Contrast-enhanced ultrasound and/or colour duplex ultrasound for surveillance after endovascular abdominal aortic aneurysm repair: a systematic review and economic evaluation.

BACKGROUND: Endovascular abdominal aortic aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) is less invasive than open surgery, but may be associated with important complications. Patients receiving EVAR require long-term surveillance to detect abnormalities and direct treatments. Computed tomography angiography (CTA) has been the most common imaging modality adopted for EVAR surveillance, but it is associated with repeated radiation exposure and the risk of contrast-related nephropathy. Colour duplex ultrasound (CDU) and, more recently, contrast-enhanced ultrasound (CEU) have been suggested as possible, safer, alternatives to CTA. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of imaging strategies, using either CDU or CEU alone or in conjunction with plain radiography, compared with CTA for EVAR surveillance. DATA SOURCES: Major electronic databases were searched, including MEDLINE, EMBASE, Science Citation Index, Scopus' Articles-in-Press, Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database from 1996 onwards. We also searched for relevant ongoing studies and conference proceedings. The final searches were undertaken in September 2016. METHODS: We conducted a systematic review of randomised controlled trials and cohort studies of patients with AAAs who were receiving surveillance using CTA, CDU and CEU with or without plain radiography. Three reviewers were involved in the study selection, data extraction and risk-of-bias assessment. We developed a Markov model based on five surveillance strategies: (1) annual CTA; (2) annual CDU; (3) annual CEU; (4) CDU together with CTA at 1 year, followed by CDU on an annual basis; and (5) CEU together with CTA at 1 year, followed by CEU on an annual basis. All of these strategies also considered plain radiography on an annual basis. RESULTS: We identified two non-randomised comparative studies and 25 cohort studies of interventions, and nine systematic reviews of diagnostic accuracy. Overall, the proportion of patients who required reintervention ranged from 1.1% (mean follow-up of 24 months) to 23.8% (mean follow-up of 32 months). Reintervention was mainly required for patients with thrombosis and types I-III endoleaks. All-cause mortality ranged from 2.7% (mean follow-up of 24 months) to 42% (mean follow-up of 54.8 months). Aneurysm-related mortality occurred in < 1% of the participants. Strategies based on early and mid-term CTA and/or CDU and long-term CDU surveillance were broadly comparable with those based on a combination of CTA and CDU throughout the follow-up period in terms of clinical complications, reinterventions and mortality. The economic evaluation showed that a CDU-based strategy generated lower expected costs and higher quality-adjusted life-year (QALYs) than a CTA-based strategy and has a 63% probability of being cost-effective at a £30,000 willingness-to-pay-per-QALY threshold. A CEU-based strategy generated more QALYs, but at higher costs, and became cost-effective only for high-risk patient groups. LIMITATIONS: Most studies were rated as being at a high or moderate risk of bias. No studies compared CDU with CEU. Substantial clinical heterogeneity precluded a formal synthesis of results. The economic model was hindered by a lack of suitable data. CONCLUSIONS: Current surveillance practice is very heterogeneous. CDU may be a safe and cost-effective alternative to CTA, with CTA being reserved for abnormal/inconclusive CDU cases. FUTURE WORK: Research is needed to validate the safety of modified, more-targeted surveillance protocols based on the use of CDU and CEU. The role of radiography for surveillance after EVAR requires clarification. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016036475. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Bariatric surgery, lifestyle interventions and orlistat for severe obesity: the REBALANCE mixed-methods systematic review and economic evaluation.

BACKGROUND: Adults with severe obesity [body mass index (BMI) of ≥ 35 kg/m2] have an increased risk of comorbidities and psychological, social and economic consequences. OBJECTIVES: Systematically review bariatric surgery, weight-management programmes (WMPs) and orlistat pharmacotherapy for adults with severe obesity, and evaluate the feasibility, acceptability, clinical effectiveness and cost-effectiveness of treatment. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials and the NHS Economic Evaluation Database were searched (last searched in May 2017). REVIEW METHODS: Four systematic reviews evaluated clinical effectiveness, cost-effectiveness and qualitative evidence for adults with a BMI of ≥ 35 kg/m2. Data from meta-analyses populated a microsimulation model predicting costs, outcomes and cost-effectiveness of Roux-en-Y gastric bypass (RYGB) surgery and the most effective lifestyle WMPs over a 30-year time horizon from a NHS perspective, compared with current UK population obesity trends. Interventions were cost-effective if the additional cost of achieving a quality-adjusted life-year is < £20,000-30,000. RESULTS: A total of 131 randomised controlled trials (RCTs), 26 UK studies, 33 qualitative studies and 46 cost-effectiveness studies were included. From RCTs, RYGB produced the greatest long-term weight change [-20.23 kg, 95% confidence interval (CI) -23.75 to -16.71 kg, at 60 months]. WMPs with very low-calorie diets (VLCDs) produced the greatest weight loss at 12 months compared with no WMPs. Adding a VLCD to a WMP gave an additional mean weight change of -4.41 kg (95% CI -5.93 to -2.88 kg) at 12 months. The intensive Look AHEAD WMP produced mean long-term weight loss of 6% in people with type 2 diabetes mellitus (at a median of 9.6 years). The microsimulation model found that WMPs were generally cost-effective compared with population obesity trends. Long-term WMP weight regain was very uncertain, apart from Look AHEAD. The addition of a VLCD to a WMP was not cost-effective compared with a WMP alone. RYGB was cost-effective compared with no surgery and WMPs, but the model did not replicate long-term cost savings found in previous studies. Qualitative data suggested that participants could be attracted to take part in WMPs through endorsement by their health-care provider or through perceiving innovative activities, with WMPs being delivered to groups. Features improving long-term weight loss included having group support, additional behavioural support, a physical activity programme to attend, a prescribed calorie diet or a calorie deficit. LIMITATIONS: Reviewed studies often lacked generalisability to UK settings in terms of participants and resources for implementation, and usually lacked long-term follow-up (particularly for complications for surgery), leading to unrealistic weight regain assumptions. The views of potential and actual users of services were rarely reported to contribute to service design. This study may have failed to identify unpublished UK evaluations. Dual, blinded numerical data extraction was not undertaken. CONCLUSIONS: Roux-en-Y gastric bypass was costly to deliver, but it was the most cost-effective intervention. Adding a VLCD to a WMP was not cost-effective compared with a WMP alone. Most WMPs were cost-effective compared with current population obesity trends. FUTURE WORK: Improved reporting of WMPs is needed to allow replication, translation and further research. Qualitative research is needed with adults who are potential users of, or who fail to engage with or drop out from, WMPs. RCTs and economic evaluations in UK settings (e.g. Tier 3, commercial programmes or primary care) should evaluate VLCDs with long-term follow-up (≥ 5 years). Decision models should incorporate relevant costs, disease states and evidence-based weight regain assumptions. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016040190. FUNDING: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit and Health Economics Research Unit are core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate.

