Anna Cantrell

Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation

BACKGROUND Varicose veins are enlarged, visibly lumpy knotted veins, usually in the legs. Uncomplicated varicose veins can cause major discomfort and some complications. They are part of chronic venous disease (CVD), which is reported to have a substantial negative impact on health-related quality of life (HRQoL). Traditional treatments for varicose veins involve surgical stripping and ligation and liquid sclerotherapy (LS), but can be invasive and painful. New minimally invasive treatments offer an alternative. These treatments typically involve use of laser, radiofrequency or foam sclerosant. They are increasingly widely used and offer potential benefits such as reduced complications, faster recovery, fewer physical limitations and improved quality of life. OBJECTIVE The aim of this report is to evaluate the clinical effectiveness, safety and cost-effectiveness of the minimally invasive techniques of foam sclerotherapy (FS), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) in comparison with other techniques, including traditional surgical techniques, LS and conservative management, in the management of varicose veins. DATA SOURCES A systematic search was made of 11 bibliographic databases of published and unpublished literature from their inception to July 2011: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library; Biological Abstracts; Science Citation Index (SCI); Social Sciences Citation Index; Conference Proceedings Citation Index-Science; UK Clinical Research Network; Current Controlled Trials; and ClinicalTrials.gov. REVIEW METHODS A systematic review of randomised controlled trials (RCTs) to assess the clinical effectiveness of minimally invasive techniques compared with other treatments, principally surgical stripping, in terms of recurrence of varicose veins, retreatment and clinical symptoms, as measured by the Venous Clinical Severity Score (VCSS), pain and quality of life. Network meta-analysis and exploratory cost-effectiveness modelling were performed. RESULTS The literature search identified 1453 unique citations, of which 34 RCTs (54 papers) satisfied the criteria for the clinical effectiveness review. The minimally invasive techniques reported clinical outcomes similar to surgery. Rates of recurrence were slightly lower for EVLA, RFA and FS, especially for longer follow-up periods; VCSS score was lower for EVLA and FS than for stripping, but slightly higher for RFA; short-term pain was less for FS and RFA but higher for EVLA; higher quality-of-life scores were reported for all evaluated interventions than for stripping. Differences between treatments were therefore negligible in terms of clinical outcomes, so the treatment with the lowest cost appears to be most cost-effective. Our central estimate is that total FS costs were lowest and FS is marginally more effective than stripping. However, this result was sensitive to the model time horizon. Threshold analysis indicated that EVLA and RFA might be considered cost-effective if their costs are equivalent to stripping. These findings are subject to uncertainty on account of the risk of bias present in the evidence base and the variation in costs. LIMITATIONS The relative clinical effectiveness and cost-effectiveness of the techniques are principally based on rates of post-operative technical recurrence rather than symptomatic recurrence, as this was the reported outcome in all trials. The true proportion of treated individuals who are likely to present with symptoms of recurrence requiring retreatment is therefore not certain. A figure reflecting the likely proportion of treated individuals who would experience symptomatic recurrence requiring retreatment (with its associated costs), therefore, had to be calculated by the authors based on a small number of studies. The findings of this report also need to be verified by data from future trials with longer follow-up and using more standardised outcome measures. CONCLUSIONS This assessment of the currently available evidence suggests there is little to choose between the minimally invasive techniques in terms of efficacy or cost, and each offers a viable, clinically effective alternative to stripping. FS might offer the most cost-effective alternative to stripping, within certain time parameters. High-quality RCT evidence is needed. Future trials should aim to measure and report outcomes in a standardised manner, which would permit more efficient pooling of their results. STUDY REGISTRATION PROSPERO number CRD42011001355. FUNDING The National Institute for Health Research Health Technology Assessment programme.

