablation techniques, foam sclerotherapy and surgical stripping for great saphenous varicose veins: extended 5-year follow-up of a RCT.
      ,
      • Flessenkamper I.
      • Hartmann M.
      • Stenger D.
      • Roll S.
      Endovenous laser ablation with and without high ligation compared with high ligation and stripping in the treatment of great saphenous varicose veins: initial results of a multicentre randomized controlled trial.
      ,
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ,
      • van der Velden S.K.
      • Biemans A.A.
      • De Maeseneer M.G.
      • et al.
      Five-year results of a randomized clinical trial of conventional surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy in patients with great saphenous varicose veins.
      ,
      • Rautio T.
      • Ohinmaa A.
      • Perälä J.
      • et al.
      Endovenous obliteration versus conventional stripping operation in the treatment of primary varicose veins: a randomized controlled trial with comparison of the costs.
      ,
      • Lurie F.
      • Creton D.
      • Eklof B.
      • et al.
      Prospective randomized study of endovenous radiofrequency obliteration (closure procedure) versus ligation and stripping in a selected patient population (EVOLVeS study).
      ,
      • Lurie F.
      • Creton D.
      • Eklof B.
      • et al.
      Prospective randomised study of endovenous radiofrequency obliteration (closure) versus ligation and vein stripping (EVOLVeS): two-year follow-up.
      ,
      • Perälä J.
      • Rautio T.
      • Biancari F.
      • et al.
      Radiofrequency endovenous obliteration versus stripping of the long saphenous vein in the management of primary varicose veins: 3-year outcome of a randomized study.
      ,
      • Michaels J.A.
      • Brazier J.E.
      • Campbell W.B.
      • et al.
      Randomized clinical trial comparing surgery with conservative treatment for uncomplicated varicose veins.
      ,
      • Rasmussen L.H.
      • Bjoern L.
      • Lawaetz M.
      • et al.
      Randomized trial comparing endovenous laser ablation of the great saphenous vein with high ligation and stripping in patients with varicose veins: short-term results.
      ,
      • Darwood R.J.
      • Theivacumar N.
      • Dellagrammaticas D.
      • et al.
      Randomized clinical trial comparing endovenous laser ablation with surgery for the treatment of primary great saphenous varicose veins.
      ,
      • Almeida J.I.
      • Kaufman J.
      • Göckeritz O.
      • et al.
      Radiofrequency endovenous ClosureFAST versus laser ablation for the treatment of great saphenous reflux: a multicenter, single-blinded, randomized study (RECOVERY study).
      ,
      • Christenson J.T.
      • Gueddi S.
      • Gemayel G.
      • Bounameaux H.
      Prospective randomized trial comparing endovenous laser ablation and surgery for treatment of primary great saphenous varicose veins with a 2-year follow-up.
      ,
      • Goode S.D.
      • Chowdhury A.
      • Crockett M.
      • et al.
      Laser and radiofrequency ablation study (LARA study): a randomised study comparing radiofrequency ablation and endovenous laser ablation (810 nm).
      ,
      • Rasmussen L.H.
      • Bjoern L.
      • Lawaetz M.
      • et al.
      Randomised clinical trial comparing endovenous laser ablation with stripping of the great saphenous vein: clinical outcome and recurrence after 2 years.
      ,
      • Shepherd A.C.
      • Gohel M.S.
      • Brown L.C.
      • et al.
      Randomized clinical trial of VNUS ClosureFAST radiofrequency ablation versus laser for varicose veins.
      ,
      • Pronk P.
      • Gauw S.A.
      • Mooij M.C.
      • et al.
      Randomised controlled trial comparing sapheno-femoral ligation and stripping of the great saphenous vein with endovenous laser ablation (980 nm) using local tumescent anaesthesia: one year results.
      ,
      • Subramonia S.
      • Lees T.
      Randomized clinical trial of radiofrequency ablation or conventional high ligation and stripping for great saphenous varicose veins.
      ,
      • Carradice D.
      • Mekako A.I.
      • Mazari F.A.K.
      • et al.
      Clinical and technical outcomes from a randomized clinical trial of endovenous laser ablation compared with conventional surgery for great saphenous varicose veins.
      ,
      • Nordon I.M.
      • Hinchliffe R.J.
      • Brar R.
      • et al.
      A prospective double-blind randomized controlled trial of radiofrequency versus laser treatment of the great saphenous vein in patients with varicose veins.
      ,
      • Rasmussen L.H.
      • Lawaetz M.
      • Bjoern L.
      • et al.
      Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins.
      ,
      • Shadid N.
      • Ceulen R.
      • Nelemans P.
      • et al.
      Randomized clinical trial of ultrasound-guided foam sclerotherapy versus surgery for the incompetent great saphenous vein.
      ,
      • Rass K.
      • Frings N.
      • Glowacki P.
      Comparable effectiveness of endovenous laser ablation and high ligation with stripping of the great saphenous vein: two-year results of a randomized clinical trial (RELACS study).
      ,
      • Lattimer C.R.
      • Azzam M.
      • Kalodiki E.
      • et al.
      Cost and effectiveness of laser with phlebectomies compared with foam sclerotherapy in superficial venous insufficiency: early results of a randomised controlled trial.
      ,
      • Biemans A.A.M.
      • Kockaert M.
      • Akkersdijk G.P.
      • et al.
      Comparing endovenous laser ablation, foam sclerotherapy, and conventional surgery for great saphenous varicose veins.
      ,
      • Flessenkämper I.
      • Hartmann M.
      • Hartmann K.
      • et al.
      Endovenous laser ablation with and without high ligation compared to high ligation and stripping for treatment of great saphenous varicose veins: results of a multicentre randomised controlled trial with up to 6 years follow-up.
      ,
      • Sell H.
      • Vikatmaa P.
      • Albäck A.
      • et al.
      Compression therapy versus surgery in the treatment of patients with varicose veins: a RCT.
      ,
      • Mozafar M.
      • Atqiaee K.
      • Haghighatkhah H.
      • et al.
      Endovenous laser ablation of the great saphenous vein versus high ligation: long-term results.
      ,
      • Morrison N.
      • Gibson K.
      • McEnroe S.
      • et al.
      Randomized trial comparing cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins (VeClose).
      ,
      • Shepherd A.C.
      • Ortega-Ortega M.
      • Gohel M.S.
      • et al.
      Cost-effectiveness of radiofrequency ablation versus laser for varicose veins.
      ,
      • Rass K.
      • Frings N.
      • Glowacki P.
      • et al.
      Same site recurrence is more frequent after endovenous laser ablation compared with high ligation and stripping of the great saphenous vein: 5 year results of a randomized clinical trial (RELACS study).
      ,
      • Bootun R.
      • Lane T.
      • Dharmarajah B.
      • et al.
      Intra-procedural pain score in a randomised controlled trial comparing mechanochemical ablation to radiofrequency ablation: the Multicentre VenefitTM versus ClariVein® for varicose veins trial.
      ,
      • Venermo M.
      • Saarinen J.
      • Eskelinen E.
      • et al.
      Randomized clinical trial comparing surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy for the treatment of great saphenous varicose veins.
      ,
      • Gauw S.A.
      • Lawson J.A.
      • Van Vlijmen-Van Keulen C.J.
      • et al.
      Five-year follow-up of a randomized, controlled trial comparing saphenofemoral ligation and stripping of the great saphenous vein with endovenous laser ablation (980 nm) using local tumescent anesthesia.
      ,
      • Lane T.
      • Bootun R.
      • Dharmarajah B.
      • et al.
      A multi-centre randomised controlled trial comparing radiofrequency and mechanical occlusion chemically assisted ablation of varicose veins—final results of the Venefit versus Clarivein for varicose veins trial.
      ,
      • Carradice D.
      • Mekako A.I.
      • Mazari F.A.K.
      • et al.
      Randomized clinical trial of endovenous laser ablation compared with conventional surgery for great saphenous varicose veins.
      ,
      • El Kaffas K.
      • El Kashef O.
      • El Baz W.
      Great saphenous vein radiofrequency ablation versus standard stripping in the management of primary varicose veins—a randomized clinical trial.
      ] (see Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012). One publication reported two separate RCTs [
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ]. The distribution of patient characteristics (those that could potentially act as event modifiers [
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ]) was reasonably similar across the included trials. All studies related to treating the GSV; six studies also included the treatment of the small saphenous vein (SSV) and three the treatment of other veins. Most studies did not include patients with recent previous treatment of varicose veins. Across studies, the mean age of patients was between 32 and 59 years, and the proportion of female patients was between 52% and 93%. Almost all studies presented a risk of bias arising from lack of blinding of patients and practitioners, although this is usual in pragmatic surgical studies (see Appendix Table 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012).
      When appropriate, NMA was carried out in STATA 14 (StataCorp, College Station, TX) using the “network meta consistency” command [
      • White I.R.
      Network meta-analysis.
      ]. The standard NMA model assumes exchangeability (i.e., all contrasts are assumed to have the same between-study variance) and consistency of treatment effects [
      • White I.R.
      Network meta-analysis.
      ]. When these assumptions seemed inappropriate, direct treatment effects were estimated by conventional random-effects meta-analysis using the “metan” command.

