Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomised, double-masked, sham-controlled device trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity. METHODS: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment. FINDINGS: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483). INTERPRETATION: SRT can reduce ranibizumab treatment burden without compromising vision. FUNDING: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration (MERLOT): A Phase 3 Randomized Controlled Trial.

PURPOSE: To assess the safety and efficacy of epimacular brachytherapy (EMB) for patients with chronic, active, neovascular age-related macular degeneration (AMD). DESIGN: Phase 3 randomized controlled trial. PARTICIPANTS: Patients (n = 363) with neovascular AMD already receiving intravitreal ranibizumab injections. INTERVENTION: Either pars plana vitrectomy with 24-gray EMB and ongoing pro re nata (PRN) ranibizumab (n = 224) or ongoing PRN ranibizumab monotherapy (n = 119). MAIN OUTCOME MEASURES: The coprimary outcomes, at 12 months, were the number of PRN ranibizumab injections and Early Treatment of Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (VA). Secondary outcomes included the proportion of participants losing fewer than 15 ETDRS letters, angiographic total lesion size, choroidal neovascularization (CNV) size, and optical coherence tomography (OCT) foveal thickness. A predefined subgroup analysis tested the influence of baseline ocular characteristics on the response to EMB. RESULTS: The mean number of PRN ranibizumab injections was 4.8 in the EMB arm and 4.1 in the ranibizumab monotherapy arm (P = 0.068). The mean VA change was -4.8 letters in the EMB arm and -0.9 letters in the ranibizumab arm (95% confidence interval of difference between groups, -6.6 to -1.8 letters). The proportion of participants losing fewer than 15 letters was 84% in the EMB arm and 92% in the ranibizumab arm (P = 0.007). In the EMB arm, the mean total lesion size increased by 1.2 mm(2) versus 0.4 mm(2) in the ranibizumab arm (P = 0.27). The CNV size decreased by 0.5 mm(2) in the EMB arm and by 1.3 mm(2) in the ranibizumab arm (P = 0.27). The OCT foveal thickness decreased by 1.0 µm in the EMB arm and by 15.7 µm in the ranibizumab arm (P = 0.43). Most subgroups favored ranibizumab monotherapy, some significantly so. One participant showed retinal vascular abnormality attributed to radiation, but otherwise safety was acceptable. CONCLUSIONS: These results do not support the use of EMB for chronic, active, neovascular AMD. Safety is acceptable out to 12 months, but radiation retinopathy can occur later, so further follow-up is planned.

Radiation exposure during videourodynamics in women.

INTRODUCTION AND HYPOTHESIS: Our aim was to calculate the total radiation exposure and the dose absorbed by specific organs during videourodynamics (VUDS) in women. METHODS: This was a retrospective study of consecutive women attending for VUDS in a tertiary referral urodynamics unit. Tests with missing data and those that were terminated during the filling phase of the cystometry were excluded from the study. The VUDS examination was tailored according to the indication for the test and the urodynamic question to be answered. The PCXMC simulation program (version 2.0) was utilised to calculate the effective dose and the dose absorbed by individual organs. RESULTS: Out of 345 consecutive VUDS, 264 were included in the study. The mean effective dose was 0.34 mSv (SD: 0.15) and the mean fluoroscopic time was 63.15 s (SD: 21.81). Multivariate linear regression analysis of factors affecting the radiation dose showed that BMI (p = 0.009) and fluoroscopy time (p < 0.001) were the only statistically significant factors. The final linear regression model for the estimation of the effective dose was Eff. Dose (mSv) = -0.049 + 0.003 · BMI (kg/m(2)) + 0.005 · fluoroscopy time (s). CONCLUSIONS: This study reveals that women are exposed to relatively small amounts of radiation during VUDS. The use of fluoroscopy only without additional static radiographic images minimises exposure to a level consistent with the "as low as reasonably achievable" radiological principle.

