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Editor's Choice – Cost Effectiveness of Primary Stenting in the Superficial Femoral Artery for Intermittent Claudication: Two Year Results of a Randomised Multicentre Trial

  • Henrik Djerf
    Correspondence
    Corresponding author. Sahlgrenska University Hospital, 11th floor, Bruna Stråket 11, SE-413 45, Gothenburg, Sweden.
    Affiliations
    Department of Vascular Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

    Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Mikael Svensson
    Affiliations
    School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Joakim Nordanstig
    Affiliations
    Department of Vascular Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

    Department for Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Anders Gottsäter
    Affiliations
    Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden

    Vascular Centre, Skåne University Hospital, Malmö, Sweden
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  • Mårten Falkenberg
    Affiliations
    Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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  • Hans Lindgren
    Affiliations
    Vascular Centre, Skåne University Hospital, Malmö, Sweden

    Department of Surgery, Helsingborg Hospital, Helsingborg, Sweden
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Open AccessPublished:August 25, 2021DOI:https://doi.org/10.1016/j.ejvs.2021.07.009

      Objective

      Invasive treatment of intermittent claudication (IC) is commonly performed, despite limited evidence of its cost effectiveness. IC symptoms are mainly caused by atherosclerotic lesions in the superficial femoral artery (SFA), and endovascular treatment is performed frequently. The aim of this study was to investigate its cost effectiveness vs. non-invasive treatment.

      Methods

      One hundred patients with IC due to lesions in the SFA were randomised to treatment with primary stenting, best medical treatment (BMT) and exercise advice (stent group), or to BMT and exercise advice alone (control group). Patients were recruited at seven hospitals in Sweden. For this analysis of cost effectiveness after 24 months, 84 patients with data on quality adjusted life years (QALY; based on the EuroQol Five Dimensions EQ-5D 3L™ questionnaire) were analysed. Patient registry and imputed cost data were used for accumulated costs regarding hospitalisation and outpatient visits.

      Results

      The mean cost per patient was €11 060 in the stent group and €4 787 in the control group, resulting in a difference of €6 273 per patient between the groups. The difference in mean QALYs between the groups was 0.26, in favour of the stent group, which resulted in an incremental cost effectiveness ratio (ICER) of € 23 785 per QALY.

      Conclusion

      The costs associated with primary stenting in the SFA for the treatment of IC were higher than for exercise advice and BMT alone. With concurrent improvement in health related quality of life, primary stenting was a cost effective treatment option according to the Swedish national guidelines (ICER < €50 000 – €70 000) and approaching the UK’s National Institute for Health and Care Excellence threshold for willingness to pay (ICER < £20 000 – £30 000). From a cost effectiveness standpoint, primary stenting of the SFA can, in many countries, be used as an adjunct to exercise training advice, but it must be considered that successful implementation of structured exercise programmes and longer follow up may alter these findings.

      Keywords

      This examination of the cost effectiveness within a randomised controlled trial for endovascular treatment of the superficial femoral artery in patients with intermittent claudication (IC) adds longer follow up data than previous studies. One hundred patients were randomised to primary stenting or non-invasive treatment. After two years of follow up, primary stenting as an adjunct to exercise training advice was a cost effective treatment option, according to Swedish national guidelines, and approaching the National Institute of Health and Care Excellence’s threshold for willingness to pay. From a cost effectiveness standpoint, primary stenting of the SFA can, in many countries, be used as an adjunct to exercise training advice, but it must be considered that successful implementation of structured exercise programmes and longer follow up may alter these findings.