      Evidence Synthesis to Estimate Parameter Values to be Used as Inputs for the Decision Model

      HRQOL in the first few days after intervention

      In the immediate postoperative period, interventional procedures may result in complications such as damage to the skin or phlebitis of the vein after EVLA, or wound hematoma after HL/S [
      • Inderhaug E.
      Costs and outcomes of five surgical treatments for great saphenous varicose veins: high ligation and stripping, laser ablation, radiofrequency ablation, steam vein sclerosis and cyanoacrylate glue.
      ]. These would be expected to have an impact on time to return to usual activities and HRQOL in the first 1 or 2 weeks. Only one trial reported the change in HRQOL at 1 week, showing a reduction in the EQ-5D score after EVLA compared with baseline (0.05; P = 0.024), but no significant difference between EVLA and HL/S [
      • Carradice D.
      • Mekako A.I.
      • Mazari F.A.K.
      • et al.
      Clinical and technical outcomes from a randomized clinical trial of endovenous laser ablation compared with conventional surgery for great saphenous varicose veins.
      ].
      On the basis of these data, the model assumed that patients have a decrease of 0.05 in the EQ-5D score for 1 week after EVLA, RFA, MOCA, CAE, and UGFS, and a decrease of 0.05 in the EQ-5D score for 2 weeks after HL/S.

      Return to work or normal activities in the first few days after intervention

      RCT data of comparisons of time to return to work or normal activities across various treatments are shown in Appendix Figure 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012. There was considerable difference in the I2 statistic (i.e., the degree of heterogeneity) across the various treatment comparisons, indicating that the exchangeability assumption might not be met for this outcome and that the standard NMA model would be inappropriate. The direct treatment comparisons in Appendix Figure 1 in Supplemental Materials show that, on average, there does not seem to be much difference in time to return to work or normal activities between EVLA and RFA, EVLA and UGFS, RFA and UGFS, or MOCA and RFA. Nevertheless, time to return to work or normal activities does seem significantly longer after HL/S than after either EVLA or RFA. This seems clinically plausible because HL/S is a more invasive surgical procedure.

