Inequalities in Uptake and Use of Digital Applications for Home-Monitoring of Neovascular Age-Related Macular Degeneration in an Elderly Visually Impaired Population: The MONARCH Study.

Purpose: To describe inequalities in the Monitoring for Neovascular Age-related Macular Degeneration Reactivation at Home (MONARCH) diagnostic test accuracy study for: recruitment; participants' ability to self-test; and adherence to testing using digital applications during follow-up. Methods: Home-monitoring vision tests included two tests implemented as software applications (apps: MyVisionTrack and MultiBit) on an iPod Touch device. Patients were provided with all hardware required to participate (iPod and MIFI device) and trained to use the apps. Regression models estimated associations of age, sex, Index of Multiple Deprivation, strata of time since first diagnosis, and baseline visual acuity at study entry on outcomes of willingness to participate, ability to perform tests, and adherence to weekly testing. Results: A minority of patients who were approached were willing-in-principle to participate. Increasing age was associated with being unwilling-in-principle to participate. Patients from the most deprived areas had a 47% decrease in odds of being willing compared to those from the middle quintile deprived areas (odds ratio, 0.53; 95% confidence interval = 0.32, 0.88). Increasing age and worse deprivation were not consistently associated either with ability to self-monitor with the index tests, or adherence to weekly testing. Conclusions: Associations of increasing age and worse deprivation index were associated with unwillingness-in-principle to participate despite the provision of hardware' highlighting the potential for inequality with interventions of the kind evaluated. Translational Relevance: The clear evidence of inequalities in participation should prompt future research on ways to encourage adoption of mobile health technologies by underserved populations.

Remote assessment of surgical site infection (SSI) using patient-taken wound images: Development and evaluation of a method for research and routine practice.

BACKGROUND/AIM: Clinical assessment of wounds for surgical site infection (SSI) after hospital discharge is challenging and resource intensive. Remote assessment using digital images may be feasible and expedite SSI diagnosis. Acceptable and accurate methods for this process are needed. This study developed and evaluated the feasibility, acceptability and usability of a method for patients to capture standardised wound images for remote wound assessment to detect SSI. MATERIALS AND METHODS: The work was conducted in two phases. Phase I involved: i) a review of literature to identify key components of photography relevant to taking wound images, ii) development of wound photography instructions for patients and a secure process for transmission of images using electronic survey software and iii) pre-testing of the photography instructions and processing method with a sample of 16 patients using cognitive interviews and observations. Phase II involved a prospective cohort study of 89 patients to evaluate the feasibility, acceptability and usability of the remote method following discharge from hospital after surgery. Quality of the images was assessed by three independent clinical reviewers. RESULTS: Some 21 key components for photographing wounds were identified from 11 documents. Of these, 16 were relevant to include in instructions for patients to photograph their wounds. Pre-testing and subsequent iterations improved understanding and ease of use of the instructions and the process for transmitting images. Fifty-two of 89 (58.4%) patients testing the method remotely took an image of their wound(s) and 46/52 (88.5%) successfully transmitted images. When it was possible to ascertain a reason for not taking/transmitting images, this was primarily health problems (n = 7) or lack of time/poor engagement with the study (n = 4) rather than problems relating to technology/competency (n = 2) or practical issues relating to the wound itself (n = 2). Eighty-seven (85.3%) of the 102 images received were evaluated to be of high quality and sufficient to remotely assess SSI by at least two independent reviewers. CONCLUSION: A simple, standardised and acceptable method for patients to take and transmit wound images suitable for remote assessment of SSI has been developed and tested and is now available for use in routine clinical care and research.

Supraglottic airway device versus tracheal intubation in the initial airway management of out-of-hospital cardiac arrest: the AIRWAYS-2 cluster RCT.

BACKGROUND: When a cardiac arrest occurs, cardiopulmonary resuscitation should be started immediately. However, there is limited evidence about the best approach to airway management during cardiac arrest. OBJECTIVE: The objective was to determine whether or not the i-gel® (Intersurgical Ltd, Wokingham, UK) supraglottic airway is superior to tracheal intubation as the initial advanced airway management strategy in adults with non-traumatic out-of-hospital cardiac arrest. DESIGN: This was a pragmatic, open, parallel, two-group, multicentre, cluster randomised controlled trial. A cost-effectiveness analysis accompanied the trial. SETTING: The setting was four ambulance services in England. PARTICIPANTS: Patients aged ≥ 18 years who had a non-traumatic out-of-hospital cardiac arrest and were attended by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017. Follow-up ended in February 2018. INTERVENTION: Paramedics were randomised 1 : 1 to use tracheal intubation (764 paramedics) or i-gel (759 paramedics) for their initial advanced airway management and were unblinded. MAIN OUTCOME MEASURES: The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred earlier, collected by assessors blinded to allocation. The modified Rankin Scale, a measure of neurological disability, was dichotomised: a score of 0-3 (good outcome) or 4-6 (poor outcome/death). The primary outcome for the economic evaluation was quality-adjusted life-years, estimated using the EuroQol-5 Dimensions, five-level version. RESULTS: A total of 9296 patients (supraglottic airway group, 4886; tracheal intubation group, 4410) were enrolled [median age 73 years; 3373 (36.3%) women]; modified Rankin Scale score was known for 9289 patients. Characteristics were similar between groups. A total of 6.4% (311/4882) of patients in the supraglottic airway group and 6.8% (300/4407) of patients in the tracheal intubation group had a good outcome (adjusted difference in proportions of patients experiencing a good outcome: -0.6%, 95% confidence interval -1.6% to 0.4%). The supraglottic airway group had a higher initial ventilation success rate than the tracheal intubation group [87.4% (4255/4868) vs. 79.0% (3473/4397), respectively; adjusted difference in proportions of patients: 8.3%, 95% confidence interval 6.3% to 10.2%]; however, patients in the tracheal intubation group were less likely to receive advanced airway management than patients in the supraglottic airway group [77.6% (3419/4404) vs. 85.2% (4161/4883), respectively]. Regurgitation rate was similar between the groups [supraglottic airway group, 26.1% (1268/4865); tracheal intubation group, 24.5% (1072/4372); adjusted difference in proportions of patients: 1.4%, 95% confidence interval -0.6% to 3.4%], as was aspiration rate [supraglottic airway group, 15.1% (729/4824); tracheal intubation group, 14.9% (647/4337); adjusted difference in proportions of patients: 0.1%, 95% confidence interval -1.5% to 1.8%]. The longer-term outcomes were also similar between the groups (modified Rankin Scale: at 3 months, odds ratio 0.89, 95% confidence interval 0.69 to 1.14; at 6 months, odds ratio 0.91, 95% confidence interval 0.71 to 1.16). Sensitivity analyses did not alter the overall findings. There were no unexpected serious adverse events. Mean quality-adjusted life-years to 6 months were 0.03 in both groups (supraglottic airway group minus tracheal intubation group difference -0.0015, 95% confidence interval -0.0059 to 0.0028), and total costs were £157 (95% confidence interval -£270 to £583) lower in the tracheal intubation group. Although the point estimate of the incremental cost-effectiveness ratio suggested that tracheal intubation may be cost-effective, the huge uncertainty around this result indicates no evidence of a difference between groups. LIMITATIONS: Limitations included imbalance in the number of patients in each group, caused by unequal distribution of high-enrolling paramedics; crossover between groups; and the fact that participating paramedics, who were volunteers, might not be representative of all paramedics in the UK. Findings may not be applicable to other countries. CONCLUSION: Among patients with out-of-hospital cardiac arrest, randomisation to the supraglottic airway group compared with the tracheal intubation group did not result in a difference in outcome at 30 days. There were no notable differences in costs, outcomes and overall cost-effectiveness between the groups. FUTURE WORK: Future work could compare alternative supraglottic airway types with tracheal intubation; include a randomised trial of bag mask ventilation versus supraglottic airways; and involve other patient populations, including children, people with trauma and people in hospital. TRIAL REGISTRATION: This trial is registered as ISRCTN08256118. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and supported by the NIHR Comprehensive Research Networks and will be published in full in Health Technology Assessment; Vol. 26, No. 21. See the NIHR Journals Library website for further project information.

