Steven J Edwards

Clinical effectiveness and cost-effectiveness of interventions for the treatment of anogenital warts: systematic review and economic evaluation

BACKGROUND Typically occurring on the external genitalia, anogenital warts (AGWs) are benign epithelial skin lesions caused by human papillomavirus infection. AGWs are usually painless but can be unsightly and physically uncomfortable, and affected people might experience psychological distress. The evidence base on the clinical effectiveness and cost-effectiveness of treatments for AGWs is limited. OBJECTIVES To systematically review the evidence on the clinical effectiveness of medical and surgical treatments for AGWs and to develop an economic model to estimate the cost-effectiveness of the treatments. DATA SOURCES Electronic databases (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Web of Science) were searched from inception (or January 2000 for Web of Science) to September 2014. Bibliographies of relevant systematic reviews were hand-searched to identify potentially relevant studies. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for ongoing and planned studies. REVIEW METHODS A systematic review of the clinical effectiveness literature was carried out according to standard methods and a mixed-treatment comparison (MTC) undertaken. The model implemented for each outcome was that with the lowest deviance information criterion. A de novo economic model was developed to assess cost-effectiveness from the perspective of the UK NHS. The model structure was informed through a systematic review of the economic literature and in consultation with clinical experts. Effectiveness data were obtained from the MTC. Costs were obtained from the literature and standard UK sources. RESULTS Of 4232 titles and abstracts screened for inclusion in the review of clinical effectiveness, 60 randomised controlled trials (RCTs) evaluating 19 interventions were included. Analysis by MTC indicated that ablative techniques were typically more effective than topical interventions at completely clearing AGWs at the end of treatment. Podophyllotoxin 0.5% solution (Condyline(®), Takeda Pharmaceutical Company Ltd; Warticon(®) solution, Stiefel Laboratories Ltd) was found to be the most effective topical treatment evaluated. Networks for other outcomes included fewer treatments, which restrict conclusions on the comparative effectiveness of interventions. In total, 84 treatment strategies were assessed using the economic model. Podophyllotoxin 0.5% solution first line followed by carbon dioxide (CO2) laser therapy second line if AGWs did not clear was most likely to be considered a cost-effective use of resources at a willingness to pay of £20,000-30,000 per additional quality-adjusted life-year gained. The result was robust to most sensitivity analyses conducted. LIMITATIONS Limited reporting in identified studies of baseline characteristics for the enrolled population generates uncertainty around the comparability of the study populations and therefore the generalisability of the results to clinical practice. Subgroup analyses were planned based on type, number and size of AGWs, all of which are factors thought to influence treatment effect. Lack of data on clinical effectiveness based on these characteristics precluded analysis of the differential effects of treatments in the subgroups of interest. Despite identification of 60 studies, most comparisons in the MTC are informed by only one RCT. Additionally, lack of head-to-head RCTs comparing key treatments, together with minimal reporting of results in some studies, precluded comprehensive analysis of all treatments for AGWs. CONCLUSIONS The results generated by the MTC are in agreement with consensus opinion that ablative techniques are clinically more effective at completely clearing AGWs after treatment. However, the evidence base informing the MTC is limited. A head-to-head RCT that evaluates the comparative effectiveness of interventions used in clinical practice would help to discern the potential advantages and disadvantages of the individual treatments. The results of the economic analysis suggest that podophyllotoxin 0.5% solution is likely to represent a cost-effective first-line treatment option. More expensive effective treatments, such as CO2 laser therapy or surgery, may represent cost-effective second-line treatment options. No treatment and podophyllin are unlikely to be considered cost-effective treatment options. There is uncertainty around the cost-effectiveness of treatment with imiquimod, trichloroacetic acid and cryotherapy. STUDY REGISTRATION This study is registered as PROSPERO CRD42013005457. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation

BACKGROUND Ovarian cancer is the fifth most common cancer in the UK, and the fourth most common cause of cancer death. Of those people successfully treated with first-line chemotherapy, 55-75% will relapse within 2 years. At this time, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrent, advanced ovarian cancer. OBJECTIVES To determine the comparative clinical effectiveness and cost-effectiveness of topotecan (Hycamtin(®), GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (PLDH; Caelyx(®), Schering-Plough), paclitaxel (Taxol(®), Bristol-Myers Squibb), trabectedin (Yondelis(®), PharmaMar) and gemcitabine (Gemzar(®), Eli Lilly and Company) for the treatment of advanced, recurrent ovarian cancer. DATA SOURCES Electronic databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) and trial registries were searched, and company submissions were reviewed. Databases were searched from inception to May 2013. METHODS A systematic review of the clinical and economic literature was carried out following standard methodological principles. Double-blind, randomised, placebo-controlled trials, evaluating topotecan, PLDH, paclitaxel, trabectedin and gemcitabine, and economic evaluations were included. A network meta-analysis (NMA) was carried out. A de novo economic model was developed. RESULTS For most outcomes measuring clinical response, two networks were constructed: one evaluating platinum-based regimens and one evaluating non-platinum-based regimens. In people with platinum-sensitive disease, NMA found statistically significant benefits for PLDH plus platinum, and paclitaxel plus platinum for overall survival (OS) compared with platinum monotherapy. PLDH plus platinum significantly prolonged progression-free survival (PFS) compared with paclitaxel plus platinum. Of the non-platinum-based treatments, PLDH monotherapy and trabectedin plus PLDH were found to significantly increase OS, but not PFS, compared with topotecan monotherapy. In people with platinum-resistant/-refractory (PRR) disease, NMA found no statistically significant differences for any treatment compared with alternative regimens in OS and PFS. Economic modelling indicated that, for people with platinum-sensitive disease and receiving platinum-based therapy, the estimated probabilistic incremental cost-effectiveness ratio [ICER; incremental cost per additional quality-adjusted life-year (QALY)] for paclitaxel plus platinum compared with platinum was £24,539. Gemcitabine plus carboplatin was extendedly dominated, and PLDH plus platinum was strictly dominated. For people with platinum-sensitive disease and receiving non-platinum-based therapy, the probabilistic ICERs associated with PLDH compared with paclitaxel, and trabectedin plus PLDH compared with PLDH, were estimated to be £25,931 and £81,353, respectively. Topotecan was strictly dominated. For people with PRR disease, the probabilistic ICER associated with topotecan compared with PLDH was estimated to be £324,188. Paclitaxel was strictly dominated. LIMITATIONS As platinum- and non-platinum-based treatments were evaluated separately, the comparative clinical effectiveness and cost-effectiveness of these regimens is uncertain in patients with platinum-sensitive disease. CONCLUSIONS For platinum-sensitive disease, it was not possible to compare the clinical effectiveness and cost-effectiveness of platinum-based therapies with non-platinum-based therapies. For people with platinum-sensitive disease and treated with platinum-based therapies, paclitaxel plus platinum could be considered cost-effective compared with platinum at a threshold of £30,000 per additional QALY. For people with platinum-sensitive disease and treated with non-platinum-based therapies, it is unclear whether PLDH would be considered cost-effective compared with paclitaxel at a threshold of £30,000 per additional QALY; trabectedin plus PLDH is unlikely to be considered cost-effective compared with PLDH. For patients with PRR disease, it is unlikely that topotecan would be considered cost-effective compared with PLDH. Randomised controlled trials comparing platinum with non-platinum-based treatments might help to verify the comparative effectiveness of these regimens. STUDY REGISTRATION This study is registered as PROSPERO CRD42013003555. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The use of fibrin sealant during non-emergency surgery: a systematic review of evidence of benefits and harms

BACKGROUND Fibrin sealants are used in different types of surgery to prevent the accumulation of post-operative fluid (seroma) or blood (haematoma) or to arrest haemorrhage (bleeding). However, there is uncertainty around the benefits and harms of fibrin sealant use. OBJECTIVES To systematically review the evidence on the benefits and harms of fibrin sealants in non-emergency surgery in adults. DATA SOURCES Electronic databases [MEDLINE, EMBASE and The Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and the Cochrane Central Register of Controlled Trials)] were searched from inception to May 2015. The websites of regulatory bodies (the Medicines and Healthcare products Regulatory Agency, the European Medicines Agency and the Food and Drug Administration) were also searched to identify evidence of harms. REVIEW METHODS This review included randomised controlled trials (RCTs) and observational studies using any type of fibrin sealant compared with standard care in non-emergency surgery in adults. The primary outcome was risk of developing seroma and haematoma. Only RCTs were used to inform clinical effectiveness and both RCTs and observational studies were used for the assessment of harms related to the use of fibrin sealant. Two reviewers independently screened all titles and abstracts to identify potentially relevant studies. Data extraction was undertaken by one reviewer and validated by a second. The quality of included studies was assessed independently by two reviewers using the Cochrane Collaboration risk-of-bias tool for RCTs and the Centre for Reviews and Dissemination guidance for adverse events for observational studies. A fixed-effects model was used for meta-analysis. RESULTS We included 186 RCTs and eight observational studies across 14 surgical specialties and five reports from the regulatory bodies. Most RCTs were judged to be at an unclear risk of bias. Adverse events were inappropriately reported in observational studies. Meta-analysis across non-emergency surgical specialties did not show a statistically significant difference in the risk of seroma for fibrin sealants versus standard care in 32 RCTs analysed [n = 3472, odds ratio (OR) 0.84, 95% confidence interval (CI) 0.68 to 1.04; p = 0.13; I2 = 12.7%], but a statistically significant benefit was found on haematoma development in 24 RCTs (n = 2403, OR 0.62, 95% CI 0.44 to 0.86; p = 0.01; I2 = 0%). Adverse events related to fibrin sealant use were reported in 10 RCTs and eight observational studies across surgical specialties, and 22 RCTs explicitly stated that there were no adverse events. One RCT reported a single death but no other study reported mortality or any serious adverse events. Five regulatory body reports noted death from air emboli associated with fibrin sprays. LIMITATIONS It was not possible to provide a detailed evaluation of individual RCTs in their specific contexts because of the limited resources that were available for this research. In addition, the number of RCTs that were identified made it impractical to conduct independent data extraction by two reviewers in the time available. CONCLUSIONS The effectiveness of fibrin sealants does not appear to vary according to surgical procedures with regard to reducing the risk of seroma or haematoma. Surgeons should note the potential risk of gas embolism if spray application of fibrin sealants is used and not to exceed the recommended pressure and spraying distance. Future research should be carried out in surgery specialties for which only limited data were found, including neurological, gynaecological, oral and maxillofacial, urology, colorectal and orthopaedics surgery (for any outcome); breast surgery and upper gastrointestinal (development of haematoma); and cardiothoracic heart or lung surgery (reoperation rates). In addition, studies need to use adequate sample sizes, to blind participants and outcome assessors, and to follow reporting guidelines. STUDY REGISTRATION This study is registered as PROSPERO CRD42015020710. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Interventions for treating hyperemesis gravidarum: a Cochrane systematic review and meta-analysis