      HRQOL over the longer term

      Once wound healing was accomplished, over the longer term, HRQOL would be impaired by recurrent symptoms of varicose veins or varicosities. The Ambulatory Varicosity avUlsion Later or Synchronized study found that patients needing further treatment had a significantly worse general HRQOL at 6 weeks, measured on the EQ-5D index: 0.719 versus 0.846, mean difference 0.127 (standard error [SE] 0.054), two-tailed P value of 0.018 [
      • Lane T.R.A.
      • Kelleher D.
      • Shepherd A.C.
      • et al.
      Ambulatory Varicosity avUlsion Later or Synchronized (AVULS).
      ]. This difference was not seen at 6 months or 12 months, because patients with poor quality of life at 6 weeks were successfully re-treated by 6 months. Therefore, the duration of impaired quality of life of the patient after failure of initial treatment largely depends on the speed with which vascular surgery services are able to arrange appropriate re-interventions. Our model assumes that HRQOL is impaired by 0.127 (SE 0.054) for 6 weeks before a re-treatment for residual varicosities (the time between the initial operation and the re-treatment). In the case of a re-intervention on the GSV, it is assumed that HRQOL is impaired for 6 months before the re-intervention. The longer time arises because if the index treatment is unsuccessful and symptoms recur, the patient will first need to schedule an outpatient appointment with the surgeon, possibly schedule another visit to have duplex ultrasound, and then be placed on a waiting list for re-intervention [
      • Tassie E.
      • Scotland G.
      • Brittenden J.
      • 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.
      ].

      Estimation of operative time of procedures

      The data for operative time for each direct treatment comparison are shown in Appendix Figure 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012. Given the different degrees of heterogeneity observed between the contrasts, the standard NMA model seemed inappropriate for this outcome and was not used. The direct comparisons indicate that UGFS requires shorter operative time than EVLA, RFA, or HL/S. The one study that evaluated CAE found that it required 5 minutes more operative time than did RFA. There are no data from RCTs on operative time using MOCA.

      Estimation of costs of interventional procedures

      Costs were informed by the review of operative time (given earlier), the literature review, and manufacturers’ list prices. The overall cost of a given procedure is estimated as the sum of the cost of operative time (staff time plus allocated operating room overheads), kit and consumables (amortized value of high-cost capital items, laser fiber, access catheter, anesthetic, and sclerosant), and other costs (preparation time, recovery time, and other equipment cost).
      The CLASS RCT estimated the mean total staff procedure costs: EVLA, mean £349 ± £163 (N = 183); UGFS, mean £157 ± £118 (N = 182); and HL/S, mean £637 ± £340 (N = 195) [
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ]. We use these estimates to represent theater staff costs for these therapies in the United Kingdom. The direct evidence synthesis described earlier found that RFA and EVLA required similar operative times, and in the model it is assumed that theater staff costs are the same for these modalities. CAE required 5 minutes more theater time than RFA. At a theater cost of £5.87/min [
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ], this translates to an increased staff cost of £30. No RCT estimated theater time for MOCA. Nonrandomized studies [
      • Vun S.
      • Rashid S.
      • Blest N.
      • Spark J.
      Lower pain and faster treatment with mechanico-chemical endovenous ablation using ClariVein(R).
      ,
      • Van Eekeren R.R.J.P.
      • Boersma D.
      • Konijn V.
      • et al.
      Postoperative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins.
      ] report less theater time for MOCA than for RFA, but because these study designs could be unreliable, the model assumes that theater staff costs for MOCA and RFA are the same.
      The kit cost of UGFS consists of the amortized cost of an ultrasound machine, sclerosant (sodium tetradecyl sulfate 1% or 3% for GSV), and intravenous cannula. Nontruncal varicosities are not treated alongside UGFS. Other interventions treat nontruncal varicosities using concomitant phlebectomies or foam as needed. EVLA requires an ultrasound machine (amortized), a laser generator (leased), and a nonreusable laser fiber [
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ]. RFA uses an ultrasound machine, a generator, and a nonreusable catheter [
      • Rautio T.
      • Ohinmaa A.
      • Perälä J.
      • et al.
      Endovenous obliteration versus conventional stripping operation in the treatment of primary varicose veins: a randomized controlled trial with comparison of the costs.
      ]. Most hospitals in the United Kingdom have an agreement with the manufacturer whereby the rental cost of the generator is included in the price of the laser fiber or catheter. Equipment costs (amortized) for HL/S include costs for an electrocardiograph, pulse oximeter, and noninvasive blood pressure monitor [
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ]. The list prices for the kits for MOCA (£375) and CAE (£800) were obtained from the manufacturers. The cost of the RFA catheter (£280) was from Rautio et al. [
      • Rautio T.
      • Ohinmaa A.
      • Perälä J.
      • et al.
      Endovenous obliteration versus conventional stripping operation in the treatment of primary varicose veins: a randomized controlled trial with comparison of the costs.
      ] (at 2015 prices). Other costs were from the CLASS study [
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ]. The estimated costs of the index procedures are presented in Table 1.
      Table 1Mean cost (£) of index procedure
      CostsHL/SEVLARFAUGFSMOCACAE
      Cost of theater staff637349349157349379
      Cost of kit
      RFA: from Rautio et al. [22], converted to 2015 pound sterling at purchasing power parity; EVLA: from Brittenden et al. [16]; and MOCA and CAE: manufacturers’ list prices.
      256280375800
      Cost of consumables and anesthetic
      EVLA, HL/S, and UGFS: Brittenden et al. [16].
      1506666506666
      Kit and equipment15032234650441866
      Cost of preparation
      EVLA, HL/S, and UGFS: Brittenden et al. [16].
      292929282929
      Cost of recovery
      EVLA, HL/S, and UGFS: Brittenden et al. [16].
      74323243232
      Cost of equipment
      EVLA, HL/S, and UGFS: Brittenden et al. [16].
      41111101111
      Other costs1077272427272
      Total cost8947437672498621,317
      SE10010010050100100
      CAE, cyanoacrylate glue occlusion; EVLA, endovenous laser ablation; HL/S, high-ligation surgery; MOCA, mechanochemical ablation; RFA, radiofrequency ablation; SE, standard error; UGFS, ultrasound-guided foam sclerotherapy.
      low asterisk RFA: from Rautio et al.
      • Rautio T.
      • Ohinmaa A.
      • Perälä J.
      • et al.
      Endovenous obliteration versus conventional stripping operation in the treatment of primary varicose veins: a randomized controlled trial with comparison of the costs.
      , converted to 2015 pound sterling at purchasing power parity; EVLA: from Brittenden et al.
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      ; and MOCA and CAE: manufacturers’ list prices.
      EVLA, HL/S, and UGFS: Brittenden et al.
      • Brittenden J.
      • Cotton S.C.
      • Elders A.
      • et al.
      Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.
      .