      Introduction

      Peripheral arterial disease (PAD) is a common disease that affects approximately 200 million people worldwide. The most common symptomatic presentation is intermittent claudication (IC), affecting 20 – 40 million people worldwide.
      • Fowkes F.G.
      • Rudan D.
      • Rudan I.
      • Aboyans V.
      • Denenberg J.O.
      • McDermott M.M.
      • et al.
      Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.
      The economic impact of PAD is substantial,
      • Chase M.R.
      • Friedman H.S.
      • Navaratnam P.
      • Heithoff K.
      • Simpson Jr., R.J.
      Comparative assessment of medical resource use and costs associated with patients with symptomatic peripheral artery disease in the United States.
      and the global prevalence is increasing.
      • Chase M.R.
      • Friedman H.S.
      • Navaratnam P.
      • Heithoff K.
      • Simpson Jr., R.J.
      Comparative assessment of medical resource use and costs associated with patients with symptomatic peripheral artery disease in the United States.
      Management of IC aims to reduce the risk of serious cardiovascular events and to treat the functional walking impairment in order to increase health related quality of life (HRQoL). This is achieved by best medical treatment (BMT) and lifestyle changes such as smoking cessation. Lower limb symptoms are reduced by exercise training and invasive procedures. Exercise, especially supervised exercise therapy (SET), is regarded as the first line treatment to reduce lower limb symptoms.
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Bjorck M.
      • Brodmann M.
      • Cohnert T.
      • et al.
      Editor's Choice – 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS).
      However, SET is often not reimbursed or available for the majority of patients, and hence simple exercise training advice is the predominating clinical practice.
      • Dua A.
      • Gologorsky R.
      • Savage D.
      • Rens N.
      • Gandhi N.
      • Brooke B.
      • et al.
      National assessment of availability, awareness, and utilization of supervised exercise therapy for peripheral artery disease patients with intermittent claudication.
      Invasive procedures are commonly offered to patients with IC and currently a large majority of these procedures are undertaken with minimally invasive endovascular treatment under local anaesthesia.
      • Lindgren H.
      • Gottsater A.
      • Qvarfordt P.
      • Bergman S.
      • Troeng T.
      Invasive treatment for infrainguinal claudication has satisfactory 1 year outcome in three out of four patients: a population-based analysis from Swedvasc.
      Frequently, lesions located in the superficial femoral artery (SFA) are targeted for invasive treatment. Evidence indicates that the primary stenting of SFA lesions is superior to balloon angioplasty alone,
      • Sabeti S.
      • Czerwenka-Wenkstetten A.
      • Dick P.
      • Schlager O.
      • Amighi J.
      • Mlekusch I.
      • et al.
      Quality of life after balloon angioplasty versus stent implantation in the superficial femoral artery: findings from a randomized controlled trial.
      • Schillinger M.
      • Sabeti S.
      • Loewe C.
      • Dick P.
      • Amighi J.
      • Mlekusch W.
      • et al.
      Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery.
      • Laird J.R.
      • Katzen B.T.
      • Scheinert D.
      • Lammer J.
      • Carpenter J.
      • Buchbinder M.
      • et al.
      Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial.
      although individual physician preferences regarding the practice of primary or bailout stenting varies.
      The economic burden of IC and its invasive procedures is increasing.
      • Chase M.R.
      • Friedman H.S.
      • Navaratnam P.
      • Heithoff K.
      • Simpson Jr., R.J.
      Comparative assessment of medical resource use and costs associated with patients with symptomatic peripheral artery disease in the United States.
      Yet cost effectiveness analyses with a follow up of more than one year in randomised trials are sparse. An earlier study showed that although an invasive treatment approach to patients with IC improved HRQoL, the added costs associated with the invasive procedure were also considerable at the two year follow up.
      • Djerf H.
      • Falkenberg M.
      • Jivegard L.
      • Lindgren H.
      • Svensson M.
      • Nordanstig J.
      Cost-effectiveness of revascularization in patients with intermittent claudication.
      As the most common location of lesions causing IC is in the SFA, and as primary stenting has been reported to be the most efficient endovascular treatment in this vascular segment, it was decided to evaluate whether it is cost effective vs. a non-invasive treatment approach. This was done within a randomised trial with two years of follow up and with cost effectiveness as a predefined secondary outcome measure.