BACKGROUND: Cardiac arrest is a serious medical emergency in which the heartbeat and breathing stop suddenly. Every year in the UK, a large number of patients (around 123 per 100,000) suffer a cardiac arrest outside hospital. Only 7­9% of these patients survive to leave hospital. The best initial treatment in cardiac arrest is cardiopulmonary resuscitation (commonly known as CPR), during which it is vital to give chest compressions and maintain a clear airway. Two main techniques are used to keep the airway clear: tracheal intubation (inserting a breathing tube into the windpipe) and a supraglottic airway device (a newer device that is inserted less deeply and sits just above the voicebox). Both techniques are used routinely by paramedics in the UK when treating a cardiac arrest, but there is no evidence about which technique is best. The AIRWAYS-2 trial aimed to find out whether or not a supraglottic airway device is better than tracheal intubation. WHO PARTICIPATED AND WHAT WAS INVOLVED?: Paramedics from four UK ambulance services were put into one of two groups at random. One group was randomly chosen to use tracheal intubation and the other group was randomly chosen to use a supraglottic airway device at all adult cardiac arrests they attended for approximately 2 years. Paramedics were able to apply their clinical judgement and use a different device if they felt that this would be best for the patient. A total of 1523 paramedics took part and enrolled 9296 patients. Following cardiac arrest, a patient's recovery was assessed as good or poor (including patients who did not survive). WHAT DID THE TRIAL FIND?: A similar percentage of patients in both groups had a good recovery. There was no evidence to suggest that the supraglottic airway device was any better than tracheal intubation for treating a cardiac arrest.

A semi-Markov model comparing the lifetime cost-effectiveness of mesh prophylaxis to prevent parastomal hernia in patients undergoing end colostomy creation for rectal cancer.

AIM: Parastomal hernia (PSH) is a common problem following colostomy. Using prophylactic mesh during end colostomy creation may reduce PSH incidence, but concerns exist regarding the optimal type of mesh, potential long-term complications, and cost-effectiveness of its use. We evaluated the cost-effectiveness of mesh prophylaxis to prevent PSH in patients undergoing end colostomy creation for rectal cancer. METHODS: We developed a decision-analytical model, stratified by rectal cancer stages I-IV, to estimate the lifetime costs, quality-adjusted life-years (QALYs) and net monetary benefits (NMBs) of synthetic, biologic and no mesh from a UK NHS perspective. We pooled the mesh-related relative risks of PSH from 13 randomised controlled trials (RCTs) and superimposed these on the baseline (no mesh) risk from a population-based cohort. Uncertainty was assessed in sensitivity analyses. RESULTS: Synthetic mesh was less costly and more effective than biologic and no mesh to prevent PSH for all rectal cancer stages. At the willingness-to-pay threshold of £20,000/QALY, the incremental NMBs (95% CI) ranged between £1,706 (£1,692 to £1,720) (stage I) and £684 (£678 to £690) (stage IV) for synthetic versus no mesh, and £2,038 (£1,997 to £2,079) (stage I) and £1,671 (£1,653 to £1,689) (stage IV) for synthetic versus biologic mesh. Synthetic mesh was more cost-effective than no mesh unless the relative risk of PSH was ≥0.95 for stages I-III and ≥0.93 for stage IV. [Correction added on 05 October 2021 after first online publication: The estimation of health outcomes (QALYs) for all three interventions evaluated (synthetic mesh; biologic mesh; no mesh) have been corrected in this version.] CONCLUSIONS: Synthetic mesh was the most cost-effective strategy to prevent the formation of PSH in patients after end colostomy for any rectal cancer stage; however, conclusions are dependent on which subset of RCTs are considered to provide the most robust evidence.

Cost-effectiveness of the i-gel supraglottic airway device compared to tracheal intubation during out-of-hospital cardiac arrest: Findings from the AIRWAYS-2 randomised controlled trial.