      Estimation of relative risk of re-intervention on the truncal vein

      Re-intervention on the GSV is the main measure of effectiveness in this model. The network of direct (pairwise) comparisons made in the RCTs is shown in Appendix Figure 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012. Appendix Figure 4 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012 shows the direct odds ratios (ORs) for the treatment comparisons from the RCTs that reported re-interventions. No RCTs evaluated re-interventions after CAE. There was moderate between-study heterogeneity (I2 < 50% [
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]) for EVLA versus HL/S and for UGFS versus HL/S, and moderate to high heterogeneity (I2 < 75%) for UGFS versus EVLA.
      Given the similar degree of between-study heterogeneity and distribution of patient characteristics, the use of an NMA was considered for this outcome. Mixed effects were estimated from data given in Appendix Figure 4 in Supplemental Materials by NMA, using HL/S as the reference treatment. The results of the NMA are presented in Appendix Table 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012, alongside ORs of the direct effects estimated by conventional pairwise meta-analysis. Consistency between the direct and indirect estimates was assessed using the “network side split all” command in STATA. None of these tests indicated significant inconsistency at the 5% level (see P values in Appendix Table 3 in Supplemental Materials).
      In general, the direct and mixed estimates gave results of similar magnitude. The exception was the contrast between RFA and UGFS. The direct comparison came from a single RCT [
      • Lawaetz M.
      • Serup J.
      • Lawaetz B.
      • et al.
      Comparison of endovenous ablation techniques, foam sclerotherapy and surgical stripping for great saphenous varicose veins: extended 5-year follow-up of a RCT.
      ]. This study reported that 43 of 44 UGFS patients required a re-intervention, compared with 19 of 68 RFA patients. These RCT results generate an extremely high OR (110.90; 95% confidence interval [CI] 14.25–863.29). An advantage of using NMA when there is less direct information on a particular contrast is that by combining both direct and indirect evidence, the mixed treatment comparison tends to shrink or moderate “outlier” estimates toward the mean [
      • Jansen J.P.
      • Fleurence R.
      • Devine B.
      • et al.
      Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices, Part 1.
      ]. In this case, the NMA produces a more plausible estimate of the relative risk of UGFS versus RFA than that provided by the direct evidence alone (OR 10.21; 95% CI 3.28–31.74).
      In our review, no studies evaluated MOCA versus HL/S. In situations in which there are no direct comparisons, any comparison of the relative effectiveness of these two treatments can be obtained only from indirect comparison. In a complex network, indirect comparisons based on multiple sequential pairwise analyses are potentially confusing and NMA is recommended [
      • Jansen J.P.
      • Fleurence R.
      • Devine B.
      • et al.
      Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices, Part 1.
      ]. In our review, the RCTs report RFA to be more effective than HL/S, and MOCA to be equally effective as RFA, and so, indirectly, MOCA is estimated by the NMA to be (on average) more effective than HL/S (OR 0.46; 95% CI 0.01–29.92). The wide CI range reflects the high degree of uncertainty (and hence limited strength of inference) generated by the indirect comparison [
      • Bucher H.
      • Guyatt G.
      • Griffith L.
      • Walter S.
      The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials.
      ].
      In the sensitivity analysis, the pairwise direct treatment effects versus HL/S were used instead of the NMA in the model (see Appendix Figure 4 in Supplemental Materials). Nevertheless, direct treatment effects versus HL/S were available only for UGFS, RFA, EVLA, and CONS. In the sensitivity analysis using direct treatment effects, in the absence of indirect information, it is assumed that MOCA and HL/S are equally effective.
      No RCT reported re-interventions after CAE, and so it is not included in the network in Appendix Figure 3 in Supplemental Materials. RCTs have reported CAE as noninferior to other procedures in terms of venous closure and quality-of-life outcomes [
      • Morrison N.
      • Gibson K.
      • McEnroe S.
      • et al.
      Randomized trial comparing cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins (VeClose).
      ]. In the main analysis and sensitivity analyses of the model, it is assumed that CAE and HL/S are equally effective, with a wide CI range (OR 1; 95% CI 0.01–30.00).