Abstract Introduction: While nausea and vomiting in early pregnancy are very common, affecting approximately 80% of the pregnancies, hyperemesis gravidarum is a severe form affecting 0.3–1.0% of the pregnancies. Although hyperemesis gravidarum is rarely a source of mortality, it is a significant source of morbidity. It is one of the most common indications for hospitalization in pregnancy. Beyond the maternal and fetal consequences of malnutrition, the severity of hyperemesis symptoms causes a major psychosocial burden leading to depression, anxiety, and even pregnancy termination. The aim of this meta-analysis was to examine all randomized controlled trials of interventions specifically for hyperemesis gravidarum and evaluate them based on both subjective and objective measures of efficacy, maternal and fetal/neonatal safety, and economic costs. Material and methods: Randomized controlled trials were identified by searching electronic databases. We included all randomized controlled trials for the treatment of hyperemesis gravidarum. The primary outcome was intervention efficacy as defined by severity, reduction, or cessation in nausea/vomiting; number of episodes of emesis; and days of hospital admission. Secondary outcomes included other measures of intervention efficacy, adverse maternal/fetal/neonatal outcomes, quality of life measures, and economic costs. Results: Twenty-five trials (2052 women) met the inclusion criteria but the majority of 18 different comparisons described in the review include data from single studies with small numbers of participants. Selected comparisons reported below: No primary outcome data were available when acupuncture was compared with placebo. There was insufficient evidence to identify clear differences between acupuncture and metoclopramide in a study with 81 participants regarding reduction/cessation in nausea or vomiting (risk ratio (RR) 1.40, 95% CI 0.79–2.49 and RR 1.51, 95% CI 0.92–2.48, respectively). Midwife-led outpatient care was associated with fewer hours of hospital admission than routine inpatient admission (mean difference (MD) − 33.20, 95% CI −46.91 to −19.49) with no difference in pregnancy-unique quantification of emesis and nausea (PUQE) score, decision to terminate the pregnancy, miscarriage, small-for-gestational age infants, or time off work when compared with routine care. Women taking vitamin B6 had a slightly longer hospital stay compared with placebo (MD 0.80 days, 95% CI 0.08–1.52). There was insufficient evidence to demonstrate a difference in other outcomes including mean number of episodes of emesis (MD 0.50, 95% CI −0.40–1.40) or side effects. A comparison between metoclopramide and ondansetron identified no clear difference in the severity of nausea or vomiting (MD 1.70, 95% CI −0.15–3.55, and MD −0.10, 95% CI −1.63–1.43; one study, 83 women, respectively). However, more women taking metoclopramide complained of drowsiness and dry mouth (RR 2.40, 95% CI 1.23–4.69, and RR 2.38, 95% CI 1.10–5.11, respectively). There were no clear differences between groups for other side effects. In a single study with 146 participants comparing metoclopramide with promethazine, more women taking promethazine reported drowsiness, dizziness, and dystonia (risk ratio (RR) 0.70, 95% CI 0.56–0.87, RR 0.48, 95% CI 0.34–0.69, and RR 0.31, 95% CI 0.11–0.90, respectively). There were no clear differences between groups for other important outcomes including quality of life and other side effects. In a single trial with 30 women, those receiving ondansetron had no difference in duration of hospital admission compared to those receiving promethazine (mean difference (MD) 0.00, 95% CI −1.39–1.39), although there was increased sedation with promethazine (RR 0.06, 95% CI 0.00–0.94). Regarding corticosteroids, in a study with 110 participants there was no difference in days of hospital admission compared to placebo (MD −0.30, 95% CI −0.70–0.10), but there was a decreased readmission rate (RR 0.69, 95% CI 0.50–0.94; 4 studies, 269 women). For hydrocortisone compared with metoclopramide, no data were available for primary outcomes and there was no difference in the readmission rate (RR 0.08, 95% CI 0.00–1.28; one study, 40 women). In a study with 80 women, compared to promethazine, those receiving prednisolone had increased nausea at 48 h (RR 2.00, 95% CI 1.08–3.72), but not at 17 days (RR 0.81, 95% CI 0.58–1.15). There was no clear difference in the number of episodes of emesis or subjective improvement in nausea/vomiting. Conclusions: While there were a wide range of interventions studied, both pharmaceutical and otherwise, there were a limited number of placebo controlled trials. In comparing the efficacy of the commonly used antiemetics, metoclopramide, ondansetron, and promethazine, the results of this review do not support the clear superiority of one over the other in symptomatic relief. Other factors such as side effect profile medication safety and healthcare costs should also be considered when selecting an intervention.