Multiple-frequency bioimpedance devices for fluid management in people with chronic kidney disease receiving dialysis: a systematic review and economic evaluation.

BACKGROUND: Chronic kidney disease (CKD) is a long-term condition requiring treatment such as conservative management, kidney transplantation or dialysis. To optimise the volume of fluid removed during dialysis (to avoid underhydration or overhydration), people are assigned a 'target weight', which is commonly assessed using clinical methods, such as weight gain between dialysis sessions, pre- and post-dialysis blood pressure and patient-reported symptoms. However, these methods are not precise, and measurement devices based on bioimpedance technology are increasingly used in dialysis centres. Current evidence on the role of bioimpedance devices for fluid management in people with CKD receiving dialysis is limited. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of multiple-frequency bioimpedance devices versus standard clinical assessment for fluid management in people with CKD receiving dialysis. DATA SOURCES: We searched major electronic databases [e.g. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Science Citation Index and Cochrane Central Register of Controlled Trials (CENTRAL)] conference abstracts and ongoing studies. There were no date restrictions. Searches were undertaken between June and October 2016. REVIEW METHODS: Evidence was considered from randomised controlled trials (RCTs) comparing fluid management by multiple-frequency bioimpedance devices and standard clinical assessment in people receiving dialysis, and non-randomised studies evaluating the use of the devices for fluid management in people receiving dialysis. One reviewer extracted data and assessed the risk of bias of included studies. A second reviewer cross-checked the extracted data. Standard meta-analyses techniques were used to combine results from included studies. A Markov model was developed to assess the cost-effectiveness of the interventions. RESULTS: Five RCTs (with 904 adult participants) and eight non-randomised studies (with 4915 adult participants) assessing the use of the Body Composition Monitor [(BCM) Fresenius Medical Care, Bad Homburg vor der Höhe, Germany] were included. Both absolute overhydration and relative overhydration were significantly lower in patients evaluated using BCM measurements than for those evaluated using standard clinical methods [weighted mean difference -0.44, 95% confidence interval (CI) -0.72 to -0.15, p = 0.003, I2 = 49%; and weighted mean difference -1.84, 95% CI -3.65 to -0.03; p = 0.05, I2 = 52%, respectively]. Pooled effects of bioimpedance monitoring on systolic blood pressure (SBP) (mean difference -2.46 mmHg, 95% CI -5.07 to 0.15 mmHg; p = 0.06, I2 = 0%), arterial stiffness (mean difference -1.18, 95% CI -3.14 to 0.78; p = 0.24, I2 = 92%) and mortality (hazard ratio = 0.689, 95% CI 0.23 to 2.08; p = 0.51) were not statistically significant. The economic evaluation showed that, when dialysis costs were included in the model, the probability of bioimpedance monitoring being cost-effective ranged from 13% to 26% at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained. With dialysis costs excluded, the corresponding probabilities of cost-effectiveness ranged from 61% to 67%. LIMITATIONS: Lack of evidence on clinically relevant outcomes, children receiving dialysis, and any multifrequency bioimpedance devices, other than the BCM. CONCLUSIONS: BCM used in addition to clinical assessment may lower overhydration and potentially improve intermediate outcomes, such as SBP, but effects on mortality have not been demonstrated. If dialysis costs are not considered, the incremental cost-effectiveness ratio falls below £20,000, with modest effects on mortality and/or hospitalisation rates. The current findings are not generalisable to paediatric populations nor across other multifrequency bioimpedance devices. FUTURE WORK: Services that routinely use the BCM should report clinically relevant intermediate and long-term outcomes before and after introduction of the device to extend the current evidence base. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016041785. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Assessing the performance of methodological search filters to improve the efficiency of evidence information retrieval: five literature reviews and a qualitative study.

BACKGROUND: Effective study identification is essential for conducting health research, developing clinical guidance and health policy and supporting health-care decision-making. Methodological search filters (combinations of search terms to capture a specific study design) can assist in searching to achieve this. OBJECTIVES: This project investigated the methods used to assess the performance of methodological search filters, the information that searchers require when choosing search filters and how that information could be better provided. METHODS: Five literature reviews were undertaken in 2010/11: search filter development and testing; comparison of search filters; decision-making in choosing search filters; diagnostic test accuracy (DTA) study methods; and decision-making in choosing diagnostic tests. We conducted interviews and a questionnaire with experienced searchers to learn what information assists in the choice of search filters and how filters are used. These investigations informed the development of various approaches to gathering and reporting search filter performance data. We acknowledge that there has been a regrettable delay between carrying out the project, including the searches, and the publication of this report, because of serious illness of the principal investigator. RESULTS: The development of filters most frequently involved using a reference standard derived from hand-searching journals. Most filters were validated internally only. Reporting of methods was generally poor. Sensitivity, precision and specificity were the most commonly reported performance measures and were presented in tables. Aspects of DTA study methods are applicable to search filters, particularly in the development of the reference standard. There is limited evidence on how clinicians choose between diagnostic tests. No published literature was found on how searchers select filters. Interviewing and questioning searchers via a questionnaire found that filters were not appropriate for all tasks but were predominantly used to reduce large numbers of retrieved records and to introduce focus. The Inter Technology Appraisal Support Collaboration (InterTASC) Information Specialists' Sub-Group (ISSG) Search Filters Resource was most frequently mentioned by both groups as the resource consulted to select a filter. Randomised controlled trial (RCT) and systematic review filters, in particular the Cochrane RCT and the McMaster Hedges filters, were most frequently mentioned. The majority indicated that they used different filters depending on the requirement for sensitivity or precision. Over half of the respondents used the filters available in databases. Interviewees used various approaches when using and adapting search filters. Respondents suggested that the main factors that would make choosing a filter easier were the availability of critical appraisals and more detailed performance information. Provenance and having the filter available in a central storage location were also important. LIMITATIONS: The questionnaire could have been shorter and could have included more multiple choice questions, and the reviews of filter performance focused on only four study designs. CONCLUSIONS: Search filter studies should use a representative reference standard and explicitly report methods and results. Performance measures should be presented systematically and clearly. Searchers find filters useful in certain circumstances but expressed a need for more user-friendly performance information to aid filter choice. We suggest approaches to use, adapt and report search filter performance. Future work could include research around search filters and performance measures for study designs not addressed here, exploration of alternative methods of displaying performance results and numerical synthesis of performance comparison results. FUNDING: The National Institute for Health Research (NIHR) Health Technology Assessment programme and Medical Research Council-NIHR Methodology Research Programme (grant number G0901496).