A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS)

Objective To determine the efficacy and safety of eculizumab for patients with atypical haemolytic uraemic syndrome (aHUS), compared with current treatment options. Design A systematic review was performed according to the general principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All study designs were included, except case histories. Participants All patients diagnosed with aHUS were included; no age restrictions were used. Interventions Eculizumab compared with current treatment options. Identification of studies 12 databases were searched. Additional searches were performed through the Food and Drug Administration (FDA) and the Electronic Medicines Compendium websites, Google internet searches and contacting clinical experts. Reference lists of relevant articles were checked for additional studies. Results 2 small, uncontrolled prospective multinational, multicentre studies and one small uncontrolled multinational, multicentre retrospective study were included. No meta-analyses were performed. Compared with baseline measures, thrombotic microangiopathy event-free status was achieved in 84% of patients in the prospective studies. Adverse events, as documented by enrolling investigators were frequent, with upper-respiratory tract infection affecting a third of patients. No deaths or episodes of meningitis or meningococcal septicaemia occurred in the prospective studies. Results of the study extension phases up to 114 weeks indicate that the benefits of the treatment are sustained. Conclusions Eculizumab is clinically effective for the treatment of aHUS. Further research is needed to evaluate eculizumab, ideally using patient-related clinical outcomes. If randomised studies are not feasible, study investigators should ensure that the threat of bias is minimised in future studies of eculizumab with respect to the reporting of patient recruitment and selection.

Systematic review, network meta‐analysis and exploratory cost‐effectiveness model of randomized trials of minimally invasive techniques versus surgery for varicose veins

A Health Technology Assessment was conducted to evaluate the relative clinical effectiveness and cost‐effectiveness of minimally invasive techniques (foam sclerotherapy (FS), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA)) for managing varicose veins, in comparison with traditional surgery.

VALIDATION OF SURROGATE ENDPOINTS IN ADVANCED SOLID TUMORS: SYSTEMATIC REVIEW OF STATISTICAL METHODS, RESULTS, AND IMPLICATIONS FOR POLICY MAKERS

OBJECTIVES Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers. METHODS We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylors framework, the German Institute of Quality and Efficiency in Health Cares (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3). RESULTS A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type. CONCLUSIONS Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiGs framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.

A systematic review, evidence synthesis and meta-analysis of quantitative and qualitative studies evaluating the clinical effectiveness, the cost-effectiveness, safety and acceptability of interventions to prevent postnatal depression.

BACKGROUND Postnatal depression (PND) is a major depressive disorder in the year following childbirth, which impacts on women, their infants and their families. A range of interventions has been developed to prevent PND. OBJECTIVES To (1) evaluate the clinical effectiveness, cost-effectiveness, acceptability and safety of antenatal and postnatal interventions for pregnant and postnatal women to prevent PND; (2) apply rigorous methods of systematic reviewing of quantitative and qualitative studies, evidence synthesis and decision-analytic modelling to evaluate the preventive impact on women, their infants and their families; and (3) estimate cost-effectiveness. DATA SOURCES We searched MEDLINE, EMBASE, Science Citation Index and other databases (from inception to July 2013) in December 2012, and we were updated by electronic alerts until July 2013. REVIEW METHODS Two reviewers independently screened titles and abstracts with consensus agreement. We undertook quality assessment. All universal, selective and indicated preventive interventions for pregnant women and women in the first 6 postnatal weeks were included. All outcomes were included, focusing on the Edinburgh Postnatal Depression Scale (EPDS), diagnostic instruments and infant outcomes. The quantitative evidence was synthesised using network meta-analyses (NMAs). A mathematical model was constructed to explore the cost-effectiveness of interventions contained within the NMA for EPDS values. RESULTS From 3072 records identified, 122 papers (86 trials) were included in the quantitative review. From 2152 records, 56 papers (44 studies) were included in the qualitative review. The results were inconclusive. The most beneficial interventions appeared to be midwifery redesigned postnatal care [as shown by the mean 12-month EPDS score difference of -1.43 (95% credible interval -4.00 to 1.36)], person-centred approach (PCA)-based and cognitive-behavioural therapy (CBT)-based intervention (universal), interpersonal psychotherapy (IPT)-based intervention and education on preparing for parenting (selective), promoting parent-infant interaction, peer support, IPT-based intervention and PCA-based and CBT-based intervention (indicated). Women valued seeing the same health worker, the involvement of partners and access to several visits from a midwife or health visitor trained in person-centred or cognitive-behavioural approaches. The most cost-effective interventions were estimated to be midwifery redesigned postnatal care (universal), PCA-based intervention (indicated) and IPT-based intervention in the sensitivity analysis (indicated), although there was considerable uncertainty. Expected value of partial perfect information (EVPPI) for efficacy data was in excess of £150M for each population. Given the EVPPI values, future trials assessing the relative efficacies of promising interventions appears to represent value for money. LIMITATIONS In the NMAs, some trials were omitted because they could not be connected to the main network of evidence or did not provide EPDS scores. This may have introduced reporting or selection bias. No adjustment was made for the lack of quality of some trials. Although we appraised a very large number of studies, much of the evidence was inconclusive. CONCLUSIONS Interventions warrant replication within randomised controlled trials (RCTs). Several interventions appear to be cost-effective relative to usual care, but this is subject to considerable uncertainty. FUTURE WORK RECOMMENDATIONS Several interventions appear to be cost-effective relative to usual care, but this is subject to considerable uncertainty. Future research conducting RCTs to establish which interventions are most clinically effective and cost-effective should be considered. STUDY REGISTRATION This study is registered as PROSPERO CRD42012003273. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Enhancements to angioplasty for peripheral arterial occlusive disease: systematic review, cost-effectiveness assessment and expected value of information analysis