      Methods

      Patients with established IC were enrolled in an open label multicentre randomised clinical trial undertaken in seven hospitals in Sweden (Eskilstuna Hospital, Helsingborg University Hospital, Kalmar Hospital, Kristianstad Hospital, Örebro University Hospital, Skåne University Hospital Malmö and Växjö Hospital).
      Patients aged > 18 years with stable IC for more than six months (Fontaine 2B) with a maximum walking capacity < 500 metres (measured by a standardised treadmill test: speed 3 km/hour, without an incline) caused by a de novo or re-stenotic TASC II a–c
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      • et al.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      SFA lesion with a lower boundary at the proximal limit of the popliteal artery (3 cm above the patella) on magnetic resonance angiography (MRA) or computed tomography angiography (CTA) were eligible for inclusion provided a patent popliteal artery and at least one patent infrapopliteal artery were present. Patients with a target artery diameter proximal or distal to the lesion < 4 mm, femoropopliteal aneurysm, previous stent treatment in the femoropopliteal segment, or with poor inflow to the SFA due to stenosis or occlusion in the aorto-iliac or common femoral artery were also excluded. Patients with preceding inflow vessel revascularisation within three months prior to inclusion were excluded, as were patients with haemorrhagic stroke within the past three months, patients with a life expectancy of < 24 months, patients previously enrolled in this or any other clinical trial, and patients with critical limb ischaemia (Fontaine III and IV).
      The sample size was determined to study a clinically relevant difference between the two groups with regard to the primary outcome variable, HRQoL. With a significance level of 5% and with 50 patients in each group, a clinically important difference of 10 scale steps in the 36 item Short Form Survey (SF-36)
      • Mazari F.A.K.
      • Khan J.A.
      • Carradice D.
      • Samuel N.
      • Abdul Rahman M.N.A.
      • Gulati S.
      • et al.
      Randomized clinical trial of percutaneous transluminal angioplasty, supervised exercise and combined treatment for intermittent claudication due to femoropopliteal arterial disease.
      ,
      • Kosinski M.
      • Zhao S.Z.
      • Dedhiya S.
      • Osterhaus J.T.
      • Ware Jr., J.E.
      Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis.
      could be detected with a power of at least 80%
      Randomisation took place directly after screening. Study patients were allocated to one of the two treatments on a 1:1 basis by sealed envelopes available at the research unit at Spenshult Hospital. The local investigator received the randomisation result via a telephone call. At randomisation, patients were stratified with regard to lesion length (over or under 90 mm), measured as the sum of stenotic or occluded segments in the SFA on pre-inclusion MRA or CTA. The study design and the clinical endpoints have been reported previously.
      • Lindgren H.
      • Qvarfordt P.
      • Akesson M.
      • Bergman S.
      • Gottsater A.
      Primary stenting of the superficial femoral artery in intermittent claudication improves health related quality of life, ABI and walking distance: 12 month results of a controlled randomised multicentre trial.
      ,
      • Lindgren H.I.V.
      • Qvarfordt P.
      • Bergman S.
      • Gottsater A.
      Primary stenting of the superficial femoral artery in patients with intermittent claudication has durable effects on health-related quality of life at 24 months: results of a randomized controlled trial.
      A CONSORT diagram is shown in Fig. 1.
      Figure 1
      Figure 1Consolidated Standards of Reporting Trials (CONSORT) diagram for cost effectiveness analysis for invasive vs. conservative treatment for intermittent claudication due to a superficial femoral artery lesion. EQ-5D = EuroQol Five Dimensions.
      Data were reported to research units in Helsingborg and Spenshult. The study was registered in the Clinical Trials.gov database (NCT01230229) and approved by the Regional Ethical Review Board of Lund University (Dnr 2009/478). All patients gave written informed consent to participate.

      Treatment

      All study patients were given advice on regular exercise and received a personal pedometer. To increase the motivation for exercise, pedometer readouts were recorded and patients received feedback during each follow up visit. For smoking, patients were advised to stop and were offered a cessation programme as needed. All participants also received BMT, including antiplatelet and lipid lowering therapy, as well as antihypertensive drugs when indicated, with treatment targets according to Swedish guidelines at the start of the study.
      Modern self expanding bare metal nitinol stents designed for the SFA were inserted percutaneously and deployed according to the instructions for use. The diameter of the stent was chosen to be 1 mm larger than the target artery diameter. Stented patients were treated with dual antiplatelet therapy for 12 weeks. If patients were already on anticoagulant therapy, aspirin was added for 12 weeks following the procedure. In general, the patients spend one post-procedural night at the hospital.

      Follow up

      All study patients were followed up at one, six, 12, and 24 months, by an angiologist, a vascular surgeon, an interventional radiologist, or a research nurse. Treadmill tests were performed at baseline and follow up.
      Follow up HRQoL questionnaires were administered by mail from the Spenshults research unit.