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review.

BACKGROUND: Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. OBJECTIVES: To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. DATA SOURCES: We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. METHODS: Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis. RESULTS: Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001). LIMITATIONS: Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors. CONCLUSIONS: Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014101. FUNDING: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

The clinical effectiveness and cost-effectiveness of open mesh repairs in adults presenting with a clinically diagnosed primary unilateral inguinal hernia who are operated in an elective setting: systematic review and economic evaluation.

BACKGROUNDS: Current open mesh techniques for inguinal hernia repair have shown similar recurrence rates. However, chronic pain has been associated with Lichtenstein mesh repair, the most common surgical procedure for inguinal hernia in the UK. The position of the mesh is probably an important factor. The Lichtenstein method requires dissection of the inguinal wall and fixation of the mesh. In contrast, in the open preperitoneal approach the mesh is placed in the preperitoneal space and held in place with intra-abdominal pressure. Currently, there is no consensus regarding the best open approach for repair of inguinal hernia. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of open preperitoneal mesh repair compared with Lichtenstein mesh repair in adults presenting with a clinically diagnosed primary unilateral inguinal hernia. DATA SOURCES: We searched major electronic databases (e.g. MEDLINE, MEDLINE In-Process & Other Non-Indexed, EMBASE, Cochrane Controlled Trials Register) from inception to November 2014 and contacted experts in the field. REVIEW METHODS: Evidence was considered from randomised controlled trials (RCTs) that compared open preperitoneal mesh repair with Lichtenstein mesh repair for the treatment of inguinal hernia. Two reviewers independently selected studies for inclusion. One reviewer completed data extraction and assessed risk of bias for included studies, and two reviewers independently cross-checked the details extracted. Meta-analyses techniques were used to combine results from included studies. A Markov model was developed to assess the cost-effectiveness of open mesh procedures from a NHS health services perspective over a 25-year time horizon. RESULTS: Twelve RCTs involving 1568 participants were included. Participants who underwent open preperitoneal mesh repair returned to work and normal activities significantly earlier than those who underwent Lichtenstein mesh repair [mean difference -1.49 days, 95% confidence interval (CI) -2.78 to -0.20 days]. Although no significant differences were observed between the two open approaches for incidence of pain [risk ratio (RR) 0.50, 95% CI 0.20 to 1.27], numbness (RR 0.48, 95% CI 0.15 to 1.56), recurrences (Peto odds ratio 0.76, 95% CI 0.38 to 1.52) or postoperative complications, fewer events were generally reported after open preperitoneal mesh repair. The results of the economic evaluation indicate that the open preperitoneal mesh repair was £256 less costly and improved health outcomes by 0.041 quality-adjusted life-years (QALYs) compared with Lichtenstein mesh repair. The open preperitoneal procedure was the most efficient and dominant treatment strategy with a high (> 98%) probability of being cost-effectiveness for the NHS at a willingness to pay of £20,000 for a QALY. Results were robust to a range of sensitivity analyses. However, the magnitude of cost saving or QALY gain was sensitive to some model assumptions. LIMITATIONS: Overall, the included trials were of small sample size (mean 130.7 participants) and at high or unclear risk of bias. Meta-analyses results demonstrated significant statistical heterogeneity for most of the assessed outcomes. CONCLUSIONS: Open preperitoneal mesh repair appears to be a safe and efficacious alternative to Lichtenstein mesh repair. Further research is required to determine the long-term effects of these surgical procedures as well as the most effective open preperitoneal repair technique in terms of both clinical efficacy and costs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013510. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation.

BACKGROUND: Dupuytren's disease is a slowly progressive condition of the hand, characterised by the formation of nodules in the palm that gradually develop into fibrotic cords. Contracture of the cords produces deformities of the fingers. Surgery is recommended for moderate and severe contractures, but complications and/or recurrences are frequent. Collagenase clostridium histolyticum (CCH) has been developed as a minimally invasive alternative to surgery for some patients. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of collagenase as an alternative to surgery for adults with Dupuytren's contracture with a palpable cord. DATA SOURCES: We searched all major electronic databases from 1990 to February 2014. REVIEW METHODS: Randomised controlled trials (RCTs), non-randomised comparative studies and observational studies involving collagenase and/or surgical interventions were considered. Two reviewers independently extracted data and assessed risk of bias of included studies. A de novo Markov model was developed to assess cost-effectiveness of collagenase, percutaneous needle fasciotomy (PNF) and limited fasciectomy (LF). Results were reported as incremental cost per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were undertaken to investigate model and parameter uncertainty. RESULTS: Five RCTs comparing collagenase with placebo (493 participants), three RCTs comparing surgical techniques (334 participants), two non-randomised studies comparing collagenase and surgery (105 participants), five non-randomised comparative studies assessing various surgical procedures (3571 participants) and 15 collagenase case series (3154 participants) were included. Meta-analyses of RCTs assessing CCH versus placebo were performed. Joints randomised to collagenase were more likely to achieve clinical success. Collagenase-treated participants experienced significant reduction in contracture and an increased range of motion compared with placebo-treated participants. Participants treated with collagenase also experienced significantly more adverse events, most of which were mild or moderate. Four serious adverse events were observed in the collagenase group: two tendon ruptures, one pulley rupture and one complex regional pain syndrome. Two tendon ruptures were also reported in two collagenase case series. Non-randomised studies comparing collagenase with surgery produced variable results and were at high risk of bias. Serious adverse events across surgery studies were low. Recurrence rates ranged from 0% (at 90 days) to 100% (at 8 years) for collagenase and from 0% (at 2.7 years for fasciectomy) to 85% (at 5 years for PNF) for surgery. The results of the de novo economic analysis show that PNF was the cheapest treatment option, whereas LF generated the greatest QALY gains. Collagenase was more costly and generated fewer QALYs compared with LF. LF was £1199 more costly and generated an additional 0.11 QALYs in comparison with PNF. The incremental cost-effectiveness ratio was £10,871 per QALY gained. Two subgroup analyses were conducted for a population of patients with moderate and severe disease and up to two joints affected. In both subgroup analyses, collagenase remained dominated. LIMITATIONS: The main limitation of the review was the lack of head-to-head RCTs comparing collagenase with surgery and the limited evidence base for estimating the effects of specific surgical procedures (fasciectomy and PNF). Substantial differences across studies further limited the comparability of available evidence. The economic model was derived from a naive indirect comparison and was hindered by a lack of suitable data. In addition, there was considerable uncertainty about the appropriateness of many assumptions and parameters used in the model. CONCLUSIONS: Collagenase was significantly better than placebo. There was no evidence that collagenase was clinically better or worse than surgical treatments. LF was the most cost-effective choice to treat moderate to severe contractures, whereas collagenase was not. However, the results of the cost-utility analysis are based on a naive indirect comparison of clinical effectiveness, and a RCT is required to confirm or refute these findings. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006248. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A Systematic Review of Economic Evaluations of the Use of Robotic Assisted Laparoscopy in Surgery Compared with Open or Laparoscopic Surgery.