AIM: Optimal airway management during out-of-hospital cardiac arrest (OHCA) is uncertain. Complications from tracheal intubation (TI) may be avoided with supraglottic airway (SGA) devices. The AIRWAYS-2 cluster randomised controlled trial (ISRCTN08256118) compared the i-gel SGA with TI as the initial advanced airway management (AAM) strategy by paramedics treating adults with non-traumatic OHCA. This paper reports the trial cost-effectiveness analysis. METHODS: A within-trial cost-effectiveness analysis of the i-gel compared with TI was conducted, with a six-month time horizon, from the perspective of the UK National Health Service (NHS) and personal social services. The primary outcome measure was quality-adjusted life years (QALYs), estimated using the EQ-5D-5L questionnaire. Multilevel linear regression modelling was used to account for clustering by paramedic when combining costs and outcomes. RESULTS: 9296 eligible patients were attended by 1382 trial paramedics and enrolled in the AIRWAYS-2 trial (4410 TI, 4886 i-gel). Mean QALYs to six months were 0.03 in both groups (i-gel minus TI difference -0.0015, 95% CI -0.0059 to 0.0028). Total costs per participant up to six months post-OHCA were £3570 and £3413 in the i-gel and TI groups respectively (mean difference £157, 95% CI -£270 to £583). Based on mean difference point estimates, TI was more effective and less costly than i-gel; however differences were small and there was great uncertainty around these results. CONCLUSION: The small differences between groups in QALYs and costs shows no difference in the cost-effectiveness of the i-gel and TI when used as the initial AAM strategy in adults with non-traumatic OHCA.

Three wound-dressing strategies to reduce surgical site infection after abdominal surgery: the Bluebelle feasibility study and pilot RCT.

BACKGROUND: Surgical site infection (SSI) affects up to 20% of people with a primary closed wound after surgery. Wound dressings may reduce SSI. OBJECTIVE: To assess the feasibility of a multicentre randomised controlled trial (RCT) to evaluate the effectiveness and cost-effectiveness of dressing types or no dressing to reduce SSI in primary surgical wounds. DESIGN: Phase A - semistructured interviews, outcome measure development, practice survey, literature reviews and value-of-information analysis. Phase B - pilot RCT with qualitative research and questionnaire validation. Patients and the public were involved. SETTING: Usual NHS care. PARTICIPANTS: Patients undergoing elective/non-elective abdominal surgery, including caesarean section. INTERVENTIONS: Phase A - none. Phase B - simple dressing, glue-as-a-dressing (tissue adhesive) or 'no dressing'. MAIN OUTCOME MEASURES: Phase A - pilot RCT design; SSI, patient experience and wound management questionnaires; dressing practices; and value-of-information of a RCT. Phase B - participants screened, proportions consented/randomised; acceptability of interventions; adherence; retention; validity and reliability of SSI measure; and cost drivers. DATA SOURCES: Phase A - interviews with patients and health-care professionals (HCPs), narrative data from published RCTs and data about dressing practices. Phase B - participants and HCPs in five hospitals. RESULTS: Phase A - we interviewed 102 participants. HCPs interpreted 'dressing' variably and reported using available products. HCPs suggested practical/clinical reasons for dressing use, acknowledged the weak evidence base and felt that a RCT including a 'no dressing' group was acceptable. A survey showed that 68% of 1769 wounds (727 participants) had simple dressings and 27% had glue-as-a-dressing. Dressings were used similarly in elective and non-elective surgery. The SSI questionnaire was developed from a content analysis of existing SSI tools and interviews, yielding 19 domains and 16 items. A main RCT would be valuable to the NHS at a willingness to pay of £20,000 per quality-adjusted life-year. Phase B - from 4 March 2016 to 30 November 2016, we approached 862 patients for the pilot RCT; 81.1% were eligible, 59.4% consented and 394 were randomised (simple, n = 133; glue, n = 129; no dressing, n = 132); non-adherence was 3 out of 133, 8 out of 129 and 20 out of 132, respectively. SSI occurred in 51 out of 281 participants. We interviewed 55 participants. All dressing strategies were acceptable to stakeholders, with no indication that adherence was problematic. Adherence aids and patients' understanding of their allocated dressing appeared to be key. The SSI questionnaire response rate overall was 67.2%. Items in the SSI questionnaire fitted a single scale, which had good reliability (test-retest and Cronbach's alpha of > 0.7) and diagnostic accuracy (c-statistic = 0.906). The key cost drivers were hospital appointments, dressings and redressings, use of new medicines and primary care appointments. LIMITATIONS: Multiple activities, often in parallel, were challenging to co-ordinate. An amendment took 4 months, restricting recruitment to the pilot RCT. Only 67% of participants completed the SSI questionnaire. We could not implement photography in theatres. CONCLUSIONS: A main RCT of dressing strategies is feasible and would be valuable to the NHS. The SSI questionnaire is sufficiently accurate to be used as the primary outcome. A main trial with three groups (as in the pilot) would be valuable to the NHS, using a primary outcome of SSI at discharge and patient-reported SSI symptoms at 4-8 weeks. TRIAL REGISTRATION: Phase A - Current Controlled Trials ISRCTN06792113; Phase B - Current Controlled Trials ISRCTN49328913. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 39. See the NIHR Journals Library website for further project information. Funding was also provided by the Medical Research Council ConDuCT-II Hub (reference number MR/K025643/1).

Wound infections are common after surgery. Some are cured with simple treatment, but others may lead to serious problems. Reducing the risk of a wound infection is important. We do not know if the type of dressing, or not using a dressing, influences the risk of infection. A study that allocated patients to receive different dressings (or no dressing) would answer this question. We did preliminary research to explore whether or not such a study is possible. We interviewed doctors, nurses and patients about their views on dressings and a future study. We also described dressings currently being used in the NHS and found that simple dressings and tissue adhesive (glue) 'as-a-dressing' are used most frequently. We studied existing evidence and interviewed experts to develop a questionnaire, completed by patients, to identify wound infections after patients leave hospital and tested its accuracy. We also explored taking photographs of wounds. We investigated whether or not a major study would be worth the cost and designed a pilot study to test its feasibility. The pilot study recruited 394 patients undergoing abdominal operations in five NHS hospitals. These patients were allocated to have a simple dressing, glue-as-a-dressing or no dressing, and 92% received the allocated dressing method. Patients and their doctors and nurses found the dressing methods to be acceptable. We showed that the new patient questionnaire accurately identified infections. Patients or their carers also found it acceptable to photograph their wounds. Our research suggests that a future large study would be worth the investment and is possible.