      Estimation of the rate of re-intervention after HL/S

      The decision model requires an estimate of the absolute re-intervention rate after the reference treatment, which is HL/S. The absolute re-intervention rate of any other treatment j can then be inferred, assuming proportional hazards, by multiplying the re-intervention rate after HL/S by the relative risk of treatment j versus HL/S, given in Appendix Table 3 in Supplemental Materials.
      The single-arm data from RCT that reported re-interventions specifically after HL/S are shown graphically in Appendix Figure 5 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012. To account for between-study heterogeneity, the average rate was calculated using a negative binomial model of the single HL/S arms of these studies, with the number of re-interventions as the dependent variable and person-years of follow-up as the exposure variable (using the STATA command “nbreg”). The estimated log-incidence rate was −3.383 (SE 0.245), which corresponds to a mean rate of 3.4 re-interventions per 100 patient-years of follow-up after HL/S.

      Estimation of probability of re-treatment for residual varicosities

      An RCT carried out in UK hospitals found that 36% (18 of 50) of patients following a strategy of delayed phlebectomy required re-treatment at the 6-week follow-up assessment, compared with 2% (1 of 51) in patients who underwent concomitant phlebectomy (OR 0.04; 95% CI 0.00–0.28) [
      • Lane T.R.A.
      • Kelleher D.
      • Shepherd A.C.
      • et al.
      Ambulatory Varicosity avUlsion Later or Synchronized (AVULS).
      ], with significantly better HRQOL in the concomitant group. It was assumed in the model that HL/S, EVLA, MOCA, RFA, and CAE applied a strategy of concomitant ablation of the varicosities, whereas UGFS used delayed ablation when required.

      Univariate Sensitivity Analyses and Scenarios

      Scenarios were developed to represent outcomes under alternative assumptions. Scenario A uses direct ORs for the relative risk of re-interventions compared with HL/S (estimated by conventional random-effects meta-analysis; Appendix Figure 4 in Supplemental Materials) instead of the results of the NMA. In this sensitivity analysis, in the absence of indirect information, it is assumed that MOCA, CAE, and HL/S are equally effective. Scenarios B− and B+ reflect the heterogeneity between studies in the absolute rate of re-intervention after HL/S (Appendix Figure 5 in Supplemental Materials). Scenario B− uses a rate of re-intervention after HL/S of 1 SD lower than the base case, and scenario B+ uses a rate of re-intervention after HL/S of 1 SD greater than the base case. Scenario C assumes that 25% of patients who receive re-intervention do not obtain full resolution of their varicose veins (the base case assumes that all patients achieve full resolution after re-intervention). Scenario D assumes that re-interventions and re-treatments might be positively correlated, rather than independent. The correlation between outcomes was implemented by assuming a correlation coefficient of 0.4. The degree of correlation affects QALYs in the model because it is assumed that a patient who required a re-intervention on the GSV will have experienced a decrement of 0.127 on the EQ-5D scale for the preceding 6 months (reflecting the discomfort of living with symptoms), and patients with residual varicosities will have had a decrement of 0.127 for 6 weeks between the index therapy and the ambulatory ablation, but patients with patency of the GSV and residual varicosities would not have experienced a “double” decrement in HRQOL. Given the assumed correlation, the model estimates the proportion of patients who required only a re-intervention, only ablation of varicosities, both procedures, or neither in the first 6 months [
      • Epstein D.
      • Sutton A.
      Modelling correlated clinical outcomes in health technology appraisal.
      ].

      Probabilistic Sensitivity Analysis

      Probabilistic sensitivity analysis was undertaken to assess the impact of uncertainty in all the inputs to the model on the total mean costs and QALYs. Uncertain parameters were assigned probability distributions.
      Costs of procedures were characterized by gamma (α, β) distributions. Given the mean and SE in Table 1, α = mean2/SE2 and β = SE2/mean [
      • Briggs A.
      • Claxton K.
      • Sculpher M.
      Decision Modelling for Health Economic Evaluation.
      ]. The decrement in HRQOL associated with symptoms of varicose veins was 0.127 (SE 0.054) and was assigned a gamma distribution (α = 5.53; β = 0.02). The log-incidence rate of re-intervention after HL/S was assigned a normal distribution (mean −3.383; SE 0.245). Relative risks of treatment effects of re-interventions compared with HL/S were assigned lognormal distributions (see Appendix Table 3 in Supplemental Materials for the means and CIs on the OR scale). The probability of re-treatment for varicosities under a delayed strategy was assigned a beta distribution (α = 18; β = 32) and the OR of re-treatment under a concomitant strategy compared with a delayed strategy was given a lognormal distribution (mean OR 0.04; 95% CI 0.00–0.28).
      One thousand Monte-Carlo simulations of the model were carried out. For each iteration, net benefit was calculated for each treatment j, defined as NBj = λ × QALYj − Costj, where λ is the decision maker’s threshold cost-effectiveness ratio. Results are presented using the cost-effectiveness acceptability curve (CEAC) [
      • Briggs A.
      • Claxton K.
      • Sculpher M.
      Decision Modelling for Health Economic Evaluation.
      ]. The CEAC, however, does not show which treatment has the highest probability of being ranked second, third, and so forth, and nor does the CEAC allow the decision maker to rank the treatments from best to worst, allowing for uncertainty. For this, we calculate the rank probabilities using the method of Salanti et al. [
      • Salanti G.
      • Ades A.E.
      • Ioannidis J.P.A.
      Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.
      ]. The rank probability is closely related to the concept of the CEAC and is commonly used in technology appraisal to compare multiple treatments in terms of effectiveness or safety, but to our knowledge has not so far been used to compare multiple treatments in economic evaluation. Nevertheless, the principles of calculating rank probabilities are readily transferable from effectiveness end points to the net benefit end point.
      The CEAC shows the probability that a given treatment has the highest net benefit at different values of the willingness-to-pay threshold. The threshold λ commonly accepted by the National Institute for Health and Care Excellence is £20,000 to £30,000/QALY [
      National Institute for Health and Care Excellence
      Guide to the Methods of Technology Appraisal.
      ], although empirical work suggests that λ could in practice be much lower in the UK NHS, at around £13,000/QALY [
      • Claxton K.
      • Martin S.
      • Soares M.
      • et al.
      Methods for the estimation of the National Institute for Health and Care Excellence cost-effectiveness threshold.
      ]. We show the CEAC for a range of λ from £0 to £100,000.
      We chose a threshold of £20,000/QALY to calculate the rank probability. In each iteration of the 1000 Monte-Carlo simulations, each treatment j is ranked according to estimated net benefit. Then the proportion of simulations in which a given treatment ranks first for net benefit out of the total gives the probability P(j = 1), that is, the probability that treatment j is the most cost-effective at the given threshold. This probability is equivalent to the CEAC at λ = £20,000/QALY. We then go on to calculate similar probabilities for being the second best, the third best, and so on—P(j = b), b = 1, …, 7. These probabilities sum to 1 for each treatment and each rank. We tabulate this information and also go on to calculate the surface under the cumulative ranking (SUCRA) for each treatment j, defined as ∑6b = 1Pcumj,b, and calculate the median and interquartile range for the rank of each treatment [
      • Salanti G.
      • Ades A.E.
      • Ioannidis J.P.A.
      Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.
      ].