BACKGROUND: Robot assisted laparoscopic (RAL) surgery developed to overcome the limitations of laparoscopy to assist in surgical procedures, has high capital and operating costs. Systematically assembled evidence demonstrating its clinical and cost effectiveness would be helpful for its adoption by decision makers. OBJECTIVE: To summarise the evidence on the cost-effectiveness of robot-assisted laparoscopic (RAL) surgery compared with relevant alternatives. Methods and results of identified studies were assessed to identify the deficiencies in evidence and areas for further research. METHODS: Studies reporting both costs and outcomes for comparisons of RAL with laparoscopy and/or open surgery were systematically identified. Searches were conducted in February 2015 on MEDLINE, EMBASE and NHS EED. Quality of the included studies was assessed against a standard checklist for economic analyses. Length of hospital stay and operating time (determinants of cost), cost of intervention, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were extracted. To aid comparison, costs were converted into a common currency and price year (2014 US dollars). RESULTS: Forty-seven eligible studies were identified (full economic evaluation n = 6 and cost analysis n = 41). Economic models were used in 11 (23%) studies. Only three studies used a model considered representative of the disease and clinical pathway with a time-horizon allowing capture of relevant differences in outcomes across strategies. The cost of RAL varied substantially between uses, ranging from US$7011 for hysterectomy to over US$30,000 for radical cystectomy. The majority of estimates were between US$15,000 and US$25,000 per person. In part this difference is explained by the difference between studies in which costs were included. It was also identified to have higher costs than the alternatives it was compared against. Incremental cost per QALY for RAL radical prostatectomy was US$28,801-$31,763 over a 10-year period assuming 200 cases per annum. CONCLUSION: The clinical evidence available for RAL overall and used within included studies is limited. RAL surgery costs were consistently higher than open and laparoscopic surgery. Therefore, in adopting the robotic technology decision makers need to take into account the cost effectiveness within their own systems. Economic models generated and published for radical prostatectomy and hysterectomy may be adapted to other health systems if the care pathway is similar to provide locally relevant data.

Ablative therapy for people with localised prostate cancer: a systematic review and economic evaluation.

BACKGROUND: For people with localised prostate cancer, active treatments are effective but have significant side effects. Minimally invasive treatments that destroy (or ablate) either the entire gland or the part of the prostate with cancer may be as effective and cause less side effects at an acceptable cost. Such therapies include cryotherapy, high-intensity focused ultrasound (HIFU) and brachytherapy, among others. OBJECTIVES: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of ablative therapies compared with radical prostatectomy (RP), external beam radiotherapy (EBRT) and active surveillance (AS) for primary treatment of localised prostate cancer, and compared with RP for salvage treatment of localised prostate cancer which has recurred after initial treatment with EBRT. DATA SOURCES: MEDLINE (1946 to March week 3, 2013), MEDLINE In-Process & Other Non-Indexed Citations (29 March 2013), EMBASE (1974 to week 13, 2013), Bioscience Information Service (BIOSIS) (1956 to 1 April 2013), Science Citation Index (1970 to 1 April 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2013), Cochrane Database of Systematic Reviews (CDSR) (issue 3, 2013), Database of Abstracts of Reviews of Effects (DARE) (inception to March 2013) and Health Technology Assessment (HTA) (inception to March 2013) databases were searched. Costs were obtained from NHS sources. REVIEW METHODS: Evidence was drawn from randomised controlled trials (RCTs) and non-RCTs, and from case series for the ablative procedures only, in people with localised prostate cancer. For primary therapy, the ablative therapies were cryotherapy, HIFU, brachytherapy and other ablative therapies. The comparators were AS, RP and EBRT. For salvage therapy, the ablative therapies were cryotherapy and HIFU. The comparator was RP. Outcomes were cancer related, adverse effects (functional and procedural) and quality of life. Two reviewers extracted data and carried out quality assessment. Meta-analysis used a Bayesian indirect mixed-treatment comparison. Data were incorporated into an individual simulation Markov model to estimate cost-effectiveness. RESULTS: The searches identified 121 studies for inclusion in the review of patients undergoing primary treatment and nine studies for the review of salvage treatment. Cryotherapy [3995 patients; 14 case series, 1 RCT and 4 non-randomised comparative studies (NRCSs)], HIFU (4000 patients; 20 case series, 1 NRCS) and brachytherapy (26,129 patients; 2 RCTs, 38 NRCSs) studies provided limited data for meta-analyses. All studies were considered at high risk of bias. There was no robust evidence that mortality (4-year survival 93% for cryotherapy, 99% for HIFU, 91% for EBRT) or other cancer-specific outcomes differed between treatments. For functional and quality-of-life outcomes, the paucity of data prevented any definitive conclusions from being made, although data on incontinence rates and erectile dysfunction for all ablative procedures were generally numerically lower than for non-ablative procedures. The safety profiles were comparable with existing treatments. Studies reporting the use of focal cryotherapy suggested that incontinence rates may be better than for whole-gland treatment. Data on AS, salvage treatment and other ablative therapies were too limited. The cost-effectiveness analysis confirmed the uncertainty from the clinical review and that there is no technology which appears superior, on the basis of current evidence, in terms of average cost-effectiveness. The probabilistic sensitivity analyses suggest that a number of ablative techniques are worthy of further research. LIMITATIONS: The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction. CONCLUSIONS: The findings indicate that there is insufficient evidence to form any clear recommendations on the use of ablative therapies in order to influence current clinical practice. Research efforts in the use of ablative therapies in the management of prostate cancer should now be concentrated on the performance of RCTs and the generation of standardised outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002461. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of point-of-care tests (CoaguChek system, INRatio2 PT/INR monitor and ProTime Microcoagulation system) for the self-monitoring of the coagulation status of people receiving long-term vitamin K antagonist therapy, compared with standard UK practice: systematic review and economic evaluation.