      Cost data

      Accumulated costs regarding hospitalisation and outpatients visits for patients treated in the Skåne region (n = 77/100; Helsingborg University Hospital, Skåne University Hospital Malmö, and Kristianstad Hospital) were retrieved from the Region Skåne Health Care Database (RSVD) registry. The RSVD registry includes accumulated costs for primary and secondary procedures; post-operative care; drugs given during surgery and post-operative care; anaesthetic procedures; additional diagnostic procedures by the radiology and clinical physiology departments; clinical chemistry; and bacteriology. The costs for healthcare staff comprised full wage costs, including costs for social security. Registry cost data for patients treated outside of Skåne was not available and costs for these patients were imputed based on costs for the patients within Skåne, in line with best practice recommendations in cost effectiveness analyses.
      • Leurent B.
      • Gomes M.
      • Carpenter J.R.
      Missing data in trial-based cost-effectiveness analysis: an incomplete journey.
      A prediction model was used for missing values (i.e., an individual with missing cost data gets the same value as the most similar patient in the dataset). Furthermore, random samples with manual calculations of estimated costs were made, assuring the accuracy of the hospitals’ cost data.

      Health outcomes

      Primary health outcomes were the SF-36 and the EuroQol Five Dimensions EQ-5D 3L™ (EQ-5D-3L; EuroQol Group, Rotterdam, the Netherlands) questionnaire scores, assessed at one, six, 12, and 24 months. The results from SF-36 have been reported previously.
      • Lindgren H.I.V.
      • Qvarfordt P.
      • Bergman S.
      • Gottsater A.
      Primary stenting of the superficial femoral artery in patients with intermittent claudication has durable effects on health-related quality of life at 24 months: results of a randomized controlled trial.
      The results from EQ-5D-3L and the Dolan tariff
      • Dolan P.
      Modeling valuations for EuroQol health states.
      were translated into quality adjusted life years (QALYs), which combines the time spent in a specific health state with the corresponding HRQoL. For the complete case analysis, linear extrapolation was performed in the case of sporadic missing EQ-5D data. Regression analysis were used to adjust for difference between groups in baseline QALY weight.
      • Manca A.
      • Hawkins N.
      • Sculpher M.J.
      Estimating mean QALYs in trial-based cost-effectiveness analysis: the importance of controlling for baseline utility.
      The EQ-5D-3L includes five domains (mobility, self care, usual activities, pain/discomfort, and anxiety/depression) where the patients value their health in three separate levels. A HRQoL index score, “QALY weight”, is calculated from the EQ-5D answers and then multiplied by the time spent in each health state, resulting in each patient’s accumulated QALYs during follow up (area under the curve).
      • Payakachat N.
      • Ali M.M.
      • Tilford J.M.
      Can the EQ-5D detect meaningful change? A systematic review.
      Linear development in HRQoL between each measurement point was assumed.

      Cost effectiveness analysis

      Costs initially measured in Swedish kronor (SEK) at the price level of 2017 were converted to euros at an exchange rate of 1 SEK= €0.101 (December 2017 exchange rate) and both costs and QALYs were discounted with a 3% annual rate. The incremental cost effectiveness ratio (ICER) was calculated from group differences in mean costs divided by the group difference in mean QALYs.
      Analyses were carried out using the intention to treat (ITT) principle. In the ITT analysis groups are compared regardless of whether patients actually received the allocated treatment.
      The cost effectiveness analysis was performed from a healthcare payer perspective. Broader potential consequences (e.g., potential production losses) for the entire society were not assessed.

      Assessment of uncertainty

      Non-parametric bootstrapping (1 000 bootstraps) using Stata version 15.1 (StataCorp, College Station, TX, USA) was performed and the results were used to create a cost effectiveness plane and acceptability curve (CEAC), the latter showing the probability of stenting + exercise training advice to be cost effective vs. exercise training advice alone, at different maximum values per QALY that a healthcare decision maker may be willing to pay.
      • Ramsey S.D.
      • Willke R.J.
      • Glick H.
      • Reed S.D.
      • Augustovski F.
      • Jonsson B.
      • et al.
      Cost-effectiveness analysis alongside clinical trials II-An ISPOR Good Research Practices Task Force report.