Virtual Touch™ Quantification to Diagnose and Monitor Liver Fibrosis in Hepatitis B and Hepatitis C: A NICE Medical Technology Guidance.

Virtual Touch™ Quantification (VTq) is a software application used with Siemens Acuson ultrasound scanners to assess the stiffness of liver tissue. The National Institute for Health and Care Excellence (NICE) Medical Technologies Advisory Committee (MTAC) selected VTq for evaluation and invited the company to submit clinical and economic evidence. King's Technology Evaluation Centre, an External Assessment Centre (EAC) commissioned by NICE, independently assessed the evidence submitted. The EAC conducted its own systematic review, meta-analysis and economic analysis to supplement the company's submitted evidence. The meta-analyses comparing VTq and transient elastography (TE) with liver biopsy (LB) provided pooled estimates of liver stiffness and stage of fibrosis for the study populations (hepatitis B, hepatitis C or combined populations). When comparing significant fibrosis (Metavir score F ≥ 2) for both hepatitis B and C, VTq had slightly higher values for both sensitivity and specificity (77 and 81 %) than TE (76 and 71 %). The overall prevalence of cirrhosis (F4, combined populations) was similar with VTq and TE (23 vs. 23 %), and significant fibrosis (F ≥ 2) was lower for VTq than for TE (55 vs. 62 %). The EAC revised the company's de novo cost model, which resulted in a cost saving of £53 (against TE) and £434 (against LB). Following public consultation, taking into account submitted comments, NICE Medical Technology Guidance MTG27 was published in September 2015. This recommended the adoption of the VTq software to diagnose and monitor liver fibrosis in patients with hepatitis B or hepatitis C.

Selecting a CT scanner for cardiac imaging: the heart of the matter.

Coronary angiography to assess the presence and degree of arterial stenosis is an examination now routinely performed on CT scanners. Although developments in CT technology over recent years have made great strides in improving the diagnostic accuracy of this technique, patients with certain characteristics can still be "difficult to image". The various groups will benefit from different technological enhancements depending on the type of challenge they present. Good temporal and spatial resolution, wide longitudinal (z-axis) detector coverage and high X-ray output are the key requirements of a successful CT coronary angiography (CTCA) scan. The requirement for optimal patient dose is a given. The different scanner models recommended for CTCA all excel in different aspects. The specification data presented here for these scanners and the explanation of the impact of the different features should help in making a more informed decision when selecting a scanner for CTCA.

Multicentre prospective survey of SeHCAT provision and practice in the UK.

OBJECTIVE: A clinical diagnosis of bile acid malabsorption (BAM) can be confirmed using SeHCAT (tauroselcholic ((75)selenium) acid), a radiolabelled synthetic bile acid. However, while BAM can be the cause of chronic diarrhoea, it is often overlooked as a potential diagnosis. Therefore, we investigated the use of SeHCAT for diagnosis of BAM in UK hospitals. DESIGN: A multicentre survey was conducted capturing centre and patient-level information detailing patient care-pathways, clinical history, SeHCAT results, treatment with bile acid sequestrants (BAS), and follow-up in clinics. Eligible data from 38 centres and 1036 patients were entered into a validated management system. RESULTS: SeHCAT protocol varied between centres, with no standardised patient positioning, and differing referral systems. Surveyed patients had a mean age of 50 years and predominantly women (65%). The mean SeHCAT retention score for all patients was 19% (95% CI 17.8% to 20.3%). However, this differed with suspected BAM type: type 1: 9% (95% CI 6.3% to 11.4%), type 2: 21% (95% CI 19.2% to 23.0%) and type 3: 22% (95% CI 19.6% to 24.2%). Centre-defined 'abnormal' and 'borderline' results represented over 50% of the survey population. BAS treatment was prescribed to only 73% of patients with abnormal results. CONCLUSIONS: The study identified a lack of consistent cut-off/threshold values, with differing centre criteria for defining an 'abnormal' SeHCAT result. BAS prescription was not related in a simple way to the SeHCAT result, nor to the centre-defined result, highlighting a lack of clear patient care-pathways. There is a clear need for a future diagnostic accuracy study and a better understanding of optimal management pathways.