      Results of Cost-Effectiveness Analysis

      Appendix Figure 6 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012 shows the total estimated costs per person over 5 years estimated in the base-case model, showing the contribution of the index procedure, re-treatments, and re-interventions. Table 2 presents the total estimated costs and QALYs per person from the model at 5 years for each treatment in each sensitivity analysis. Figure 2 shows the total costs (including initial procedure cost and re-interventions) and QALYs per person from the base-case model over 5 years in the cost-effectiveness plane.
      Table 2Results of cost-effectiveness analysis at 5 years (Markov model)
      TreatmentBase caseSensitivity analysis ASensitivity analysis B+Sensitivity analysis B−Sensitivity analysis CSensitivity analysis D
      QALYCost (£)QALYCost (£)QALYCost (£)QALYCost (£)QALYCost (£)QALYCost (£)
      CONS4.5524404.5524404.5424874.5613934.4494404.553440
      UGFS4.5666094.5626294.5576554.5755654.4906094.568609
      RFA4.6238084.6238114.6218184.6258014.6148084.623808
      EVLA4.6148294.6148304.6108494.6178134.5938294.614829
      MOCA4.6249024.6169404.6229114.6258954.6159024.624902
      HL/S4.6149724.6149724.6109904.6179574.5959724.614972
      CAE4.6161,3954.6161,3954.6121,4134.6191,3804.5971,3954.6161,395
      ICER (£/QALY)
       RFA vs. CONS5,1485,2114,2066,4232,2235,258
       MOCA vs. RFA311,101247,301392,718138,444314,085
      Note. The ICERs for only RFA vs. CONS and MOCA vs. RFA are calculable. Other treatments are dominated (higher costs and less effective than another treatment) or extended-dominated (not on the efficiency frontier). Scenario A uses direct treatment effects rather than NMA. Scenario B− uses low rate of re-intervention after surgery. Scenario B+ uses higher rate of re-intervention after surgery. Scenario C assumes that only 75% of re-interventions are successful. Scenario D assumes that re-interventions on truncal vein and re-treatments for superficial varicosities are correlated (correlation coefficient = 0.4).
      CAE, cyanoacrylate glue occlusion; CONS, conservative care; EVLA, endovenous laser ablation; HL/S, high-ligation surgery; ICER, incremental cost-effectiveness ratio; MOCA, mechanochemical ablation; NMA, network meta-analysis; QALY, quality-adjusted life-year; RFA, radiofrequency ablation; UGFS, ultrasound-guided foam sclerotherapy.
      Fig. 2
      Fig. 2Total mean cost and mean QALY per person over 5 years for each strategy (base case). CAE, cyanoacrylate glue occlusion; CONS, conservative care; EVLA, endovenous laser ablation; HL/S, high-ligation surgery; MOCA, mechanochemical ablation; QALY, quality-adjusted life-year; RFA, radiofrequency ablation; UGFS, ultrasound-guided foam sclerotherapy.
      On current evidence, RFA appears to be the most effective treatment. The incremental cost per QALY of RFA versus CONS is £5,148/QALY. The incremental cost per QALY of MOCA versus RFA is calculated as £311,101/QALY. The large ratio occurs because the difference in effectiveness (the denominator of the ratio) is close to 0. Nevertheless, the differences in QALYs and costs between HL/S, MOCA, RFA, and EVLA are very small.
      The CEAC shows that at a threshold of £20,000/QALY, RFA has 53% probability of having the highest net benefit, MOCA has 34% probability of having the highest net benefit, and CONS and EVLA each have 6% probability of having the highest net benefit (Fig. 3). We also calculated rank probabilities and median rank (Table 3). At a threshold of £20,000/QALY, RFA ranked first, MOCA second, EVLA third, HL/S fourth, CAE fifth, with CONS and UGFS sixth. The SUCRA expresses the percentage of cumulative rank of net benefit each treatment has compared with an “ideal” treatment that always ranked first without uncertainty [
      • Salanti G.
      • Ades A.E.
      • Ioannidis J.P.A.
      Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.
      ]. RFA has 90% SUCRA, whereas MOCA and EVLA have a similar SUCRA, with 67% to 68% of the cumulative rank of a perfect treatment (Table 3). MOCA has a higher probability than EVLA of ranking first (34% vs. 6%), but it also has a higher probability of ranking last (12% vs. 0%). This indicates that MOCA is promising but the evidence for its effectiveness is still very uncertain. This uncertainty is also seen in the wide interquartile range for the rank of MOCA. In more than 25% of simulations, it ranks first, and in 25% of simulations it ranks fifth or worse (Table 3).
      Fig. 3
      Fig. 3Cost-effectiveness acceptability curves for each treatment option. The curve shows the probability that a given treatment obtains the highest net benefit at different thresholds for cost-effectiveness. CAE, cyanoacrylate glue occlusion; CONS, conservative care; EVLA, endovenous laser ablation; HL/S, high-ligation surgery; MOCA, mechanochemical ablation; QALY, quality-adjusted life-year; RFA, radiofrequency ablation; UGFS, ultrasound-guided foam sclerotherapy.
      Table 3Rank of net benefit for each treatment, at a threshold of £20,000/QALY
      RankRFAMOCAEVLAHL/SCAECONSUGFS
      Rank probabilities
      First53%34%6%1%0%6%0%
      Second36%25%26%7%3%3%0%
      Third8%9%42%26%9%5%1%
      Fourth3%7%18%47%14%6%5%
      Fifth1%8%8%17%27%15%26%
      Sixth0%5%1%2%17%30%44%
      Seventh0%12%0%0%30%33%25%
      Cumulative rank probabilities
      First53%34%6%1%0%6%0%
      Second88%59%32%8%3%10%0%
      Third96%68%74%34%12%15%1%
      Fourth99%75%92%81%26%21%6%
      Fifth100%83%99%98%52%36%31%
      Sixth100%88%100%100%70%67%76%
      Seventh100%100%100%100%100%100%100%
      SUCRA90%68%67%54%27%26%19%
      Median rank (IQR)1 (1–2)2 (1–5)3 (2–4)4 (3–4)5 (4–7)6 (5–7)6 (5–6)
      Note. The table shows the probabilities to achieve one of seven possible ranks P(j = b), the cumulative probability, the SUCRA, and the median rank (IQR).
      CAE, cyanoacrylate glue occlusion; CONS, conservative care; EVLA, endovenous laser ablation; HL/S, high-ligation surgery; IQR, interquartile range; MOCA, mechanochemical ablation; RFA, radiofrequency ablation; SUCRA, surface under cumulative ranking curve; UGFS, ultrasound-guided foam sclerotherapy.
      Under univariate sensitivity analysis A, using direct treatment effects instead of NMA substantially reduces the estimated effectiveness of MOCA. This is because there are no direct treatment effects for re-interventions available for MOCA versus HL/S, and in sensitivity analysis A, we assume that the re-intervention rates for these two treatments are the same. Other univariate sensitivity analyses do not substantially alter the main results (Table 2).