Cardiovascular magnetic resonance in emergency patients with multivessel disease or unobstructed coronary arteries: a cost-effectiveness analysis in the UK.

OBJECTIVE: To identify the key drivers of cost-effectiveness for cardiovascular magnetic resonance (CMR) when patients activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Economic decision models for two patient subgroups populated from secondary sources, each with a 1 year time horizon from the perspective of the National Health Service (NHS) and personal social services in the UK. SETTING: Usual care (with or without CMR) in the NHS. PARTICIPANTS: Patients who activated the PPCI pathway, and for Model 1: underwent an emergency coronary angiogram and PPCI, and were found to have multivessel coronary artery disease. For Model 2: underwent an emergency coronary angiogram and were found to have unobstructed coronary arteries. INTERVENTIONS: Model 1 (multivessel disease) compared two different ischaemia testing methods, CMR or fractional flow reserve (FFR), versus stress echocardiography. Model 2 (unobstructed arteries) compared CMR with standard echocardiography versus standard echocardiography alone. MAIN OUTCOME MEASURES: Key drivers of cost-effectiveness for CMR, incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. RESULTS: In both models, the incremental costs and QALYs between CMR (or FFR, Model 1) versus no CMR (stress echocardiography, Model 1 and standard echocardiography, Model 2) were small (CMR: -£64 (95% CI -£232 to £187)/FFR: £360 (95% CI -£116 to £844) and CMR/FFR: 0.0012 QALYs (95% CI -0.0076 to 0.0093)) and (£98 (95% CI -£199 to £488) and 0.0005 QALYs (95% CI -0.0050 to 0.0077)), respectively. The diagnostic accuracy of the tests was the key driver of cost-effectiveness for both patient groups. CONCLUSIONS: If CMR were introduced for all subgroups of patients who activate the PPCI pathway, it is likely that diagnostic accuracy would be a key determinant of its cost-effectiveness. Further research is needed to definitively answer whether revascularisation guided by CMR or FFR leads to different clinical outcomes in acute coronary syndrome patients with multivessel disease.

Health-related quality of life impact of minor and major bleeding events during dual antiplatelet therapy: a systematic literature review and patient preference elicitation study.

BACKGROUND: Dual antiplatelet therapy (DAPT) is the recommended preventative treatment for secondary ischaemic events, but increases the risk of bleeding, potentially affecting patients' health-related quality-of-life (HRQoL). Varied utility decrements have been used in cost-effectiveness models assessing alternative DAPT regimens, but it is unclear which of these decrements are most appropriate. Therefore, we reviewed existing sources of utility decrements for bleeds in patients receiving DAPT and undertook primary research to estimate utility decrements through a patient elicitation exercise using vignettes and the EuroQol EQ-5D. METHODS: MEDLINE, PubMed and references of included studies were searched. Primary research and decision analytic modelling studies reporting utility decrements for bleeds related to DAPT were considered. For the primary research study, 21 participants completed an elicitation exercise involving vignettes describing minor and major bleeds and the EQ-5D-3 L and EQ-5D-5 L. Utility decrements were derived using linear regression and compared to existing estimates. RESULTS: Four hundred forty-two citations were screened, of which 12 studies were included for review. Reported utility decrements ranged from - 0.002 to - 0.03 for minor bleeds and - 0.007 to - 0.05 for major bleeds. Data sources used to estimate the decrements, however, lacked relevance to our population group and few studies adequately reported details of their measurement and valuation approaches. No study completely adhered to reimbursement agency requirements in the UK according to the National Institute for Health and Care Excellence reference case. Our primary research elicited utility decrements overlapped existing estimates, ranging from - 0.000848 to - 0.00828 for minor bleeds and - 0.0187 to - 0.0621 for major bleeds. However, the magnitude of difference depended on the instrument, estimation method and valuation approach applied. CONCLUSIONS: Several sources of utility decrements for bleeds are available for use in cost-effectiveness analyses, but are of limited quality and relevance. Our elicitation exercise has derived utility decrements from a relevant patient population, based on standardised definitions of minor and major bleeding events, using a validated HRQoL instrument and have been valued using general population tariffs. We suggest that our utility decrements be used in future cost-effectiveness analyses of DAPT.

A longitudinal study to assess the frequency and cost of antivascular endothelial therapy, and inequalities in access, in England between 2005 and 2015.

OBJECTIVES: High-cost antivascular endothelial growth factor (anti-VEGF) medicines for eye disorders challenge ophthalmologists and policymakers to provide fair access for patients while minimising costs. We describe the growth in the use and costs of these medicines and measure inequalities in access. DESIGN: Longitudinal study using Hospital Episode Statistics (2005/2006 to 2014/2015) and hospital prescribing cost reports (2008/2009 to 2015/2016). We used Poisson regression to estimate standardised rates and explore temporal and geographical variations. SETTING: National Health Service (NHS) care in England. POPULATION: Patients receiving anti-VEGF injections for age-related macular degeneration, diabetic macular oedema and other eye disorders. INTERVENTIONS: Higher-cost drugs (ranibizumab or aflibercept) recommended by the National Institute for Health and Care Excellence or lower-cost drug (bevacizumab) not licensed for eye disorders. MAIN OUTCOME MEASURES: National procedure rates and variation between and within clinical commissioning groups (CCGs). Cost of ranibizumab and aflibercept prescribing. RESULTS: Injection procedures increased by 215% between 2010/2011 and 2014/2015. In 2014/2015 there were 388 031 procedures (714 per 100 000). There is no evidence that the dramatic growth in rates is slowing down. Since 2010/2011 the estimated cost of ranibizumab and aflibercept increased by 247% to £447 million in 2015/2016, equivalent to the entire annual budget of a CCG. There are large inequalities in access; in 2014/2015 procedure rates in a 'high use' CCG were 9.08 times higher than in a 'low use' CCG. In the South-West of England there was twofold variation in injections per patient per year (range 2.9 to 5.9). CONCLUSIONS: The high and rising cost of anti-VEGF therapy affects the ability of the NHS to provide care for other patients. Current regulations encourage the increasing use of ranibizumab and aflibercept rather than bevacizumab, which evidence suggests is more cost-effective. NHS patients in England do not have equal access to the most cost-effective care.