A Multicenter Prospective Study to Investigate the Diagnostic Accuracy of the SeHCAT Test in Measuring Bile Acid Malabsorption: Research Protocol.

BACKGROUND: Bile acid malabsorption (BAM) is one possible explanation for chronic diarrhea. BAM may be idiopathic, or result from ileal resection or inflammation including Crohn's disease, or may be secondary to other conditions, including cholecystectomy, peptic ulcer surgery, and chronic pancreatitis. No "gold standard" exists for clinical diagnosis of BAM, but response to treatment with a bile acid sequestrant (BAS) is often accepted as confirmation. The SeHCAT (tauroselcholic [selenium-75] acid) test uses a radiolabeled synthetic bile acid and provides a diagnostic test for BAM, but its performance against "trial of treatment" is unknown. Fibroblast growth factor 19 (FGF-19) and 7-alpha-hydroxy-4-cholesten-3-one (C4) also offer potential new biomarkers of BAM. OBJECTIVE: This protocol describes a multicenter prospective study to evaluate the diagnostic accuracy of SeHCAT and 2 biomarkers in predicting BAM as assessed by trial of treatment. METHODS: Participating gastroenterology centers should have a minimum workload of 30 SeHCAT patients per annum. Patients should not be pregnant, on medication that could confound follow-up, or have any severe comorbidity. All eligible patients attending a gastrointestinal appointment will be invited to participate. On attending the SeHCAT test, blood and fecal samples will be collected for analysis of FGF-19 by enzyme-linked immunosorbent assay and for C4 and fractionated bile acids by liquid chromatography-mass spectrometry. A capsule containing radiolabeled SeHCAT will be administered orally and a scan performed to measure SeHCAT activity. Patients will return on day 7 to undergo a second scan to measure percentage SeHCAT retention. The test result will be concealed from clinicians and patients. BAS will be dispensed to all patients, with a follow-up gastroenterologist appointment at 2 weeks for clinical assessment of treatment response and adherence. Patients responding positively will continue treatment for a further 2 weeks and all patients will have a final follow-up at 8 weeks. The diagnostic accuracy of the SeHCAT test and biomarkers will be analyzed at different thresholds using sensitivity, specificity, positive and negative predictive value, likelihood ratios, and area under the curve in a sample of 600 patients. Multivariable logistic regression models will be used to assess the association between presence of BAM and continuous SeHCAT retention levels after adjustment for confounders. RESULTS: Funding is being sought to conduct this research. CONCLUSIONS: The SeHCAT test for diagnosis of BAM has been in common use in the United Kingdom for more than 30 years and an evidence-based assessment of its accuracy is overdue. The proposed study has some challenges. Some forms of BAS treatment are unpleasant due to the texture and taste of the resin powder, which may negatively affect recruitment and treatment adherence. Trial of treatment is not as "golden" a standard as would be ideal, and itself warrants further study.

StereoTactic radiotherapy for wet Age-Related macular degeneration (STAR): study protocol for a randomised controlled clinical trial.