BACKGROUND: Self-monitoring (self-testing and self-management) could be a valid option for oral anticoagulation therapy monitoring in the NHS, but current evidence on its clinical effectiveness or cost-effectiveness is limited. OBJECTIVES: We investigated the clinical effectiveness and cost-effectiveness of point-of-care coagulometers for the self-monitoring of coagulation status in people receiving long-term vitamin K antagonist therapy, compared with standard clinic monitoring. DATA SOURCES: We searched major electronic databases (e.g. MEDLINE, MEDLINE In Process & Other Non-Indexed Citations, EMBASE, Bioscience Information Service, Science Citation Index and Cochrane Central Register of Controlled Trials) from 2007 to May 2013. Reports published before 2007 were identified from the existing Cochrane review (major databases searched from inception to 2007). The economic model parameters were derived from the clinical effectiveness review, other relevant reviews, routine sources of cost data and clinical experts' advice. REVIEW METHODS: We assessed randomised controlled trials (RCTs) evaluating self-monitoring in people with atrial fibrillation or heart valve disease requiring long-term anticoagulation therapy. CoaguChek(®) XS and S models (Roche Diagnostics, Basel, Switzerland), INRatio2(®) PT/INR monitor (Alere Inc., San Diego, CA USA), and ProTime Microcoagulation system(®) (International Technidyne Corporation, Nexus Dx, Edison, NJ, USA) coagulometers were compared with standard monitoring. Where possible, we combined data from included trials using standard inverse variance methods. Risk of bias assessment was performed using the Cochrane risk of bias tool. A de novo economic model was developed to assess the cost-effectiveness over a 10-year period. RESULTS: We identified 26 RCTs (published in 45 papers) with a total of 8763 participants. CoaguChek was used in 85% of the trials. Primary analyses were based on data from 21 out of 26 trials. Only four trials were at low risk of bias. Major clinical events: self-monitoring was significantly better than standard monitoring in preventing thromboembolic events [relative risk (RR) 0.58, 95% confidence interval (CI) 0.40 to 0.84; p = 0.004]. In people with artificial heart valves (AHVs), self-monitoring almost halved the risk of thromboembolic events (RR 0.56, 95% CI 0.38 to 0.82; p = 0.003) and all-cause mortality (RR 0.54, 95% CI 0.32 to 0.92; p = 0.02). There was greater reduction in thromboembolic events and all-cause mortality through self-management but not through self-testing. Intermediate outcomes: self-testing, but not self-management, showed a modest but significantly higher percentage of time in therapeutic range, compared with standard care (weighted mean difference 4.44, 95% CI 1.71 to 7.18; p = 0.02). Patient-reported outcomes: improvements in patients' quality of life related to self-monitoring were observed in six out of nine trials. High preference rates were reported for self-monitoring (77% to 98% in four trials). Net health and social care costs over 10 years were £7295 (self-monitoring with INRatio2); £7324 (standard care monitoring); £7333 (self-monitoring with CoaguChek XS) and £8609 (self-monitoring with ProTime). The estimated quality-adjusted life-year (QALY) gain associated with self-monitoring was 0.03. Self-monitoring with INRatio2 or CoaguChek XS was found to have ≈ 80% chance of being cost-effective, compared with standard monitoring at a willingness-to-pay threshold of £20,000 per QALY gained. CONCLUSIONS: Compared with standard monitoring, self-monitoring appears to be safe and effective, especially for people with AHVs. Self-monitoring, and in particular self-management, of anticoagulation status appeared cost-effective when pooled estimates of clinical effectiveness were applied. However, if self-monitoring does not result in significant reductions in thromboembolic events, it is unlikely to be cost-effective, based on a comparison of annual monitoring costs alone. Trials investigating the longer-term outcomes of self-management are needed, as well as direct comparisons of the various point-of-care coagulometers. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004944. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Is self-monitoring an effective option for people receiving long-term vitamin K antagonist therapy? A systematic review and economic evaluation.

OBJECTIVES: To investigate the clinical and cost-effectiveness of self-monitoring of coagulation status in people receiving long-term vitamin K antagonist therapy compared with standard clinic care. DESIGN: Systematic review of current evidence and economic modelling. DATA SOURCES: Major electronic databases were searched up to May 2013. The economic model parameters were derived from the clinical effectiveness review, routine sources of cost data and advice from clinical experts. STUDY ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) comparing self-monitoring versus standard clinical care in people with different clinical conditions. Self-monitoring included both self-management (patients conducted the tests and adjusted their treatment according to an algorithm) and self-testing (patients conducted the tests, but received treatment recommendations from a clinician). Various point-of-care coagulometers were considered. RESULTS: 26 RCTs (8763 participants) were included. Both self-management and self-testing were as safe as standard care in terms of major bleeding events (RR 1.08, 95% CI 0.81 to 1.45, p=0.690, and RR 0.99, 95% CI 0.80 to 1.23, p=0.92, respectively). Self-management was associated with fewer thromboembolic events (RR 0.51, 95% CI 0.37 to 0.69, p ≤ 0.001) and with a borderline significant reduction in all-cause mortality (RR 0.68, 95% CI 0.46 to 1.01, p=0.06) than standard care. Self-testing resulted in a modest increase in time in therapeutic range compared with standard care (weighted mean difference, WMD 4.4%, 95% CI 1.71 to 7.18, p=0.02). Total health and social care costs over 10 years were £7324 with standard care and £7326 with self-monitoring (estimated quality adjusted life year, QALY gain was 0.028). Self-monitoring was found to have ∼ 80% probability of being cost-effective compared with standard care applying a ceiling willingness-to-pay threshold of £20,000 per QALY gained. Within the base case model, applying the pooled relative effect of thromboembolic events, self-management alone was highly cost-effective while self-testing was not. CONCLUSIONS: Self-monitoring appears to be a safe and cost-effective option. TRIAL REGISTRATION NUMBER: PROSPERO CRD42013004944.

Systematic review of the clinical and cost effectiveness of cholecystectomy versus observation/conservative management for uncomplicated symptomatic gallstones or cholecystitis.