BACKGROUND There have been rapid technological developments aimed at improving short- and long-term results of percutaneous transluminal balloon angioplasty (PTA) in peripheral arterial occlusive disease (PAD). OBJECTIVES To assess current clinical effectiveness and cost-effectiveness evidence of additional techniques to standard PTA for PAD, develop a health economic model to assess cost-effectiveness and to identify where further research is needed. DATA SOURCES Relevant electronic databases, including MEDLINE, EMBASE and The Cochrane Library were searched from inception to 2011, between May and October 2011. METHODS Systematic reviews were conducted of clinical effectiveness and cost-effectiveness. The population was participants with symptomatic PAD undergoing endovascular treatment for disease distal to the inguinal ligament. Interventions were modifications of and adjuncts to PTA in the peripheral circulation, compared with conventional PTA. Outcomes included measures of clinical effectiveness and costs. Data were extracted from randomised controlled trials (RCTs), which were quality assessed using standard criteria. Where appropriate, meta-analyses using fixed- and random-effects methods produced relative risks (RRs). A discrete-event simulation model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The patient populations of intermittent claudication (IC) and critical limb ischaemia (CLI) were modelled separately. Univariate and probabilistic sensitivity analyses were undertaken. RESULTS In total, 40 RCTs were included, many of which had small sample sizes. Significantly reduced restenosis rates were shown in meta-analyses of self-expanding stents (SES) {RR 0.67 [95% confidence interval (CI) 0.52 to 0.87]}, endovascular brachytherapy (EVBT) [RR 0.63 (95% CI 0.48 to 0.83)] at 12 months and drug-coated balloons (DCBs) at 6 months [RR 0.40 (95% CI 0.23 to 0.69)], and single studies of stent-graft or drug-eluting stent (DES), compared with PTA; a single study showed improvements with DES versus bare-metal stents (BMSs). Compared with PTA, walking capacity was not significantly affected by cutting balloon, balloon-expandable stents or EVBT; in SES, there was evidence of improvement in walking capacity after up to 12 months. The use of DCBs dominated both the assumed standard practice of PTA with bailout BMS and all other interventions because it lowered lifetime costs and improved quality of life (QoL). These results were seen for both patient populations (IC and CLI). Sensitivity analyses showed that the results were robust to different assumptions about the clinical benefits attributable to the interventions, suggesting that the use of DCBs is cost-saving. LIMITATIONS Differing definitions of restenosis made direct comparison across trials difficult. There were few data available for walking capacity and QoL. CONCLUSIONS The evidence showed a significant benefit to reducing restenosis rates for self-expanding and DESs, stent-graft, EVBT and DCBs. If it is assumed that patency translates into beneficial long-term clinical outcomes, then DCB and bail-out DES are most likely to be the cost-effective enhancements to PTA. A RCT comparing current recommended practice (PTA with bail-out BMS) with DCB and bail-out DES could assess long-term follow-up and cost-effectiveness. Data relating patency status to the need for reintervention and to the probability of symptoms returning should be collected, as should health-related QoL measures [European Quality of Life-5 Dimensions (EQ-5D) and maximum walking distance]. STUDY REGISTRATION This study is registered as PROSPERO CRD42012002014. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The state of the art in non‐pharmacological interventions for developmental stuttering. Part 1: a systematic review of effectiveness