      Discussion

      Summary of Main Findings

      CONS is the least expensive option, but has the highest likelihood of re-intervention on the GSV and re-treatment for residual varicosity. Among the interventional procedures, UGFS has the lowest cost over 5 years, but is also the least effective as indicated by the greater need for re-intervention and re-treatment. Other economic reviews [
      • Marsden G.
      • Perry M.
      • Bradbury A.
      • et al.
      A cost-effectiveness analysis of surgery, endodermal ablation, ultrasound-guided foam sclerotherapy and compression stockings for symptomatic varicose veins.
      ,
      • Tassie E.
      • Scotland G.
      • Brittenden J.
      • 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.
      ,
      • Gohel M.S.
      • Epstein D.M.
      • Davies A.H.
      Cost-effectiveness of traditional and endovenous treatments for varicose veins.
      ,
      • Carroll C.
      • Hummel S.
      • Leaviss J.
      • et al.
      Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation.
      ] also found UGFS to be the cheapest interventional option, and one [
      • Carroll C.
      • Hummel S.
      • Leaviss J.
      • et al.
      Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation.
      ] found it to be more effective than HL/S.
      The cost per QALY of RFA versus CONS in our model is about £5,148/QALY, which is considered cost-effective in the United Kingdom. Other treatments have very high incremental cost-effectiveness ratios or are dominated by RFA. Nevertheless, the incremental cost-effectiveness ratios assume that only one therapy (the most cost-effective) will be financed by the UK NHS. In practice, health payers and providers will often want to offer a range of options for patients, encourage innovation, and promote competition between manufacturers [
      Institut de Quebec
      Adopting Health Care Innovations in Quebec.
      ]. In this sense, MOCA, EVLA, and HL/S have similar costs and outcomes and so might broadly be considered as having similar value for money. HL/S requires longer time in the operating theater and longer time off work for the patient, which is why it has been superseded as standard treatment by endothermal procedures in recent years. There is still less information on MOCA, but current evidence indicates similar effectiveness to endothermal procedures [
      • Lane T.
      • Bootun R.
      • Dharmarajah B.
      • et al.
      A multi-centre randomised controlled trial comparing radiofrequency and mechanical occlusion chemically assisted ablation of varicose veins—final results of the Venefit versus Clarivein for varicose veins trial.
      ]. The list price of its kit, however, makes this procedure relatively expensive compared with established modalities. Finally, CAE has a much higher acquisition cost than do other modalities, but there is as yet no evidence about re-interventions. We have assumed in this article that the outcomes are the same as for HL/S. CAE would need to be considerably more effective to be considered value for money in the UK NHS.