      Results

      Screening and enrolment

      Between 2010 and 2015, 310 patients were assessed for eligibility. One hundred patients with IC were randomised 1:1 to primary SFA stenting plus BMT and exercise training advice (stent group) vs. BMT and exercise training advice alone (control group).

      Economic costs and health outcomes

      The clinical results have been reported previously. The stent group had favourable HRQoL results vs. the control group, after both one and two years of follow up.
      • Lindgren H.
      • Qvarfordt P.
      • Akesson M.
      • Bergman S.
      • Gottsater A.
      Primary stenting of the superficial femoral artery in intermittent claudication improves health related quality of life, ABI and walking distance: 12 month results of a controlled randomised multicentre trial.
      ,
      • Lindgren H.I.V.
      • Qvarfordt P.
      • Bergman S.
      • Gottsater A.
      Primary stenting of the superficial femoral artery in patients with intermittent claudication has durable effects on health-related quality of life at 24 months: results of a randomized controlled trial.
      EQ-5D-3L data were available for 84 patients (stent group, n = 42; control group, n = 42). In Table 1, the baseline characteristics for these patients is displayed. The mean QALYs per patient in the primary stent group and the control group were 1.35 and 0.95, respectively. In an ITT analysis, after adjustment for difference in QALY weight at baseline,
      • Manca A.
      • Hawkins N.
      • Sculpher M.J.
      Estimating mean QALYs in trial-based cost-effectiveness analysis: the importance of controlling for baseline utility.
      the mean QALY differed by 0.26 between the groups (Table 2).
      Table 1Baseline demographic data and superficial femoral artery lesion characteristics by treatment group for the cost effectiveness analysis of 84 patients treated for intermittent claudication
      Stent group (n = 42)Control group (n = 42)
      Age – y71.1 ± 5.470.1 ± 4.9
      Male20 (48)23 (55)
      Ankle brachial index0.60 ± 0.120.6 ± 0.17
      Walking distance – m170 ± 86192 ± 97
      Duration of IC – months29 ± 2936 ± 42
      Smoking
       Active7 (17)9 (21)
       Former24 (57)28 (67)
       Never11 (26)5 (12)
      LDL cholesterol – mmol/L2.6 ± 0.92.6 ± 0.8
      Blood glucose – mmol/L7.1 ± 3.06.0 ± 1.3
      BP systolic – mmHg153 ± 21149 ± 21
      BP diastolic – mmHg80 ± 1180 ± 8
      Creatinine – μmol/L84 ± 2580 ± 18
      Lesion length – mm148 ± 9199 ± 95
      Occlusion28 (67)32 (76)
      Stenosis14 (33)10 (24)
      Degree of stenosis – %93.9 ± 1397.9 ± 4
      Patent crural vessels – n2.5 ± 0.62.4 ± 0.7
      Data are presented as n (%) or mean ± standard deviation. LDL = low density lipoprotein; BP = blood pressure.
      Table 2Costs of stent treatment plus exercise training advice vs. exercise training advice alone for the main analysis of 84 patients with a superficial femoral artery lesion receiving treatment for intermittent claudication
      Mean (95% CI) cost per patient – €Mean (95% CI) QALYs per patientITT (n = 84)
      Stent treatment + exercise advice11 060 (9 804–12 316)1.35 (1.23–1.47)
      Exercise advice alone4 787 (2 697–6 877)0.95 (0.79–1.10)
      Difference6 2730.26
      The difference was adjusted for the difference in baseline QALY weight (higher for the group with stent treatment), resulting in a slightly different result than the difference in raw values.
      (0.10–0.43)
      ICER – € per QALY23 785
      CI = confidence interval; QALY = quality adjusted life years; ITT = intention to treat; ICER = incremental cost effectiveness ratio.
      The difference was adjusted for the difference in baseline QALY weight (higher for the group with stent treatment), resulting in a slightly different result than the difference in raw values.
      For the main ITT analysis with all patients with EQ-5D-3L data (n = 84 [stent, n = 42; control, n = 42]), missing cost registry data were imputed.
      • Leurent B.
      • Gomes M.
      • Carpenter J.R.
      Missing data in trial-based cost-effectiveness analysis: an incomplete journey.
      The mean cumulative cost per patient for the stent group was €11 060 and for the control group €4787, resulting in a mean difference of €6 273. The group with primary stenting had a gain of 0.26 QALYs and an ICER (the difference in cost divided by the difference in effect) of €23 785 per QALY.
      As a robustness test, a subgroup analysis was done for patients with data on both costs and EQ-5D at the two year follow up (n = 65). The mean cumulative cost per patient for the stent group was €11 691 and for the control group €3 489, resulting in a mean difference of €8 203. This translated into a gain of 0.24 QALYs (for the stent group), and an ICER of €33 543 per QALY, similar to the main ITT analysis.