Effectiveness and cost-effectiveness of serum B-type natriuretic peptide testing and monitoring in patients with heart failure in primary and secondary care: an evidence synthesis, cohort study and cost-effectiveness model.

BACKGROUND: Heart failure (HF) affects around 500,000 people in the UK. HF medications are frequently underprescribed and B-type natriuretic peptide (BNP)-guided therapy may help to optimise treatment. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of BNP-guided therapy compared with symptom-guided therapy in HF patients. DESIGN: Systematic review, cohort study and cost-effectiveness model. SETTING: A literature review and usual care in the NHS. PARTICIPANTS: (a) HF patients in randomised controlled trials (RCTs) of BNP-guided therapy; and (b) patients having usual care for HF in the NHS. INTERVENTIONS: Systematic review: BNP-guided therapy or symptom-guided therapy in primary or secondary care. Cohort study: BNP monitored (≥ 6 months' follow-up and three or more BNP tests and two or more tests per year), BNP tested (≥ 1 tests but not BNP monitored) or never tested. Cost-effectiveness model: BNP-guided therapy in specialist clinics. MAIN OUTCOME MEASURES: Mortality, hospital admission (all cause and HF related) and adverse events; and quality-adjusted life-years (QALYs) for the cost-effectiveness model. DATA SOURCES: Systematic review: Individual participant or aggregate data from eligible RCTs. Cohort study: The Clinical Practice Research Datalink, Hospital Episode Statistics and National Heart Failure Audit (NHFA). REVIEW METHODS: A systematic literature search (five databases, trial registries, grey literature and reference lists of publications) for published and unpublished RCTs. RESULTS: Five RCTs contributed individual participant data (IPD) and eight RCTs contributed aggregate data (1536 participants were randomised to BNP-guided therapy and 1538 participants were randomised to symptom-guided therapy). For all-cause mortality, the hazard ratio (HR) for BNP-guided therapy was 0.87 [95% confidence interval (CI) 0.73 to 1.04]. Patients who were aged < 75 years or who had heart failure with a reduced ejection fraction (HFrEF) received the most benefit [interactions (p = 0.03): < 75 years vs. ≥ 75 years: HR 0.70 (95% CI 0.53 to 0.92) vs. 1.07 (95% CI 0.84 to 1.37); HFrEF vs. heart failure with a preserved ejection fraction (HFpEF): HR 0.83 (95% CI 0.68 to 1.01) vs. 1.33 (95% CI 0.83 to 2.11)]. In the cohort study, incident HF patients (1 April 2005-31 March 2013) were never tested (n = 13,632), BNP tested (n = 3392) or BNP monitored (n = 71). Median survival was 5 years; all-cause mortality was 141.5 out of 1000 person-years (95% CI 138.5 to 144.6 person-years). All-cause mortality and hospital admission rate were highest in the BNP-monitored group, and median survival among 130,433 NHFA patients (1 January 2007-1 March 2013) was 2.2 years. The admission rate was 1.1 patients per year (interquartile range 0.5-3.5 patients). In the cost-effectiveness model, in patients aged < 75 years with HFrEF or HFpEF, BNP-guided therapy improves median survival (7.98 vs. 6.46 years) with a small QALY gain (5.68 vs. 5.02) but higher lifetime costs (£64,777 vs. £58,139). BNP-guided therapy is cost-effective at a threshold of £20,000 per QALY. LIMITATIONS: The limitations of the trial were a lack of IPD for most RCTs and heterogeneous interventions; the inability to identify BNP monitoring confidently, to determine medication doses or to distinguish between HFrEF and HFpEF; the use of a simplified two-state Markov model; a focus on health service costs and a paucity of data on HFpEF patients aged < 75 years and HFrEF patients aged ≥ 75 years. CONCLUSIONS: The efficacy of BNP-guided therapy in specialist HF clinics is uncertain. If efficacious, it would be cost-effective for patients aged < 75 years with HFrEF. The evidence reviewed may not apply in the UK because care is delivered differently. FUTURE WORK: Identify an optimal BNP-monitoring strategy and how to optimise HF management in accordance with guidelines; update the IPD meta-analysis to include the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) RCT; collect routine long-term outcome data for completed and ongoing RCTs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37248047 and PROSPERO CRD42013005335. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 40. See the NIHR Journals Library website for further project information. The British Heart Foundation paid for Chris A Rogers' and Maria Pufulete's time contributing to the study. Syed Mohiuddin's time is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West at University Hospitals Bristol NHS Foundation Trust. Rachel Maishman contributed to the study when she was in receipt of a NIHR Methodology Research Fellowship.

A mixed-methods feasibility and external pilot study to inform a large pragmatic randomised controlled trial of the effects of surgical wound dressing strategies on surgical site infections (Bluebelle Phase B): study protocol for a randomised controlled trial.

