BackgroundFoam sclerotherapy (foam) and endovenous laser ablation (EVLA) have emerged as alternative treatments to surgery for patients with varicose veins, but uncertainty exists regarding their effectiveness in the medium to longer term.ObjectivesTo assess the clinical effectiveness and cost-effectiveness of foam, EVLA and surgery for the treatment of varicose veins.DesignA parallel-group randomised controlled trial (RCT) without blinding, and economic modelling evaluation.SettingEleven UK specialist vascular centres.ParticipantsSeven hundred and ninety-eight patients with primary varicose veins (foam,n = 292; surgery,n = 294; EVLA,n = 212).InterventionsPatients were randomised between all three treatment options (eight centres) or between foam and surgery (three centres).Primary outcome measuresDisease-specific [Aberdeen Varicose Vein Questionnaire (AVVQ)] and generic [European Quality of Life-5 Dimensions (EQ-5D), Short Form questionnaire-36 items (SF-36) physical and mental component scores] quality of life (QoL) at 6 months. Cost-effectiveness as cost per quality-adjusted life-year (QALY) gained.Secondary outcome measuresQuality of life at 6 weeks; residual varicose veins; Venous Clinical Severity Score (VCSS); complication rates; return to normal activity; truncal vein ablation rates; and costs.ResultsThe results appear generalisable in that participants’ baseline characteristics (apart from a lower-than-expected proportion of females) and post-treatment improvement in outcomes were comparable with those in other RCTs. The health gain achieved in the AVVQ with foam was significantly lower than with surgery at 6 months [effect size −1.74, 95% confidence interval (CI) −2.97 to −0.50;p = 0.006], but was similar to that achieved with EVLA. The health gain in SF-36 mental component score for foam was worse than that for EVLA (effect size 1.54, 95% CI 0.01 to 3.06;p = 0.048) but similar to that for surgery. There were no differences in EQ-5D or SF-36 component scores in the surgery versus foam or surgery versus EVLA comparisons at 6 months.The trial-based cost-effectiveness analysis showed that, at 6 months, foam had the highest probability of being considered cost-effective at a ceiling willingness-to-pay ratio of £20,000 per QALY. EVLA was found to cost £26,107 per QALY gained versus foam, and was less costly and generated slightly more QALYs than surgery. Markov modelling using trial costs and the limited recurrence data available suggested that, at 5 years, EVLA had the highest probability (≈ 79%) of being cost-effective at conventional thresholds, followed by foam (≈ 17%) and surgery (≈ 5%).With regard to secondary outcomes, health gains at 6 weeks (p < 0.005) were greater for EVLA than for foam (EQ-5D,p = 0.004). There were fewer procedural complications in the EVLA group (1%) than after foam (7%) and surgery (8%) (p < 0.001). Participants returned to a wide range of behaviours more quickly following foam or EVLA than following surgery (p < 0.05). There were no differences in VCSS between the three treatments. Truncal ablation rates were higher for surgery (p < 0.001) and EVLA (p < 0.001) than for foam, and were similar for surgery and EVLA.ConclusionsConsiderations of both the 6-month clinical outcomes and the estimated 5-year cost-effectiveness suggest that EVLA should be considered as the treatment of choice for suitable patients.Future workFive-year trial results are currently being evaluated to compare the cost-effectiveness of foam, surgery and EVLA, and to determine the recurrence rates following each treatment. This trial has highlighted the need for long-term outcome data from RCTs on QoL, recurrence rates and costs for foam sclerotherapy and other endovenous techniques compared against each other and against surgery.Trial registrationCurrent Controlled Trials ISRCTN51995477.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 27. See the NIHR Journals Library website for further project information.

Current Controlled Trials ISRCTN15517081.

