Summary Background Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related ...choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. Methods In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Findings Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference −1·37 letters, 95% CI −3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (−1·63 letters, −4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 6% of 314 participants) and bevacizumab (12 4% of 296; odds ratio OR 1·69, 95% CI 0·80–3·57; p=0·16), or those given continuous (12 4% of 308) and discontinuous treatment (20 7% of 302; 0·56, 0·27–1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22–1·03; p=0·05), but did not differ by drug group (0·96, 0·46–2·02; p=0·91). Interpretation Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought. Funding UK National Institute for Health Research Health Technology Assessment programme.
Red blood cell transfusion can both benefit and harm. To inform decisions about transfusion, we aimed to quantify associations of transfusion with clinical outcomes and cost in patients having ...cardiac surgery.
Clinical, hematology, and blood transfusion databases were linked with the UK population register. Additional hematocrit information was obtained from intensive care unit charts. Composite infection (respiratory or wound infection or septicemia) and ischemic outcomes (myocardial infarction, stroke, renal impairment, or failure) were prespecified as coprimary end points. Secondary outcomes were resource use, cost, and survival. Associations were estimated by regression modeling with adjustment for potential confounding. All adult patients having cardiac surgery between April 1, 1996, and December 31, 2003, with key exposure and outcome data were included (98%). Adjusted odds ratios for composite infection (737 of 8516) and ischemic outcomes (832 of 8518) for transfused versus nontransfused patients were 3.38 (95% confidence interval CI, 2.60 to 4.40) and 3.35 (95% CI, 2.68 to 4.35), respectively. Transfusion was associated with increased relative cost of admission (any transfusion, 1.42 times 95% CI, 1.37 to 1.46, varying from 1.11 for 1 U to 3.35 for >9 U). At any time after their operations, transfused patients were less likely to have been discharged from hospital (hazard ratio HR, 0.63; 95% CI, 0.60 to 0.67) and were more likely to have died (0 to 30 days: HR, 6.69; 95% CI, 3.66 to 15.1; 31 days to 1 year: HR, 2.59; 95% CI, 1.68 to 4.17; >1 year: HR, 1.32; 95% CI, 1.08 to 1.64).
Red blood cell transfusion in patients having cardiac surgery is strongly associated with both infection and ischemic postoperative morbidity, hospital stay, increased early and late mortality, and hospital costs.
Neovascular age-related macular degeneration (nAMD) is a chronic, progressive condition and the commonest cause of visual disability in older adults. This study formed part of a diagnostic test ...accuracy study to quantify the ability of three index home monitoring (HM) tests (one paper-based and two digital tests) to identify reactivation in nAMD. The aim of this qualitative research was to investigate patients' or participants' views about acceptability and explore adherence to weekly HM. Semi-structured interviews were held with 78/297 participants (26%), with close family members (n = 11) and with healthcare professionals involved in training participants in HM procedures (n = 9) (n = 98 in total). A directed thematic analytical approach was applied to the data using a deductive and inductive coding framework informed by theories of technology acceptance. Five themes emerged related to: 1. The role of HM; 2. Suitability of procedures and instruments; 3. Experience of HM; 4. Feasibility of HM in usual practice; and 5. Impediments to patient acceptability of HM. Various factors influenced acceptability including a patient's understanding about the purpose of monitoring. While initial training and ongoing support were regarded as essential for overcoming unfamiliarity with use of digital technology, patients viewed HM as relatively straightforward and non-burdensome. There is a need for further research about how use of performance feedback, level of support and nature of tailoring might facilitate further the implementation of routinely conducted HM. Home monitoring was acceptable to patients and they recognised its potential to reduce clinic visits during non-active treatment phases. Findings have implications for implementation of digital HM in the care of older people with nAMD and other long-term conditions.
Concerns have been expressed about the relationship between reduced levels of health care utilisation and the COVID-19 pandemic. This study aimed to elicit and explore the views of patients with ...neovascular age-related macular degeneration (nAMD) regarding the COVID-19 pandemic and their ophthalmic care. Semi-structured telephone interviews were conducted with thirty-five patients with nAMD taking part in a larger diagnostic accuracy study of home-monitoring tests. Participants were recruited using maximum variation sampling to capture a range of key characteristics including age, gender and time since initial treatment. Transcribed interview data were analysed using a deductive and inductive thematic approach. Three themes emerged from the analysis: i. access to eye clinic care. ii. COVID-19-mitigating factors and care delivery and iii. social and personal circumstances. Participants reported anxieties about cancelled or delayed appointments, limited communication from clinic-based services about appointments, and the impact of this on their ongoing care. Despite these concerns, there was apprehension about attending appointments due to infection risk and a perception that nAMD patients are a ‘high risk’ group. Views of those who attended clinics during the study period were, however, positive, with social distancing and infection control measures providing reassurance. These findings contribute to our understanding about experiences of patients with nAMD during the COVID-19 pandemic and may have potential implications for future planning of care services in similar circumstances. Innovative approaches may be required to address issues related to access to care, including concerns about delayed or cancelled appointments.