Dual-chamber pacemakers for treating symptomatic bradycardia due to sick sinus syndrome without atrioventricular block: a systematic review and economic evaluation.

BACKGROUND Bradycardia [resting heart rate below 60 beats per minute (b.p.m.)] can be caused by conditions affecting the natural pacemakers of the heart, such as sick sinus syndrome (SSS) and atrioventricular (AV) blocks. People suffering from bradycardia may present with palpitations, exercise intolerance and fainting. The only effective treatment for patients suffering from symptomatic bradycardia is implantation of a permanent pacemaker. OBJECTIVE To appraise the clinical effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber atrial pacemakers for treating symptomatic bradycardia in people with SSS and no evidence of AV block. DATA SOURCES All databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) were searched from inception to June 2014. METHODS A systematic review of the clinical and economic literature was carried out in accordance with the general principles published by the Centre for Reviews and Dissemination. Randomised controlled trials (RCTs) evaluating dual-chamber and single-chamber atrial pacemakers and economic evaluations were included. Pairwise meta-analysis was carried out. A de novo economic model was developed. RESULTS Of 493 references, six RCTs were included in the review. The results were predominantly influenced by the largest trial DANPACE. Dual-chamber pacing was associated with a statistically significant reduction in reoperation [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.36 to 0.63] compared with single-chamber atrial pacing. The difference is primarily because of the development of AV block requiring upgrade to a dual-chamber device. The risk of paroxysmal atrial fibrillation was also reduced with dual-chamber pacing compared with single-chamber atrial pacing (OR 0.75, 95% CI 0.59 to 0.96). No statistically significant difference was found between the pacing modes for mortality, heart failure, stroke, chronic atrial fibrillation or quality of life. However, the risk of developing heart failure may vary with age and device. The de novo economic model shows that dual-chamber pacemakers are more expensive and more effective than single-chamber atrial devices, resulting in a base-case incremental cost-effectiveness ratio (ICER) of £6506. The ICER remains below £20,000 in probabilistic sensitivity analysis, structural sensitivity analysis and most scenario analyses and one-way sensitivity analyses. The risk of heart failure may have an impact on the decision to use dual-chamber or single-chamber atrial pacemakers. Results from an analysis based on age (> 75 years or ≤ 75 years) and risk of heart failure indicate that dual-chamber pacemakers dominate single-chamber atrial pacemakers (i.e. are less expensive and more effective) in older patients, whereas dual-chamber pacemakers are dominated by (i.e. more expensive and less effective) single-chamber atrial pacemakers in younger patients. However, these results are based on a subgroup analysis and should be treated with caution. CONCLUSIONS In patients with SSS without evidence of impaired AV conduction, dual-chamber pacemakers appear to be cost-effective compared with single-chamber atrial pacemakers. The risk of developing a complete AV block and the lack of tools to identify patients at high risk of developing the condition argue for the implantation of a dual-chamber pacemaker programmed to minimise unnecessary ventricular pacing. However, considerations have to be made around the risk of developing heart failure, which may depend on age and device. STUDY REGISTRATION This study is registered as PROSPERO CRD42013006708. FUNDING The National Institute for Health Research Health Technology Assessment programme.