      Strengths and Weaknesses

      In our analysis, the main effectiveness end point is re-intervention, rather than technical and clinical outcomes such as recurrence and occlusion, which were used in previous decision models [
      • Marsden G.
      • Perry M.
      • Bradbury A.
      • et al.
      A cost-effectiveness analysis of surgery, endodermal ablation, ultrasound-guided foam sclerotherapy and compression stockings for symptomatic varicose veins.
      ,
      • Tassie E.
      • Scotland G.
      • Brittenden J.
      • 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.
      ,
      • Gohel M.S.
      • Epstein D.M.
      • Davies A.H.
      Cost-effectiveness of traditional and endovenous treatments for varicose veins.
      ,
      • Carroll C.
      • Hummel S.
      • Leaviss J.
      • et al.
      Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation.
      ]. Recurrence is defined inconsistently in the literature [
      • Nesbitt C.
      • Bedenis R.
      • Bhattacharya V.
      • Stansby G.
      Endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus open surgery for great saphenous vein varices.
      ,
      • Rasmussen L.H.
      • Lawaetz M.
      • Bjoern L.
      • et al.
      Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins.
      ], which makes it an unsuitable outcome for meta-analysis. In some cases, it represents a technical or efficacy end point that is unimportant to patients [
      • Rasmussen L.H.
      • Bjoern L.
      • Lawaetz M.
      • et al.
      Randomised clinical trial comparing endovenous laser ablation with stripping of the great saphenous vein: clinical outcome and recurrence after 2 years.
      ]. Nevertheless, re-interventions are an objective end point and indicate that the patient, after initial treatment, has continued to experience unacceptable symptoms that their clinician considered severe enough to warrant further procedures.
      The model has a simple structure, but is nevertheless a reasonably realistic representation of the decision problem. All these procedures usually work well in most patients, and in the few cases in which symptoms are not resolved satisfactorily, surgeons would normally consider only one further re-intervention in the current economic climate. The inputs to the model were based on systematic review and evidence synthesis. We use direct treatment effects to synthesize end points when the assumptions of NMA do not seem to be met, and NMA for the re-intervention end point when the assumptions of exchangeability and consistency seemed justified. NMA takes account of both direct and indirect evidence and, when direct data are sparse, can provide more credible estimates of treatment effects. In any event, there are no RCTs of MOCA versus HL/S, and hence any estimate of relative risk must be made from indirect comparison. Using direct evidence about re-interventions in the model instead of NMA does not substantially change the main conclusions. We have aimed to comply with the best practice for model construction [
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.
      ] that is internally valid, transparent, and reproducible. In any evidence synthesis, it is essential that the population, interventions, and outcomes are selected and measured on a common basis [
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ]. We conducted risk of bias assessment [

      Higgins J, Green S. Cochrane handbook for systematic reviews of interventions, version 5.1.0. 2011. Available from: www.handbook.cochrane.org. [Accessed October 31, 2017].

      ] and assessed the similarity of effect modifiers across studies [
      • Jansen J.P.
      • Fleurence R.
      • Devine B.
      • et al.
      Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices, Part 1.
      ]. We have shown all the primary data extracted from the RCTs in Supplemental Materials found at https://doi.org/10.1016/j.jval.2018.01.012 [
      • Jansen J.P.
      • Fleurence R.
      • Devine B.
      • et al.
      Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices, Part 1.
      ]. These data are sufficient for anyone to re-create the meta-analyses and model.
      Our model, nevertheless, has several limitations. The objective of this article was to compare interventional procedures against CONS, broadly defined. There may be a range of CONS options in practice, each with different costs and outcomes [
      • Gohel M.S.
      • Davies A.H.
      Pharmacological agents in the treatment of venous disease: an update of the available evidence.
      ]. The evidence base on MOCA and CAE is still immature and unreliable. We assume that concomitant phlebectomy will be used to treat nontruncal varicosities when required in all interventional procedures except UGFS. Concomitant phlebectomy has been shown to greatly improve patient outcomes compared with delayed treatment [
      • Lane T.R.A.
      • Kelleher D.
      • Shepherd A.C.
      • et al.
      Ambulatory Varicosity avUlsion Later or Synchronized (AVULS).
      ]. In practice, the decision to treat nontruncal varicosities immediately or to wait and see may depend on surgeon and patient preference. Patients return to work significantly faster after MOCA, RFA, and EVLA than after surgery. Our economic model included costs to the health service provider and patient utility from faster recovery time, but did not include other societal impacts such as the lost production from work absence. Because most patients are of working age, these concerns may influence a decision taken from a societal perspective as well as patient preference. Costs of MOCA and CAE kits are based on list prices. The prices actually paid depend on negotiated discounts and vary widely between centers. This will influence the cost-effectiveness of each option from the provider’s perspective.

      Conclusions

      Endothermal procedures would be cost-effective therapeutic options in adult patients requiring treatment in the upper leg for incompetence of the GSV. MOCA appears to be promising, but more RCT evidence on effectiveness and HRQOL is needed. At current prices, CAE is not a cost-effective option because it is costlier but has not been shown to be more effective than other options.

      Acknowledgment

      We acknowledge financial support from Vascular Insights.
      Source of financial support: This study was financed by Vascular Insights, manufacturer of ClariVein. Funders were informed of decisions made by the researchers relating to study design and analysis, and received an early draft of results, but did not have any involvement in the interpretation of the results, drafting of the manuscript, or the decision to publish the results. The authors are all independent academic researchers who vouch for the integrity of the work and do not rely on private financial contributions.

      Appendix A. Supplementary material

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