BACKGROUND: Surgical site infections (SSIs) are common, occurring in up to 25% of > 4 million operations performed in England each year. Previous trials of the effect of wound dressings on the risk of developing a SSI are of poor quality and underpowered. METHODS/DESIGN: This study is a feasibility and pilot trial to examine the feasibility of a full trial that will compare simple dressings, no dressing and tissue-glue as a dressing. It is examining the overall acceptability of trial participation, identifying opportunities for refinement, testing the feasibility of and validating new outcome tools to assess SSI, wound management issues and patients' wound symptom experiences. It is also exploring methods for avoiding performance bias and blinding outcome assessors by testing the feasibility of collecting wound photographs taken in theatre immediately after wound closure and, at 4-8 weeks after surgery, taken by participants themselves or their carers. Finally, it is identifying the main cost drivers for an economic evaluation of dressing types. Integrated qualitative research is exploring acceptability and reasons for non-adherence to allocation. Adults undergoing primary elective or unplanned abdominal general surgery or Caesarean section are eligible. The main exclusion criteria are abdominal or other major surgery less than three months before the index operation or contraindication to dressing allocation. The trial is scheduled to recruit for nine months. The findings will be used to inform the design of a main trial. DISCUSSION: This pilot trial is the first pragmatic study to randomise participants to no dressing or tissue-glue as a dressing versus a simple dressing. Early evidence from the ongoing pilot shows that recruitment is proceeding well and that the interventions are acceptable to participants. Combined with the qualitative findings, the findings will inform whether a main, large trial is feasible and, if so, how it should be designed. TRIAL REGISTRATION: ISRCTN49328913 . Registered on 20 October 2015.

Formal consensus to identify clinically important changes in management resulting from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway.

OBJECTIVE: To define important changes in management arising from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Formal consensus study using literature review and cardiologist expert opinion to formulate consensus statements and setting up a consensus panel to review the statements (by completing a web-based survey, attending a face-to-face meeting to discuss survey results and modify the survey to reflect group discussion and completing the modified survey to determine which statements were in consensus). PARTICIPANTS: Formulation of consensus statements: four cardiologists (two CMR and two interventional) and six non-clinical researchers. Formal consensus: seven cardiologists (two CMR and three interventional, one echocardiography and one heart failure). Forty-nine additional cardiologists completed the modified survey. RESULTS: Thirty-seven draft statements describing changes in management following CMR were generated; these were condensed into 12 statements and reviewed through the formal consensus process. Three of 12 statements were classified in consensus in the first survey; these related to the role of CMR in identifying the cause of out-of-hospital cardiac arrest, providing a definitive diagnosis in patients found to have unobstructed arteries on angiography and identifying patients with left ventricular thrombus. Two additional statements were in consensus in the modified survey, relating to the ability of CMR to identify patients who have a poor prognosis after PPCI and assess ischaemia and viability in patients with multivessel disease. CONCLUSION: There was consensus that CMR leads to clinically important changes in management in five subgroups of patients who activate the PPCI pathway.

Comparative costs and activity from a sample of UK clinical trials units.

BACKGROUND: The costs of medical research are a concern. Clinical Trials Units (CTUs) need to better understand variations in the costs of their activities. METHODS: Representatives of ten CTUs and two grant-awarding bodies pooled their experiences in discussions over 1.5 years. Five of the CTUs provided estimates of, and written justification for, costs associated with CTU activities required to implement an identical protocol. The protocol described a 5.5-year, nonpharmacological randomized controlled trial (RCT) conducted at 20 centres. Direct and indirect costs, the number of full time equivalents (FTEs) and the FTEs attracting overheads were compared and qualitative methods (unstructured interviews and thematic analysis) were used to interpret the results. Four members of the group (funding-body representatives or award panel members) reviewed the justification statements for transparency and information content. Separately, 163 activities common to trials were assigned to roles used by nine CTUs; the consistency of role delineation was assessed by Cohen's κ. RESULTS: Median full economic cost of CTU activities was £769,637 (range: £661,112 to £1,383,323). Indirect costs varied considerably, accounting for between 15% and 59% (median 35%) of the full economic cost of the grant. Excluding one CTU, which used external statisticians, the total number of FTEs ranged from 2.0 to 3.0; total FTEs attracting overheads ranged from 0.3 to 2.0. Variation in directly incurred staff costs depended on whether CTUs: supported particular roles from core funding rather than grants; opted not to cost certain activities into the grant; assigned clerical or data management tasks to research or administrative staff; employed extensive on-site monitoring strategies (also the main source of variation in non-staff costs). Funders preferred written justifications of costs that described both FTEs and indicative tasks for funded roles, with itemised non-staff costs. Consistency in role delineation was fair (κ = 0.21-0.40) for statisticians/data managers and poor for other roles (κ < 0.20). CONCLUSIONS: Some variation in costs is due to factors outside the control of CTUs such as access to core funding and levels of indirect costs levied by host institutions. Research is needed on strategies to control costs appropriately, especially the implementation of risk-based monitoring strategies.

Quasi-experimental study designs series-paper 5: a checklist for classifying studies evaluating the effects on health interventions-a taxonomy without labels.

OBJECTIVES: The aim of the study was to extend a previously published checklist of study design features to include study designs often used by health systems researchers and economists. Our intention is to help review authors in any field to set eligibility criteria for studies to include in a systematic review that relate directly to the intrinsic strength of the studies in inferring causality. We also seek to clarify key equivalences and differences in terminology used by different research communities. STUDY DESIGN AND SETTING: Expert consensus meeting. RESULTS: The checklist comprises seven questions, each with a list of response items, addressing: clustering of an intervention as an aspect of allocation or due to the intrinsic nature of the delivery of the intervention; for whom, and when, outcome data are available; how the intervention effect was estimated; the principle underlying control for confounding; how groups were formed; the features of a study carried out after it was designed; and the variables measured before intervention. CONCLUSION: The checklist clarifies the basis of credible quasi-experimental studies, reconciling different terminology used in different fields of investigation and facilitating communications across research communities. By applying the checklist, review authors' attention is also directed to the assumptions underpinning the methods for inferring causality.

The Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES): a virtual randomised balanced incomplete block trial.