      Sensitivity analysis

      Figure 2, Figure 3 show the cost effectiveness plane and the CEAC based on 1 000 bootstrap replicates of the original data for an ITT analysis. The cost effectiveness plane showed that the bootstrapped results were focused mainly in the northeast quadrant (where revascularisation is more expensive and health outcomes are better). A slope representing the often used threshold for cost effectiveness in Swedish health policy (about €50 000 per QALY is also shown in the figure). Figure 3 shows that most estimated ICERs fall below (“passes”) the cost effectiveness threshold. The CEAC shows the likelihood that revascularisation is more cost effective than non-revascularisation for a range of threshold values per QALY (“willingness to pay” per QALY). For example, at a threshold value of €50 000 per QALY, the likelihood that revascularisation is cost effective is about 77%. At €75 000 per QALY, the likelihood that revascularisation is cost effective is about 90%.
      Figure 2
      Figure 2Cost effectiveness plane based on intention to treat analysis in the main analysis of 84 patients with a superficial femoral artery lesion receiving invasive or conservative treatment for intermittent claudication. Each dot represents one bootstrapped result (in total, 1 000). The incremental cost effectiveness ratio (ICER) threshold was €50 000/quality adjusted life years (QALY).
      Figure 3
      Figure 3Cost effectiveness acceptability curve based on intention to treat analysis in the main analysis of 84 patients with a superficial femoral artery lesion receiving invasive or conservative treatment for intermittent claudication. QALY = quality adjusted life year.

      Discussion

      This study, which examined the cost effectiveness of endovascular treatment in the SFA for patients with IC within a randomised controlled trial (RCT), showed favourable cost effectiveness results for endovascular treatment. Although primary stenting was more expensive than a non-invasive approach, it generated a mean benefit of 0.24 – 0.26 QALYs and a cost effectiveness ratio of about €24 000 – €34 000 per QALY with two years of follow up.
      To the authors’ knowledge, this is the first study to have examined the cost effectiveness of the common practice of endovascular treatment in the SFA within a RCT with follow up extending beyond one year. Compared with previous shorter studies within the field, more favourable cost effectiveness results for endovascular treatment were demonstrated in this vessel segment.
      • Spronk S.
      • Bosch J.L.
      • den Hoed P.T.
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      • Pattynama P.M.
      • Hunink M.G.
      Cost-effectiveness of endovascular revascularization compared to supervised hospital-based exercise training in patients with intermittent claudication: a randomized controlled trial.
      ,
      • Mazari F.A.
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      • Carradice D.
      • Samuel N.
      • Gohil R.
      • McCollum P.T.
      • et al.
      Economic analysis of a randomized trial of percutaneous angioplasty, supervised exercise or combined treatment for intermittent claudication due to femoropopliteal arterial disease.
      The national guidelines of the Swedish National Board of Health have suggested a limit of about €50 000 for medical technologies to be considered expensive.

      Swedish National Board of Health and Welfare (Socialstyrelsen). Nationella riktlinjer: Hälsoekonomiskt underlag. Available at: http://www.socialstyrelsen.se [Accessed 1 August 2019].