Objective Off-pump coronary artery bypass grafting reduces postoperative morbidity and uses fewer resources than conventional surgical intervention with cardiopulmonary bypass. However, only 15% to ...20% of coronary artery bypass grafting operations use off-pump coronary artery bypass. One reason for not using off-pump coronary artery bypass might be the surgeon's concern about the long-term patency of grafts performed with this technique. Therefore our objective was to compare long-term outcomes in patients randomized to off-pump coronary artery bypass or coronary artery bypass grafting with cardiopulmonary bypass. Methods Participants in 2 randomized trials comparing off-pump coronary artery bypass and coronary artery bypass grafting with cardiopulmonary bypass were followed up for 6 to 8 years after surgical intervention to assess graft patency, major adverse cardiac-related events, and health-related quality of life. Patency was assessed by using multidetector computed tomographic coronary angiographic analysis with a 16-slice scanner. Two blinded observers classified proximal, body, and distal segments of each graft as occluded or not. Major adverse cardiac-related events and health-related quality of life were obtained from questionnaires given to participants and family practitioners. Results Patency was studied in 199 and health-related quality of life was studied in 299 of 349 survivors. There was no evidence of attrition bias. The likelihood of graft occlusion was no different between off-pump coronary artery bypass (10.6%) and coronary artery bypass grafting with cardiopulmonary bypass (11.0%) groups (odds ratio, 1.00; 95% confidence interval, 0.55–1.81; P > .99). Graft occlusion was more likely at the distal than the proximal anastomosis (odds ratio, 1.11; 95% confidence interval, 1.02–1.20). There were also no differences between the off-pump coronary artery bypass and coronary artery bypass grafting with cardiopulmonary bypass groups in the hazard of death (hazard ratio, 1.24; 95% confidence interval, 0.72–2.15) or major adverse cardiac-related events or death (hazard ratio, 0.84; 95% confidence interval, 0.58–1.24), or mean health-related quality of life across a range of domains and instruments. Conclusions Long-term health outcomes with off-pump coronary artery bypass are similar to those with coronary artery bypass grafting with cardiopulmonary bypass when both operations are performed by experienced surgeons.
Randomised controlled trials ('trials') are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to ...improve recruitment and retention. However, relatively few of these have been conducted.
PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial.
A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously.
Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible.
Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom.
Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial.
Number of host trials funded.
Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials.
The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (
= 2) or prematurely terminated (
= 3).
PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial.
Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice.
All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository.
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in
; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.
This study aims to quantify the diagnostic test-accuracy of three visual function self-monitoring tests for detection of active disease in patients with neovascular age-related macular degeneration ...(nAMD) when compared with usual care. An integrated qualitative study will investigate the acceptability of these home-based testing strategies.
All consenting participants are provided with an equipment pack containing an iPod touch with two vision test applications installed and a paper journal of reading tests. Participants self-monitor their vision at home each week with all three tests for 12-18 months. Usual care continues over this period. Key eligibility criteria are: age ≥50 years; at least one eye with AMD with ≥6-≤42 months since first AMD treatment; and vision not worse than Snellen 6/60, LogMAR 1.04 or 33 letters. The primary outcome, and reference standard, is diagnosis of active disease during usual care monitoring in the Hospital Eye Service. Secondary outcomes include duration of study participation, ability of participants to do the tests, adherence to weekly testing and acceptability of the tests to participants.
Recruitment is in progress at five NHS centres. Challenges in procuring equipment, setting up the devices and transporting devices containing lithium batteries to participating sites delayed the start of recruitment. The study will describe the performance of the tests self-administered at home in detecting active disease compared to usual care monitoring. It will also describe the feasibility of the NHS implementing patient-administered electronic tests or similar applications at home for monitoring health.
In early 2021, the Department of Health and Social Care in the UK called for research on the safety and immunogenicity of concomitant administration of COVID-19 and influenza vaccines. ...Co-administration of these vaccines would facilitate uptake and reduce the number of healthcare visits required. The ComFluCOV trial was designed to deliver the necessary evidence in time to inform the autumn (September-November) 2021 vaccination policy. This paper presents the statistical methodology applied to help successfully deliver the trial results in 6 months.
ComFluCOV was a parallel-group multicentre randomised controlled trial managed by the Bristol Trials Centre. Two study statisticians, supported by a senior statistician, worked together on all statistical tasks. Tools were developed to aid the pre-screening process. Automated data monitoring reports of clinic data and electronic diaries were produced daily and reviewed by the trial team and feedback provided to sites. Analyses were performed independently in parallel, and derivations and results of all outcomes were compared.
Set-up was achieved in less than a month, and 679 participants were recruited over 8 weeks. A total of 537 at least daily reports outlining recruitment, protocol adherence, and data quality, and 695 daily reports of participant electronic diaries identifying any missed diary entries and adverse events were produced over a period of 16 weeks. A preliminary primary outcome analysis of validated data was reported to the Department of Health and Social Care in May 2021. The database was locked 6 weeks after the final participant follow-up and final analyses completed 3 weeks later. A pre-print publication was submitted within 14 days of the results being made available. The results were reported 6 months after first discussions about the trial.
The statistical methodologies implemented in ComFluCOV helped to deliver the study in the timescale set. Working in a new clinical area to tight timescales was challenging. Having two statisticians working together on the study provided a quality assurance process that enabled analyses to be completed efficiently and ensured data were interpreted correctly. Processes developed could be applied to other studies to maximise quality, reduce the risk of errors, and overall provide enhanced validation methods.
ISRCTN14391248, registered on 30 March 2021.
Introduction
Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients ...undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6 mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection.
Methods and Analysis
The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12 mcg/ml), low dose of propofol (6 mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48 hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate).
Ethics and Dissemination
The trial received research ethics approval from South Central – Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters.
Trial Registration
ISRCTN15255199. Registered in March 2019.
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