1 The interactions between pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) on Larginine transporter and inducible nitric oxide synthase (iNOS) activities were examined in rat cultured aortic smooth muscle cells. 2 LPS induced a concentration (0.01-100 4g ml-') and time (8-24 h)-dependent stimulation of nitrite production which was accompanied by a parallel increase in L-arginine transport.3 Unlike LPS, activation of smooth muscle cells with either interferon-y (IFN-y, 100 u ml-'), tumour necrosis factor-a (TNF-a, 300 u ml-') or interleukin-la (IL-la, 100 u ml-') failed to stimulate L-arginine transport or increase nitrite accumulation.4 When applied in combination with LPS (100 pg ml-') both IFN-y and TNF-a, but not IL-la, enhanced the effects observed with LPS alone. Furthermore, activation of cells with LPS and IFN-y had no effect on uptake of the neutral amino acid L-citrulline but selectively increased the Vm,,, for L-arginine transport 2.8 fold and nitrite levels from 24+7 to 188+14 pmol ug-' protein 24 h-'. 5 The substrate specificity, Na+ and pH-independence of saturable L-arginine transport in both unactivated (Km= 44 jM, Vma. = 3 pmol pg' protein min') and activated (Km = 75 gM, V,, = 8.3 pmol pg-' protein min'-) smooth muscle cells were characteristic of the cationic amino acid transport system y+.6 Cycloheximide (1 pM) abolished induction of L-arginine transport and nitrite accumulation in response to LPS and IFN-y. In contrast, the glucocorticoid dexamethasone (10 pM, 24 h) selectively inhibited nitrite production. 7 Our results demonstrate that pro-inflammatory mediators selectively enhance transport of L-arginine under conditions of sustained NO synthesis by vascular smooth muscle cells. In addition, the differential inhibition of iNOS and L-arginine transporter activity by dexamethasone suggests that distinct signalling pathways mediate induction of the cationic transport protein and iNOS. The close coupling between substrate supply and NO production may have important implications in the pathogenesis of several disease states including endotoxin shock.

OBJECTIVE: To determine the relative benefits and risks of laparoscopic fundoplication surgery as an alternative to long term drug treatment for chronic gastro-oesophageal reflux disease (GORD). DESIGN: Multicentre, pragmatic randomised trial (with parallel preference groups). SETTING: 21 hospitals in the United Kingdom. PARTICIPANTS: 357 randomised participants (178 surgical, 179 medical) and 453 preference participants (261, 192); mean age 46; 66% men. All participants had documented evidence of GORD and symptoms for >12 months. INTERVENTION: The type of laparoscopic fundoplication used was left to the discretion of the surgeon. Those allocated to medical treatment had their treatment reviewed and adjusted as necessary by a local gastroenterologist, and subsequent clinical management was at the discretion of the clinician responsible for care. MAIN OUTCOME MEASURES: The disease specific REFLUX quality of life score (primary outcome), SF-36, EQ-5D, and medication use, measured at time points equivalent to three and 12 months after surgery, and surgical complications. MAIN RESULTS: Randomised participants had received drugs for GORD for median of 32 months before trial entry. Baseline REFLUX scores were 63.6 (SD 24.1) and 66.8 (SD 24.5) in the surgical and medical randomised groups, respectively. Of those randomised to surgery, 111 (62%) actually had total or partial fundoplication. Surgical complications were uncommon with a conversion rate of 0.6% and no mortality. By 12 months, 38% (59/154) randomised to surgery (14% (14/104) among those who had fundoplication) were taking reflux medication versus 90% (147/164) randomised medical management. The REFLUX score favoured the randomised surgical group (14.0, 95% confidence interval 9.6 to 18.4; P>0.001). Differences of a third to half of 1 SD in other health status measures also favoured the randomised surgical group. Baseline scores in the preference for surgery group were the worst; by 12 months these were better than in the preference for medical treatment group. CONCLUSION: At least up to 12 months after surgery, laparoscopic fundoplication significantly increased measures of health status in patients with GORD. TRIAL REGISTRATION: ISRCTN15517081

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