      However, the Swedish Dental and Pharmaceutical Benefits agency, which decides which pharmacotherapies should be considered for public funding, has implicitly shown an even higher threshold of €70 000 per QALY.
      • Svensson M.
      • Nilsson F.O.
      • Arnberg K.
      Reimbursement decisions for pharmaceuticals in Sweden: the impact of disease severity and cost effectiveness.
      Interestingly, and in contrast, the UK’s National Institute for Health and Care Excellence (NICE) uses a lower cost effectiveness threshold ranging between £20 000 (€22 600) and £30 000 (€33 900) (December 2017 exchange rate) per QALY. However, in practice, interventions with a cost/QALY < £40 000 have had a 50% chance of being accepted by NICE.
      • Dakin H.
      • Devlin N.
      • Feng Y.
      • Rice N.
      • O'Neill P.
      • Parkin D.
      The influence of cost-effectiveness and other factors on nice decisions.
      The results approach the border of the formal willingness to pay threshold range for NICE. As the actual acceptance threshold for previous NICE decisions has been higher, as referenced above, primary SFA stent treatment in patients with IC may be acceptable for UK standards.
      Possible consequences for society (e.g., productivity costs and benefits) were not included in the cost analysis. However, it is less likely that this would have a tangible impact on the study results, considering the age profile of the patient cohort.
      EQ-5D data were missing at earlier (one, six, or 12 months) follow ups for 12 of 84 patients (stent, n = 6; control, n = 6). Linear extrapolation was performed in these cases.
      One limitation is that protocol driven follow up in the study setting might increase the costs for both groups vs. a clinical practice scenario.
      Patients received the treatment that reflects clinical practice (i.e., non-supervised exercise). SET is generally regarded as being more effective than exercise advice only.
      • Ramsey S.D.
      • Willke R.J.
      • Glick H.
      • Reed S.D.
      • Augustovski F.
      • Jonsson B.
      • et al.
      Cost-effectiveness analysis alongside clinical trials II-An ISPOR Good Research Practices Task Force report.
      However, there remains uncertainty about the long term benefit of SET.
      • Back M.
      • Jivegard L.
      • Johansson A.
      • Nordanstig J.
      • Svanberg T.
      • Adania U.W.
      • et al.
      Home-based supervised exercise versus hospital-based supervised exercise or unsupervised walk advice as treatment for intermittent claudication: a systematic review.
      Furthermore, SET is often unavailable in most countries,
      • Dua A.
      • Gologorsky R.
      • Savage D.
      • Rens N.
      • Gandhi N.
      • Brooke B.
      • et al.
      National assessment of availability, awareness, and utilization of supervised exercise therapy for peripheral artery disease patients with intermittent claudication.
      and none of the groups was entered in a formal supervised exercise programme. Instead, they were given structured exercise training advice and a free pedometer, and pedometer readouts were used to encourage ongoing exercise during follow up.
      Home based exercise therapy (HET) has been suggested as a promising alternative,
      • Back M.
      • Jivegard L.
      • Johansson A.
      • Nordanstig J.
      • Svanberg T.
      • Adania U.W.
      • et al.
      Home-based supervised exercise versus hospital-based supervised exercise or unsupervised walk advice as treatment for intermittent claudication: a systematic review.
      and may be less costly than SET while resulting in similar or superior exercise doses. It is possible that if SET or HET had been used in this study the results would have been different. Arguably, the money invested in invasive treatment might be better spent in the development and re-imbursement of SET and/or HET programmes. However, from a cost effectiveness endpoint perspective, the optimal exercise therapy is yet to be determined.
      One limitation of the study is the duration of follow up. As differences in HRQoL might change over time, longer follow up would be valuable. The few studies with follow ups longer than two years have not shown any benefit of invasive treatment vs. non-invasive treatment.
      • Djerf H.
      • Millinger J.
      • Falkenberg M.
      • Jivegård L.
      • Svensson M.
      • Nordanstig J.
      Absence of long-term benefit of revascularization in patients with intermittent claudication: five-year results from the IRONIC randomized controlled trial.
      • Fakhry F.
      • Rouwet E.V.
      • den Hoed P.T.
      • Hunink M.G.
      • Spronk S.
      Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial.
      • Mazari F.A.
      • Khan J.A.
      • Samuel N.
      • Smith G.
      • Carradice D.
      • McCollum P.C.
      • et al.
      Long-term outcomes of a randomized clinical trial of supervised exercise, percutaneous transluminal angioplasty or combined treatment for patients with intermittent claudication due to femoropopliteal disease.