Abstract Background The growing range of available treatment options for people who stutter presents a challenge for clinicians, service managers and commissioners, who need to have access to the best available treatment evidence to guide them in providing the most appropriate interventions. While a number of reviews of interventions for specific populations or a specific type of intervention have been carried out, a broad‐based systematic review across all forms of intervention for adults and children was needed to provide evidence to underpin future guidelines, inform the implementation of effective treatments and identify future research priorities. Aims To identify and synthesize the published research evidence on the clinical effectiveness of the broad range of non‐pharmacological interventions for the management of developmental stuttering. Methods & Procedures A systematic review of the literature reporting interventions for developmental stuttering was carried out between August 2013 and April 2014. Searches were not limited by language or location, but were restricted by date to studies published from 1990 onwards. Methods for the identification of relevant studies included electronic database searching, reference list checking, citation searching and hand searching of key journals. Appraisal of study quality was performed using a tool based on established criteria for considering risk of bias. Due to heterogeneity in intervention content and outcomes, a narrative synthesis was completed. Main Contribution The review included all available types of intervention and found that most may be of benefit to at least some people who stutter. There was evidence, however, of considerable individual variation in response to these interventions. The review indicated that effects could be maintained following all types of interventions (although this was weakest with regard to feedback and technology interventions). Conclusions This review highlights a need for greater consensus with regard to the key outcomes used to evaluate stuttering interventions, and also a need for enhanced understanding of the process whereby interventions effect change. Further analysis of the variation in effectiveness for different individuals or groups is needed in order to identify who may benefit most from which intervention.