BACKGROUND: Gallstone disease is a common gastrointestinal disorder in industrialised countries. Although symptoms can be severe, some people can be symptom free for many years after the original attack. Surgery is the current treatment of choice, but evidence suggests that observation is also feasible and safe. We reviewed the evidence on cholecystectomy versus observation for uncomplicated symptomatic gallstones and conducted a cost-effectiveness analysis. METHODS: We searched six electronic databases (last search April 2014). We included randomised controlled trials (RCTs) or non-randomised comparative studies where adults received either cholecystectomy or observation/conservative management for the first episode of symptomatic gallstone disease (biliary pain or cholecystitis) being considered for surgery in secondary care. Meta-analysis was used to combine results. A de novo Markov model was developed to assess the cost effectiveness of the interventions. RESULTS: Two RCTs (201 participants) were included. Eighty-eight percent of people randomised to surgery and 45 % of people randomised to observation underwent cholecystectomy during the 14-year follow-up period. Participants randomised to observation were significantly more likely to experience gallstone-related complications (RR = 6.69, 95 % CI = 1.57-28.51, p = 0.01), in particular acute cholecystitis (RR = 9.55, 95 % CI = 1.25-73.27, p = 0.03), and less likely to undergo surgery (RR = 0.50, 95 % CI = 0.34-0.73, p = 0.0004) or experience surgery-related complications (RR = 0.36, 95 % CI = 0.16-0.81, p = 0.01) than those randomised to surgery. Fifty-five percent of people randomised to observation did not require surgery, and 12 % of people randomised to cholecystectomy did not undergo surgery. On average, surgery costs £1,236 more per patient than conservative management, but was more effective. CONCLUSIONS: Cholecystectomy is the preferred treatment for symptomatic gallstones. However, approximately half the observation group did not require surgery or suffer complications indicating that it may be a valid alternative to surgery. A multicentre trial is needed to establish the effects, safety and cost effectiveness of observation/conservative management relative to cholecystectomy.

Optical coherence tomography for the monitoring of neovascular age-related macular degeneration: a systematic review.

TOPIC: To compare the accuracy of optical coherence tomography (OCT) with alternative tests for monitoring neovascular age-related macular degeneration (nAMD) and detecting disease activity among eyes previously treated for this condition. CLINICAL RELEVANCE: Traditionally, fundus fluorescein angiography (FFA) has been considered the reference standard to detect nAMD activity, but FFA is costly and invasive. Replacement of FFA by OCT can be justified if there is a substantial agreement between tests. METHODS: Systematic review and meta-analysis. The index test was OCT. The comparator tests were visual acuity, clinical evaluation (slit lamp), Amsler chart, color fundus photographs, infrared reflectance, red-free images and blue reflectance, fundus autofluorescence imaging, indocyanine green angiography (ICGA), preferential hyperacuity perimetry, and microperimetry. We searched the following databases: MEDLINE, MEDLINE In-Process, EMBASE, Biosis, Science Citation Index, the Cochrane Library, Database of Abstracts of Reviews of Effects, MEDION, and the Health Technology Assessment database. The last literature search was conducted in March 2013. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) to assess risk of bias. RESULTS: We included 8 studies involving more than 400 participants. Seven reported the performance of OCT (3 time-domain [TD] OCT, 3 spectral-domain [SD] OCT, 1 both types) and 1 reported the performance of ICGA in the detection of nAMD activity. We did not find studies directly comparing tests in the same population. The pooled sensitivity and specificity of TD OCT and SD OCT for detecting active nAMD was 85% (95% confidence interval [CI], 72%-93%) and 48% (95% CI, 30%-67%), respectively. One study reported ICGA with sensitivity of 75.9% and specificity of 88.0% for the detection of active nAMD. Half of the studies were considered to have a high risk of bias. CONCLUSIONS: There is substantial disagreement between OCT and FFA findings in detecting active disease in patients with nAMD who are being monitored. Both methods may be needed to monitor patients comprehensively with nAMD.

Optical coherence tomography for the diagnosis, monitoring and guiding of treatment for neovascular age-related macular degeneration: a systematic review and economic evaluation.

BACKGROUND: Age-related macular degeneration is the most common cause of sight impairment in the UK. In neovascular age-related macular degeneration (nAMD), vision worsens rapidly (over weeks) due to abnormal blood vessels developing that leak fluid and blood at the macula. OBJECTIVES: To determine the optimal role of optical coherence tomography (OCT) in diagnosing people newly presenting with suspected nAMD and monitoring those previously diagnosed with the disease. DATA SOURCES: Databases searched: MEDLINE (1946 to March 2013), MEDLINE In-Process & Other Non-Indexed Citations (March 2013), EMBASE (1988 to March 2013), Biosciences Information Service (1995 to March 2013), Science Citation Index (1995 to March 2013), The Cochrane Library (Issue 2 2013), Database of Abstracts of Reviews of Effects (inception to March 2013), Medion (inception to March 2013), Health Technology Assessment database (inception to March 2013). REVIEW METHODS: Types of studies: direct/indirect studies reporting diagnostic outcomes. INDEX TEST: time domain optical coherence tomography (TD-OCT) or spectral domain optical coherence tomography (SD-OCT). COMPARATORS: clinical evaluation, visual acuity, Amsler grid, colour fundus photographs, infrared reflectance, red-free images/blue reflectance, fundus autofluorescence imaging, indocyanine green angiography, preferential hyperacuity perimetry, microperimetry. Reference standard: fundus fluorescein angiography (FFA). Risk of bias was assessed using quality assessment of diagnostic accuracy studies, version 2. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic curves. A Markov model was developed (65-year-old cohort, nAMD prevalence 70%), with nine strategies for diagnosis and/or monitoring, and cost-utility analysis conducted. NHS and Personal Social Services perspective was adopted. Costs (2011/12 prices) and quality-adjusted life-years (QALYs) were discounted (3.5%). Deterministic and probabilistic sensitivity analyses were performed. RESULTS: In pooled estimates of diagnostic studies (all TD-OCT), sensitivity and specificity [95% confidence interval (CI)] was 88% (46% to 98%) and 78% (64% to 88%) respectively. For monitoring, the pooled sensitivity and specificity (95% CI) was 85% (72% to 93%) and 48% (30% to 67%) respectively. The FFA for diagnosis and nurse-technician-led monitoring strategy had the lowest cost (£ 39,769; QALYs 10.473) and dominated all others except FFA for diagnosis and ophthalmologist-led monitoring (£ 44,649; QALYs 10.575; incremental cost-effectiveness ratio £ 47,768). The least costly strategy had a 46.4% probability of being cost-effective at £ 30,000 willingness-to-pay threshold. LIMITATIONS: Very few studies provided sufficient information for inclusion in meta-analyses. Only a few studies reported other tests; for some tests no studies were identified. The modelling was hampered by a lack of data on the diagnostic accuracy of strategies involving several tests. CONCLUSIONS: Based on a small body of evidence of variable quality, OCT had high sensitivity and moderate specificity for diagnosis, and relatively high sensitivity but low specificity for monitoring. Strategies involving OCT alone for diagnosis and/or monitoring were unlikely to be cost-effective. Further research is required on (i) the performance of SD-OCT compared with FFA, especially for monitoring but also for diagnosis; (ii) the performance of strategies involving combinations/sequences of tests, for diagnosis and monitoring; (iii) the likelihood of active and inactive nAMD becoming inactive or active respectively; and (iv) assessment of treatment-associated utility weights (e.g. decrements), through a preference-based study. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012001930. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clinical effectiveness and cost-effectiveness of cholecystectomy compared with observation/conservative management for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones or cholecystitis: a systematic review and economic evaluation.