      Nevertheless, the results from these earlier studies only emphasise the important need to distinguish which patients with endovascular IC treatment can be justified from a health economic standpoint.
      The larger increase in HRQoL in the stent group was related to a greater increase in mean walking distance in the treadmill tests (control group from 209 ± 106 to 331 ± 304 metres; stent group from 171 ± 90 to 615 ± 375 metres) (Fig. 4).
      • Lindgren H.I.V.
      • Qvarfordt P.
      • Bergman S.
      • Gottsater A.
      Primary stenting of the superficial femoral artery in patients with intermittent claudication has durable effects on health-related quality of life at 24 months: results of a randomized controlled trial.
      Figure 4
      Figure 4EuroQol Five Dimensions (EQ-5D) and maximum walking distance (MWD) for the stent (n = 42) and control groups (n = 42) at baseline and at 24 months follow up in patients with a superficial femoral artery lesion treated for intermittent claudication. Numbers are presented as mean (standard deviation).
      As individual patient cost registry data were used, this reduced the risk of bias when estimating costs. The study was also performed together with a professor in health economics, to ensure the robustness of the analysis.
      In general, patients spend one post-procedural night at the hospital. However, a recent article indicated that outpatient procedures for IC were not cost effective when compared with inpatient hospitalisation.
      • Gouëffic Y.
      • Pin J.L.
      • Sabatier J.
      • Alimi Y.
      • Steinmetz E.
      • Magnan P.E.
      • et al.
      A Cost effectiveness analysis of outpatient versus inpatient hospitalisation for lower extremity arterial disease endovascular revascularisation in France: a randomised controlled trial.
      One limitation in this study and many other randomised studies is the long inclusion periods, which may limit the generalisability.
      • Mazari F.A.K.
      • Khan J.A.
      • Carradice D.
      • Samuel N.
      • Abdul Rahman M.N.A.
      • Gulati S.
      • et al.
      Randomized clinical trial of percutaneous transluminal angioplasty, supervised exercise and combined treatment for intermittent claudication due to femoropopliteal arterial disease.
      ,
      • Spronk S.
      • Bosch J.L.
      • den Hoed P.T.
      • Veen H.F.
      • Pattynama P.M.
      • Hunink M.G.
      Intermittent claudication: clinical effectiveness of endovascular revascularization versus supervised hospital-based exercise training – randomized controlled trial.
      • Murphy T.P.
      • Cutlip D.E.
      • Regensteiner J.G.
      • Mohler 3rd, E.R.
      • Cohen D.J.
      • Reynolds M.R.
      • et al.
      Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study.
      • Greenhalgh R.M.
      • Belch J.J.
      • Brown L.C.
      • Gaines P.A.
      • Gao L.
      • Reise J.A.
      • et al.
      The adjuvant benefit of angioplasty in patients with mild to moderate intermittent claudication (MIMIC) managed by supervised exercise, smoking cessation advice and best medical therapy: results from two randomised trials for stenotic femoropopliteal and aortoiliac arterial disease.
      • Fakhry F.
      • Spronk S.
      • van der Laan L.
      • Wever J.J.
      • Teijink J.A.
      • Hoffmann W.H.
      • et al.
      Endovascular revascularization and supervised exercise for peripheral artery disease and intermittent claudication: a randomized clinical trial.
      Nevertheless, this randomised trial was one of few studies to evaluate HRQoL for endovascular treatment beyond one year. Previous attempts to study stenting of the SFA in a randomised setting have failed because of difficulties in recruiting patients.
      • Hobbs S.D.
      • Bradbury A.W.
      The EXercise versus Angioplasty in Claudication Trial (EXACT): reasons for recruitment failure and the implications for research into and treatment of intermittent claudication.
      In conclusion, primary stenting of the SFA in addition to exercise training advice and BMT resulted in higher costs and improved HRQoL compared with exercise training advice and BMT alone. The ICER after two years of follow up was within the accepted threshold for public willingness to pay, according to the Swedish National Guidelines, and approaching NICE thresholds in the UK. From a cost effectiveness standpoint, in many countries primary stenting of the SFA can be used as an adjunct to exercise training advice, but it must be considered that successful implementation of structured exercise programmes and longer follow up may alter these findings.

      Conflict of interest

      H. Djerf has received occasional lecture grants from Gore.

      Funding

      The Swedish Research Council, and grants from the Swedish state under the agreement between the Swedish government and the county councils – the ALF agreement (agreement on medical education and research; ref. ALFGBG-785741 and ALFGBG-822921) and by the Swedish Heart–Lung Foundation (20190194). Mikael Svensson gratefully acknowledges financial support from the Kamprad Family Foundation.

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