BACKGROUND: The standard of care for neovascular age-related macular degeneration (nAMD) involves ongoing intravitreal injections of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF). The most commonly used anti-VEGF drugs are ranibizumab, bevacizumab and aflibercept. The main objective of the STAR trial is to determine if stereotactic radiotherapy can reduce the number of anti-VEGF injections that patients with nAMD require. METHODS/DESIGN: STAR is a multicentre, double-masked, randomised, sham-controlled clinical trial. It evaluates a new device (manufactured by Oraya, Newark, CA, USA) designed to deliver stereotactic radiotherapy (SRT) to nAMD lesions. The trial enrols participants with chronic, active nAMD. Participants receive a single SRT treatment (16 Gy or sham) with a concomitant baseline intravitreal injection of 0.5 mg ranibizumab. Thereafter, they attend every month for 24 months, and ranibizumab is administered at the visit if retreatment criteria are met. The primary outcome is the number of pro re nata ranibizumab injections during the first 24 months. Secondary outcomes include visual acuity, lesion morphology, quality of life and safety. Additional visits occur at 36 and 48 months to inspect for radiation retinopathy. The target sample size of 411 participants (randomised 2:1 in favour of radiation) is designed to detect a reduction of 2.5 injections against ranibizumab monotherapy, at 90% power, and a significance level (alpha) of 0.025 (one-sided two-sample t test). This gives 97% power to detect non-inferiority of visual acuity at a five-letter margin. The primary analyses will be by intention to treat. DISCUSSION: The safety and efficacy outcomes will help determine the role of SRT in the management of chronic, active nAMD. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN12884465. Registered on 28 November 2014. ClinicalTrials.gov: NCT02243878 . Registered on 17 September 2014.

The geko™ electro-stimulation device for venous thromboembolism prophylaxis: a NICE medical technology guidance.

The geko™ device is a single-use, battery-powered, neuromuscular electrostimulation device that aims to reduce the risk of venous thromboembolism (VTE). The National Institute for Health and Care Excellence (NICE) selected the geko™ device for evaluation, and invited the manufacturer, Firstkind Ltd, to submit clinical and economic evidence. King's Technology Evaluation Centre, an External Assessment Centre (EAC) commissioned by the NICE, independently assessed the evidence submitted. The sponsor submitted evidence related to the geko™ device and, in addition, included studies of other related devices as further clinical evidence to support a link between increased blood flow and VTE prophylaxis. The EAC assessed this evidence, conducted its own systematic review and concluded that there is currently limited direct evidence that geko™ prevents VTE. The sponsor's cost model is based on the assumption that patients with an underlying VTE risk and subsequently treated with geko™ will experience a reduction in their baseline risk. The EAC assessed this cost model but questioned the validity of some model assumptions. Using the EACs revised cost model, the cost savings for geko™ prophylaxis against a 'no prophylaxis' strategy were estimated as £197 per patient. Following a second public consultation, taking into account a change in the original draft recommendations, the NICE medical technologies guidance MTG19 was issued in June 2014. This recommended the adoption of the geko™ for use in people with a high risk of VTE and when other mechanical/pharmacological methods of prophylaxis are impractical or contraindicated in selected patients within the National Health Service in England.

E-vita open plus for treating complex aneurysms and dissections of the thoracic aorta: a NICE medical technology guidance.

The E-vita open plus is a one-stage endoluminal stent graft system used for treating complex aneurysms and dissections of the thoracic aorta. The National Institute for Health and Care Excellence (NICE), as a part of its Medical Technologies Evaluation Programme (MTEP), selected this device for evaluation and invited the manufacturer, JOTEC GmbH, to submit clinical and economic evidence. King's Technology Evaluation Centre (KiTEC), an External Assessment Centre (EAC) commissioned by the NICE, independently critiqued the manufacturer's submissions. The EAC considered that the manufacturer had included most of the relevant evidence for the E-vita open plus, based on international E-vita open registry data for 274 patients, but had provided only limited evidence for the comparators. The EAC therefore conducted a systematic review and meta-analysis of all comparators to supplement the information, and found ten additional studies providing outcome data for the three two-stage comparators. The EAC noted that the cost model submitted by the manufacturer did not include key complications during the procedures. The EAC developed a new economic model incorporating data on complications along with their long-term costs. The revised model indicated that the E-vita open plus might not provide cost savings when compared with some of the comparators in the short-term (1 year), but would have high cost savings in the long-term, from the second year onwards. The NICE Medical Technologies Guidance MTG 16, issued in December 2013, recommended the adoption of the E-vita open plus in selected patients within the National Health Service in England.