BACKGROUND: Patients with neovascular age-related macular degeneration (nAMD) usually attend regular reviews, even when the disease is quiescent. Reviews are burdensome to health services, patients and carers. OBJECTIVES: To compare the proportion of correct lesion classifications made by community-based optometrists and ophthalmologists from vignettes of patients; to estimate the cost-effectiveness of community follow-up by optometrists compared with follow-up by ophthalmologists in the Hospital Eye Service (HES); to ascertain views of patients, their representatives, optometrists, ophthalmologists and clinical commissioners on the proposed shared care model. DESIGN: Community-based optometrists and ophthalmologists in the HES classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomography images. Participants' classifications were validated against experts' classifications (reference standard). SETTING: Internet-based application. PARTICIPANTS: Ophthalmologists had to have ≥ 3 years post-registration experience in ophthalmology, have passed part 1 of the Royal College of Ophthalmologists, Diploma in Ophthalmology or equivalent examination, and have experience in the age-related macular degeneration service. Optometrists had to be fully qualified, be registered with the General Optical Council for ≥ 3 years and not be participating in nAMD shared care. INTERVENTIONS: The trial sought to emulate a conventional trial in comparing optometrists' and ophthalmologists' decision-making, but vignettes, not patients, were assessed; therefore, there were no interventions. Participants received training prior to assessing vignettes. MAIN OUTCOME MEASURES: Primary outcome - correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes - frequencies of potentially sight-threatening errors, participants' judgements about specific lesion components, participant-rated confidence in their decisions and cost-effectiveness of follow-up by community-based optometrists compared with HES ophthalmologists. RESULTS: In total, 155 participants registered for the trial; 96 (48 in each professional group) completed training and main assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702 out of 2016 (84.4%) and 1722 out of 2016 (85.4%) correct classifications, respectively [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.66 to 1.25; p = 0.543]. Optometrists' decision-making was non-inferior to ophthalmologists' with respect to the pre-specified limit of 10% absolute difference (0.298 on the odds scale). Frequencies of sight-threatening errors were similar for optometrists and ophthalmologists [57/994 (5.7%) vs. 62/994 (6.2%), OR 0.93, 95% CI 0.55 to 1.57; p = 0.789]. Ophthalmologists assessed lesion components as present less often than optometrists and were more confident about their lesion classifications than optometrists. The mean care-pathway cost for assessment was very similar by group, namely £397.33 for ophthalmologists and £410.78 for optometrists. The optometrist-led monitoring reviews were slightly more costly and less effective than ophthalmologist-led reviews, although the differences were extremely small. There was consensus that optometrist-led monitoring has the potential to reduce clinical workload and be more patient-centred. However, potential barriers are ophthalmologists' perceptions of optometrists' competence, the need for clinical training, the ability of the professions to work collaboratively and the financial feasibility of shared care for Clinical Commissioning Groups. CONCLUSIONS: The ability of optometrists to make nAMD retreatment decisions from vignettes is non-inferior to that of ophthalmologists. Various barriers to implementing shared cared for nAMD were identified. FUTURE WORK RECOMMENDATIONS: The Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES) study web application was robust and could be used for future training or research. The benefit of reducing HES workload was not considered in the economic evaluation. A framework of programme budgeting and marginal analysis could explicitly explore the resource implications of shifting resources within a given health service area, as the benefit of reducing HES workload was not considered in the economic evaluation. Future qualitative research could investigate professional differences of opinion that were identified in multidisciplinary focus groups. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07479761. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 80. See the NIHR Journals Library website for further project information.

Design and implementation of the AIRWAYS-2 trial: A multi-centre cluster randomised controlled trial of the clinical and cost effectiveness of the i-gel supraglottic airway device versus tracheal intubation in the initial airway management of out of hospital cardiac arrest.

Health outcomes after out of hospital cardiac arrest (OHCA) are extremely poor, with only 7-9% of patients in the United Kingdom (UK) surviving to hospital discharge. Currently emergency medical services (EMS) use either tracheal intubation or newer supraglottic airway devices (SGAs) to provide advanced airway management during OHCA. Equipoise between the two techniques has led to calls for a well-designed randomised controlled trial. The primary objective of the AIRWAYS-2 trial is to assess whether the clinical effectiveness of the i-gel, a second-generation SGA, is superior to tracheal intubation in the initial airway management of OHCA patients in the UK. Paramedics recruited to the AIRWAYS-2 trial are randomised to use either tracheal intubation or i-gel as their first advanced airway intervention. Adults who have had a non-traumatic OHCA and are attended by an AIRWAYS-2 paramedic are retrospectively assessed against eligibility criteria for inclusion. The primary outcome is the modified Rankin Scale score at hospital discharge. Secondary objectives are to: (i) estimate differences between groups in outcome measures relating to airway management, hospital stay and recovery at 3 and 6 months; (ii) estimate the cost effectiveness of the i-gel compared to tracheal intubation. Because OHCA patient needs immediate treatment there are several unusual features and challenges to the design and implementation of this trial; these include level of randomisation, the automatic enrolment model, enrolment of patients that lack capacity and minimisation of bias. Patient enrolment began in June 2015. The trial will enrol 9070 patients over two years. The results are expected to influence future resuscitation guidelines. Trial Registration ISRCTN: 08256118.

The healthcare costs of heart failure during the last five years of life: A retrospective cohort study.

BACKGROUND: Evidence on the economic impact of heart failure (HF) is vital in order to predict the cost-effectiveness of novel interventions. We estimate the health system costs of HF during the last five years of life. METHODS: We used linked primary care and mortality data accessed through the Clinical Practice Research Datalink (CPRD) to identify 1555 adults in England who died with HF in 2012/13. We used CPRD and linked Hospital Episode Statistics to estimate the cost of medications, primary and hospital healthcare. Using GLS regression we estimated the relationship between costs, HF diagnosis, proximity to death and patient characteristics. RESULTS: In the last 3months of life, healthcare costs were £8827 (95% CI £8357 to £9296) per patient, more than 90% of which were for inpatient or critical care. In the last 3months, patients spent on average 17.8 (95% CI 16.8 to 18.8) days in hospital and had 8.8 (95% CI 8.4 to 9.1) primary care consultations. Most (931/1555; 59.9%) patients were in hospital on the day of death. Mean quarterly healthcare costs in quarters after HF diagnosis were higher (£1439; [95% CI £1260 to £1619]) than in quarters preceding diagnosis. Older patients and patients with lower comorbidity scores had lower costs. CONCLUSIONS: Healthcare costs increase sharply at the end of life and are dominated by hospital care. There is potential to save money by implementation and evaluation of interventions that are known to reduce hospitalisations for HF, particularly at the end of life.