BACKGROUND: Approximately 10-15% of the adult population suffer from gallstone disease, cholelithiasis, with more women than men being affected. Cholecystectomy is the treatment of choice for people who present with biliary pain or acute cholecystitis and evidence of gallstones. However, some people do not experience a recurrence after an initial episode of biliary pain or cholecystitis. As most of the current research focuses on the surgical management of the disease, less attention has been dedicated to the consequences of conservative management. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of cholecystectomy compared with observation/conservative management in people presenting with uncomplicated symptomatic gallstones (biliary pain) or cholecystitis. DATA SOURCES: We searched all major electronic databases (e.g. MEDLINE, EMBASE, Science Citation Index, Bioscience Information Service, Cochrane Central Register of Controlled Trials) from 1980 to September 2012 and we contacted experts in the field. REVIEW METHODS: Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies that enrolled people with symptomatic gallstone disease (pain attacks only and/or acute cholecystitis). Two reviewers independently extracted data and assessed the risk of bias of included studies. Standard meta-analysis techniques were used to combine results from included studies. A de novo Markov model was developed to assess the cost-effectiveness of the interventions. RESULTS: Two Norwegian RCTs involving 201 participants were included. Eighty-eight per cent of people randomised to surgery and 45% of people randomised to observation underwent cholecystectomy during the 14-year follow-up period. Participants randomised to observation were significantly more likely to experience gallstone-related complications [risk ratio = 6.69; 95% confidence interval (CI) 1.57 to 28.51; p = 0.01], in particular acute cholecystitis (risk ratio = 9.55; 95% CI 1.25 to 73.27; p = 0.03), and less likely to undergo surgery (risk ratio = 0.50; 95% CI 0.34 to 0.73; p = 0.0004), experience surgery-related complications (risk ratio = 0.36; 95% CI 0.16 to 0.81; p = 0.01) or, more specifically, minor surgery-related complications (risk ratio = 0.11; 95% CI 0.02 to 0.56; p = 0.008) than those randomised to surgery. Fifty-five per cent of people randomised to observation did not require an operation during the 14-year follow-up period and 12% of people randomised to cholecystectomy did not undergo the scheduled operation. The results of the economic evaluation suggest that, on average, the surgery strategy costs £1236 more per patient than the conservative management strategy but was, on average, more effective. An increase in the number of people requiring surgery while treated conservatively corresponded to a reduction in the cost-effectiveness of the conservative strategy. There was uncertainty around some of the parameters used in the economic model. CONCLUSIONS: The results of this assessment indicate that cholecystectomy is still the treatment of choice for many symptomatic people. However, approximately half of the people in the observation group did not require surgery or suffer complications in the long term indicating that a conservative therapeutic approach may represent a valid alternative to surgery in this group of people. Owing to the dearth of current evidence in the UK setting a large, well-designed, multicentre trial is needed. STUDY REGISTRATION: The study was registered as PROSPERO CRD42012002817. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Assessing methods to specify the target difference for a randomised controlled trial: DELTA (Difference ELicitation in TriAls) review.

BACKGROUND: The randomised controlled trial (RCT) is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to the design and validity of a RCT is a calculation of the number of participants needed (the sample size). The value used to determine the sample size can be considered the 'target difference'. From both a scientific and an ethical standpoint, selecting an appropriate target difference is of crucial importance. Determination of the target difference, as opposed to statistical approaches to calculating the sample size, has been greatly neglected though a variety of approaches have been proposed the current state of the evidence is unclear. OBJECTIVES: The aim was to provide an overview of the current evidence regarding specifying the target difference in a RCT sample size calculation. The specific objectives were to conduct a systematic review of methods for specifying a target difference; to evaluate current practice by surveying triallists; to develop guidance on specifying the target difference in a RCT; and to identify future research needs. DESIGN: The biomedical and social science databases searched were MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, Education Resources Information Center (ERIC) and Scopus for in-press publications. All were searched from 1966 or the earliest date of the database coverage and searches were undertaken between November 2010 and January 2011. There were three interlinked components: (1) systematic review of methods for specifying a target difference for RCTs - a comprehensive search strategy involving an electronic literature search of biomedical and some non-biomedical databases and clinical trials textbooks was carried out; (2) identification of current trial practice using two surveys of triallists - members of the Society for Clinical Trials (SCT) were invited to complete an online survey and respondents were asked about their awareness and use of, and willingness to recommend, methods; one individual per triallist group [UK Clinical Research Collaboration (UKCRC)-registered Clinical Trials Units (CTUs), Medical Research Council (MRC) UK Hubs for Trials Methodology Research and National Institute for Health Research (NIHR) UK Research Design Services (RDS)] was invited to complete a survey; (3) production of a structured guidance document to aid the design of future trials - the draft guidance was developed utilising the results of the systematic review and surveys by the project steering and advisory groups. SETTING: Methodological review incorporating electronic searches, review of books and guidelines, two surveys of experts (membership of an international society and UK- and Ireland-based triallists) and development of guidance. PARTICIPANTS: The two surveys were sent out to membership of the SCT and UK- and Ireland-based triallists. INTERVENTIONS: The review focused on methods for specifying the target difference in a RCT. It was not restricted to any type of intervention or condition. MAIN OUTCOME MEASURES: Methods for specifying the target difference for a RCT were considered. RESULTS: The search identified 11,485 potentially relevant studies. In total, 1434 were selected for full-text assessment and 777 were included in the review. Seven methods to specify the target difference for a RCT were identified - anchor, distribution, health economic, opinion-seeking, pilot study, review of evidence base (RoEB) and standardised effect size (SES) - each having important variations in implementation. A total of 216 of the included studies used more than one method. A total of 180 (15%) responses to the SCT survey were received, representing 13 countries. Awareness of methods ranged from 38% (n =69) for the health economic method to 90% (n =162) for the pilot study. Of the 61 surveys sent out to UK triallist groups, 34 (56%) responses were received. Awareness ranged from 97% (n =33) for the RoEB and pilot study methods to only 41% (n =14) for the distribution method. Based on the most recent trial, all bar three groups (91%, n =30) used a formal method. Guidance was developed on the use of each method and the reporting of the sample size calculation in a trial protocol and results paper. CONCLUSIONS: There is a clear need for greater use of formal methods to determine the target difference and better reporting of its specification. Raising the standard of RCT sample size calculations and the corresponding reporting of them would aid health professionals, patients, researchers and funders in judging the strength of the evidence and ensuring better use of scarce resources. FUNDING: The Medical Research Council UK and the National Institute for Health Research Joint Methodology Research programme.