Interventions to treat premature ejaculation: a systematic review short report

BACKGROUND Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE can be either lifelong and present since first sexual experiences (primary), or acquired (secondary), beginning later (Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130-4). Treatments include behavioural and pharmacological interventions. OBJECTIVE To systematically review evidence for clinical effectiveness of behavioural, topical and systemic treatments for PE. DATA SOURCES The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched. METHODS Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs). RESULTS A total of 103 studies (102 RCTs, 65 from reviews) were included. RCTs were available for all interventions except yoga. The following interventions demonstrated significant improvements (p < 0.05) in arithmetic mean difference in IELT compared with placebo: topical anaesthetics - eutectic mixture of local anaesthetics (EMLA(®), AstraZeneca), topical eutectic mixture for PE (Plethora Solutions Ltd) spray; selective serotonin reuptake inhibitors (SSRIs) - citalopram (Cipramil(®), Lundbeck), escitalopram (Cipralex(®), Lundbeck), fluoxetine, paroxetine, sertraline, dapoxetine (Priligy(®), Menarini), 30 mg or 60 mg; serotonin-noradrenaline reuptake inhibitors - duloxetine (Cymbalta(®), Eli Lilly & Co Ltd); tricyclic antidepressants - inhaled clomipramine 4 mg; phosphodiesterase-5 (PDE5) inhibitors - vardenafil (Levitra(®), Bayer), tadalafil (Cialis(®), Eli Lilly & Co Ltd); opioid analgesics - tramadol (Zydol SR(®), Grünenthal). Improvements in sexual satisfaction and other outcomes compared with placebo were evident for SSRIs, PDE5 inhibitors and tramadol. Outcomes for interventions not compared with placebo were as follows: behavioural therapies - improvements over wait list control in IELT and other outcomes, behavioural therapy plus pharmacotherapy better than either therapy alone; alpha blockers - terazosin (Hytrin(®), AMCO) not significantly different to antidepressants in ejaculation control; acupuncture - improvements over sham acupuncture in IELT, conflicting results for comparisons with SSRIs; Chinese medicine - improvements over treatment as usual; delay device - improvements in IELT when added to stop-start technique; yoga - improved IELT over baseline, fluoxetine better than yoga. Treatment-related AEs were evident with most pharmacological interventions. LIMITATIONS Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report. CONCLUSIONS Several interventions significantly improved IELT. Many interventions also improved sexual satisfaction and other outcomes. However, assessment of longer-term safety and effectiveness is required to evaluate whether or not initial treatment effects are maintained long term, whether or not dose escalation is required, how soon treatment effects end following treatment cessation and whether or not treatments can be stopped and resumed at a later time. In addition, assessment of the AEs associated with long-term treatment and whether or not different doses have differing AE profiles is required. STUDY REGISTRATION This study is registered as PROSPERO CRD42013005289. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Systematic review and meta-analysis of additional technologies to enhance angioplasty for infrainguinal peripheral arterial occlusive disease.

There are several additional techniques designed to enhance conventional percutaneous transluminal balloon angioplasty (PTA). This systematic review assessed current evidence on the clinical effectiveness of additional techniques for infrainguinal peripheral arterial occlusive disease (PAD).

Tramadol for premature ejaculation: a systematic review and meta-analysis

BackgroundTramadol is a centrally acting analgesic prescribed off-label for the treatment of premature ejaculation (PE). However, tramadol may cause addiction and difficulty in breathing and the beneficial effect of tramadol in PE is yet not supported by a high level of evidence. The purpose of this study was to systematically review the evidence from randomised controlled trials (RCT) for tramadol in the management of PE.MethodsWe searched bibliographic databases including MEDLINE to August 2014 for RCTs. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. Between-group differences in IELT and other outcomes were pooled across RCTs in a meta-analysis. Statistical and clinical between-trial heterogeneity was assessed.ResultsA total of eight RCTs that evaluated tramadol against a comparator were included. The majority of RCTs were of unclear methodological quality due to limited reporting. Pooled evidence (four RCTs, 721 participants), suggests that tramadol is significantly more effective than placebo at increasing IELT over eight to 12 weeks (p = 0.0007). However, a high level of statistical heterogeneity is evident (I-squared = 74%). Single RCT evidence indicates that tramadol is significantly more effective than paroxetine taken on-demand, sildenafil, lidocaine gel, or behavioural therapy on IELT in men with PE. Tramadol is associated with significantly more adverse events including: erectile dysfunction, constipation, nausea, headache, somnolence, dry mouth, dizziness, pruritus, and vomiting, than placebo or behavioural therapy over eight to 12 weeks of treatment. However, addiction problems or breathing difficulties reported by patients for PE is not assessed in the current evidence base.ConclusionsTramadol appears effective in the treatment of PE. However, these findings should be interpreted with caution given the observed levels of between-trial heterogeneity and the reporting quality of the available evidence. The variability across placebo-controlled trials in terms of the tramadol dose evaluated and the treatment duration does not permit any assessment of a safe and effective minimum daily dose. The long-term effects and side effects, including addiction potential, for men with PE have not been evaluated in the current evidence base.Trial registrationThe review is registered on PROSPERO 2013:CRD42013005289.