A multicentre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and health-care resource use following cardiac surgery (TITRe2).

BACKGROUND: Uncertainty about optimal red blood cell transfusion thresholds in cardiac surgery is reflected in widely varying transfusion rates between surgeons and cardiac centres. OBJECTIVE: To test the hypothesis that a restrictive compared with a liberal threshold for red blood cell transfusion after cardiac surgery reduces post-operative morbidity and health-care costs. DESIGN: Multicentre, parallel randomised controlled trial and within-trial cost-utility analysis from a UK NHS and Personal Social Services perspective. We could not blind health-care staff but tried to blind participants. Random allocations were generated by computer and minimised by centre and operation. SETTING: Seventeen specialist cardiac surgery centres in UK NHS hospitals. PARTICIPANTS: Patients aged > 16 years undergoing non-emergency cardiac surgery with post-operative haemoglobin < 9 g/dl. Exclusion criteria were: unwilling to have transfusion owing to beliefs; platelet, red blood cell or clotting disorder; ongoing or recurrent sepsis; and critical limb ischaemia. INTERVENTIONS: Participants in the liberal group were eligible for transfusion immediately after randomisation (post-operative haemoglobin < 9 g/dl); participants in the restrictive group were eligible for transfusion if their post-operative haemoglobin fell to < 7.5 g/dl during the index hospital stay. MAIN OUTCOME MEASURES: The primary outcome was a composite outcome of any serious infectious (sepsis or wound infection) or ischaemic event (permanent stroke, myocardial infarction, gut infarction or acute kidney injury) during the 3 months after randomisation. Events were verified or adjudicated by blinded personnel. Secondary outcomes included blood products transfused; infectious events; ischaemic events; quality of life (European Quality of Life-5 Dimensions); duration of intensive care or high-dependency unit stay; duration of hospital stay; significant pulmonary morbidity; all-cause mortality; resource use, costs and cost-effectiveness. RESULTS: We randomised 2007 participants between 15 July 2009 and 18 February 2013; four withdrew, leaving 1000 and 1003 in the restrictive and liberal groups, respectively. Transfusion rates after randomisation were 53.4% (534/1000) and 92.2% (925/1003). The primary outcome occurred in 35.1% (331/944) and 33.0% (317/962) of participants in the restrictive and liberal groups [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.91 to 1.34; p = 0.30], respectively. There were no subgroup effects for the primary outcome, although some sensitivity analyses substantially altered the estimated OR. There were no differences for secondary clinical outcomes except for mortality, with more deaths in the restrictive group (4.2%, 42/1000 vs. 2.6%, 26/1003; hazard ratio 1.64, 95% CI 1.00 to 2.67; p = 0.045). Serious post-operative complications excluding primary outcome events occurred in 35.7% (354/991) and 34.2% (339/991) of participants in the restrictive and liberal groups, respectively. The total cost per participant from surgery to 3 months postoperatively differed little by group, just £182 less (standard error £488) in the restrictive group, largely owing to the difference in red blood cells cost. In the base-case cost-effectiveness results, the point estimate suggested that the restrictive threshold was cost-effective; however, this result was very uncertain partly owing to the negligible difference in quality-adjusted life-years gained. CONCLUSIONS: A restrictive transfusion threshold is not superior to a liberal threshold after cardiac surgery. This finding supports restrictive transfusion due to reduced consumption and costs of red blood cells. However, secondary findings create uncertainty about recommending restrictive transfusion and prompt a new hypothesis that liberal transfusion may be superior after cardiac surgery. Reanalyses of existing trial datasets, excluding all participants who did not breach the liberal threshold, followed by a meta-analysis of the reanalysed results are the most obvious research steps to address the new hypothesis about the possible harm of red blood cell transfusion. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70923932. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 60. See the NIHR Journals Library website for further project information.

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN).

BACKGROUND: Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD. DESIGN: Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed. SETTING: Twenty-three ophthalmology departments in NHS hospitals. PARTICIPANTS: Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required. INTERVENTIONS: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated. MAIN OUTCOME MEASURES: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes. RESULTS: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses. CONCLUSIONS: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92166560. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.

Comparing different dosing regimens of bevacizumab in the treatment of neovascular macular degeneration: study protocol for a randomised controlled trial.

BACKGROUND: Bevacizumab (Avastin®) is as effective as ranibizumab (Lucentis®) in the treatment of neovascular age-related macular degeneration (nAMD). However it has two important structural differences. First, it has two active sites instead of one; second, it retains the Fc portion of the antibody which would be expected to confer a significantly longer half-life. These agents have been associated with systemic complications including strokes, so it is desirable to use the smallest effective dose. Furthermore, the standard dosing regimen requires monthly hospital visits, which present a significant challenge both to the hospital services and to the patients (who are elderly). METHODS/DESIGN: Patients ≥50 years who are eligible for anti-vascular endothelial growth factor (VEGF) treatment of nAMD in the NHS, who are either newly referred for treatment or have reactivation of nAMD and who have not received treatment to either eye for the previous six months. We have designed a factorial multi-centre masked randomised controlled trial using bevacizumab as the intervention, with patients randomised to one of four arms: to standard or low dose and to monthly or two-monthly patient review. The aim is to recruit sufficient patients (around 1,000) to obtain 304 patients meeting the endpoint over a four-year period. The primary endpoint is time to treatment failure to be analysed using Cox regression. DISCUSSION: This randomised control trial will show if half dose and two monthly as required is as effective as full dose and monthly regimes. A two monthly as required regimen of Bevacizumab would significantly reduce both the cost and the service delivery burden for the treatment of nAMD while a reduced dose would be expected to enhance the safety profile of this treatment regime. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN95654194 , registered on 22 September 2009.