Relative effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of localised prostate cancer: a systematic review and mixed treatment comparison meta-analysis.

OBJECTIVE: To compare the effectiveness of robot-assisted and standard laparoscopic prostatectomy. METHODS: A care pathway was described. We performed a systematic literature review based on a search of Medline, Medline in Process, Embase, Biosis, Science Citation Index, Cochrane Controlled Trials Register, Current Controlled Trials, Clinical Trials, WHO International Clinical Trials Registry and NIH Reporter, the Health Technology Assessment databases, the Database of Abstracts of Reviews of Effects, and relevant conference abstracts up to 31st October 2010). Additionally, reference lists were scanned, an expert panel consulted, and websites of manufacturers, professional organisations, and regulatory bodies were checked. We selected randomised controlled trials (RCTs) and non-randomised comparative studies, published after 1st January 1995, including men with localised prostate cancer undergoing robot-assisted or laparoscopic prostatectomy compared with the other procedure or with open prostatectomy. Studies where at least 90% of included men had clinical tumour stages T1 to T2 and which reported at least one of our specified outcomes were eligible for inclusion. A mixed-treatment comparison meta-analysis was performed to generate comparative statistics on specified outcomes. RESULTS: We included data from 19 064 men across one RCT and 57 non-randomised comparative reports. Robotic prostatectomy had a lower risk of major intra-operative harms such as organ injury [0.4% robotic vs 2.9% laparoscopic], odds ratio ([OR] {95% credible interval [CrI]} 0.16 [0.03 to 0.76]), and a lower rate of surgical margins positive for cancer [17.6% robotic vs 23.6% laparoscopic], OR [95% CrI] 0.69 [0.51 to 0.96]). There was no evidence of a difference in the proportion of men with urinary incontinence at 12 months (OR [95% CrI] 0.55 [0.09 to 2.84]). There were insufficient data on sexual dysfunction. Surgeon learning rates for the procedures did not differ, although data were limited. CONCLUSIONS: Men undergoing robotic prostatectomy appear to have reduced surgical morbidity, and a lower risk of a positive surgical margin, which may reduce rates of cancer recurrence and the need for further treatment, but considerable uncertainty surrounds these results. We found no evidence that men undergoing robotic prostatectomy are disadvantaged in terms of early outcomes. We were unable to determine longer-term relative effectiveness.

Pazopanib for the first-line treatment of patients with advanced and/or metastatic renal cell carcinoma : a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of pazopanib hydrochloride (GlaxoSmithKline) to submit evidence of the clinical and cost effectiveness of the drug for the first-line treatment of advanced and/or metastatic renal cell carcinoma, as part of the Institute's single technology appraisal (STA) process. The Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The objective of this paper is to summarize the independent review and critique of the evidence submitted for the consideration of the NICE Appraisal Committee and NICE's subsequently issued guidance. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. For progression-free survival (PFS), there was a statistically significant longer survival for pazopanib compared with placebo (as assessed by the ERG, based upon the original manufacturer submission with a clinical cut-off date of 23 May 2008) [median 11.1 vs. 2.8 months; hazard ratio (HR) 0.40; 95 % CI 0.27, 0.60]. Data from the indirect comparison suggested that pazopanib had a greater survival than interferon alpha (IFN-α) [HR 0.512; 95 % CI 0.326, 0.802] but provided no evidence of any difference compared with sunitinib (HR 0.949; 95 % CI 0.575, 1.568). With regard to overall survival, 64 % (n = 99) of patients in the pazopanib arm and 63 % (n = 49) of patients in the placebo arm had died and a total of 51 % (n = 40) of placebo patients had crossed over to receive pazopanib. Although data were provided on an intention-to-treat basis, crossover between therapies made such data difficult to interpret. There was no evidence of any statistically significant difference between pazopanib and best supportive care (HR 0.501; 95 % CI 0.136, 2.348). In the indirect comparison, there were no statistically significant differences between pazopanib and IFN-α (HR 0.627; 95 % CI 0.173, 2.269) or between pazopanib and sunitinib (HR 0.969; 95 % CI 0.359, 2.608). Based upon the work presented including a 12.5 % discount for pazopanib, sunitinib was extendedly dominated by a combination of pazopanib and IFN-α. As a consequence, the incremental cost per QALY for pazopanib versus IFN-α was £38,925. The results were not greatly altered over the range of univariate deterministic sensitivity analyses conducted by the manufacturer but pair-wise probabilistic sensitivity analyses suggested that given a threshold value of £30,000, there is a 54 % probability that pazopanib was preferred to sunitinib, 40 % chance against IFN-α and 47 % chance against best supportive care. The Appraisal Committee concluded that pazopanib should be recommended as a first-line treatment option for people with advanced renal cell carcinoma who have not received prior cytokine therapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and if the manufacturer provides pazopanib with a 12.5 % discount on the list price and provides a possible future rebate linked to the outcome of the head-to-head COMPARZ trial, as agreed under the terms of the patient access scheme and to be confirmed when the COMPARZ trial data are made available.

The effect of primary care management on lipids testing and LDL-C control of elderly patients with comorbidities.

PURPOSE: This article presents results of a randomized clinical trial evaluating the effectiveness of the Medicare Coordinated Care Demonstration, Illinois site, on selected clinical outcomes over 36 months. PRIMARY PRACTICE SETTINGS: Interdisciplinary teams, located at primary care practices, provided case and disease management services to 999 patients. RESULTS: Intervention group patients had higher lipids-testing rates during the first 2 years than control group patients. Once tested, more than 80% of patients in both groups were retested in subsequent years. There were no differences in the percentage of intervention group patients who were in low-density lipoprotein cholesterol (LDL-C) control at program entry and at the end of 36 months as compared with control group patients (maintained control). However, a higher percentage of intervention group patients who were not in the LDL-C control at baseline were in control after 36 months as compared with control group patients (achieved control). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: This study suggests that physician-nurse case management team care has the potential to augment the effectiveness of primary care by increasing adherence to testing protocols among elderly patients with multiple chronic illnesses, but this effect diminishes over time as guidelines are adopted into general practice. It suggests that LDL-C therapeutic control can be improved through increased lipids testing and the use of lipid-lowering medications. The results also indicate that care management strategies targeting more intensive patients versus less intensive patients are cost-effective strategies that can be expanded beyond lipids testing and control to other clinical health status measures.