Search

Background Eyes sustaining open globe trauma are at high risk of severe visual impairment. Proliferative vitreoretinopathy is the most common cause of retinal detachment and visual loss in eyes with open globe trauma. There is evidence from experimental studies and pilot clinical trials that the use of adjunctive steroid medication triamcinolone acetonide can reduce the incidence of proliferative vitreoretinopathy and improve outcomes of surgery for open globe trauma. Objective The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study aimed to investigate the clinical effectiveness of adjunctive triamcinolone acetonide given at the time of vitreoretinal surgery for open globe trauma. Design A phase 3 multicentre double-masked randomised controlled trial randomising patients undergoing vitrectomy following open globe trauma to either adjunctive triamcinolone acetonide or standard care. Setting Hospital vitreoretinal surgical services dealing with open globe trauma. Participants Patients undergoing vitrectomy surgery who had sustained open globe trauma. Interventions Triamcinolone acetonide 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon’s or standard vitreoretinal surgery and postoperative care. Main outcome measures The primary outcome was the proportion of patients with at least 10 letters of improvement in corrected visual acuity at six months. Secondary outcomes included retinal detachment secondary to proliferative vitreoretinopathy, retinal reattachment, macula reattachment, tractional retinal detachment, number of operations, hypotony, elevated intraocular pressure and quality of life. Health-related quality of life was assessed using the EuroQol Five Domain and Visual Function Questionnaire 25 questionnaires. Results A total of 280 patients were randomised; 129 were analysed from the control group and 130 from the treatment group. The treatment group appeared, by chance, to have more severe pathology on presentation. The primary outcome (improvement in visual acuity) and principal secondary outcome (change in visual acuity) did not demonstrate any treatment benefit for triamcinolone acetonide. The proportion of patients with improvement in visual acuity was 47% for triamcinolone acetonide and 43% for standard care (odds ratio 1.03, 95% confidence interval 0.61 to 1.75, p = 0.908); the baseline adjusted mean difference in the six-month change in visual acuity was –2.65 (95% confidence interval –9.22 to 3.92, p = 0.430) for triamcinolone acetonide relative to control. Similarly, the secondary outcome measures failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal reattachment and stable macular retinal reattachment, outcomes for the treatment group were significantly worse for triamcinolone acetonide at the 5% level (respectively, odds ratio 0.59, 95% confidence interval 0.36 to 0.99, p = 0.044 and odds ratio 0.59, 95% confidence interval 0.35 to 0.98, p = 0.041) compared with control in favour of control. The cost of the intervention was £132 per patient. Health economics outcome measures (Early Treatment Diabetic Retinopathy Study, Visual Function Questionnaire 25 and EuroQol Five Dimensions) did not demonstrate any significant difference in quality-adjusted life-years. Conclusions The use of combined intraocular and sub-Tenon’s capsule triamcinolone acetonide is not recommended as an adjunct to vitrectomy surgery for intraocular trauma. Secondary outcome measures are suggestive of a negative effect of the adjunct, although the treatment group appeared to have more severe pathology on presentation. Future work The use of alternative adjunctive medications in cases undergoing surgery for open globe trauma should be investigated. Refinement of clinical grading and case selection will enable better trail design for future studies. Trial registration This trial is registered as ISRCTN 30012492, EudraCT number 2014-002193-37, REC 14/LNO/1428, IRAS 156358, Local R&D registration CHAD 1031. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (12/35/64) and will be published in full in Health Technology Assessment; Vol. 27, No. 12. See the NIHR Journals Library website for further project information. Plain language summary Despite advances in surgical techniques, eye trauma remains a leading cause of blindness and visual impairment. The main cause of trauma is a scarring process within the eye – proliferative vitreoretinopathy. There is good evidence from laboratory work and small-scale clinical studies that the addition of a steroid medication, triamcinolone acetonide, given in and around the eye at the time of surgery for eye trauma, can reduce the incidence of proliferative vitreoretinopathy scarring and improve the outcomes of surgery. The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study was a multicentre clinical trial designed to test the use of triamcinolone acetonide as an addition to surgery to improve outcomes in eyes with ‘open globe’ penetrating injuries. A total of 280 patients were recruited and randomised to receive standard surgery or surgery with the additional steroid (triamcinolone acetonide). No benefit was found from the addition of the steroid medication. The addition of steroid medication was not good value for money. Secondary outcome measures suggested that triamcinolone acetonide may have had a negative effect on outcomes, although this may have been due to the presence of more severe cases amongst the patients allocated to receive the additional steroid (triamcinolone acetonide). The use of adjunctive triamcinolone acetonide in eye trauma cases undergoing surgery is therefore not recommended. Future studies with different additional medications and/or more targeted case selection are indicated to improve outcomes for eyes experiencing penetrating trauma. Scientific summary Background Eyes sustaining penetrating or open globe trauma (OGT) are a group at high risk of severe visual impairment. Retinal detachment (RD) is common in these eyes and multiple surgical interventions are often necessary. Proliferative vitreoretinopathy (PVR) is the most common cause of recurrent RD and visual loss in eyes, with OGT occurring in 10–45% of cases. There is good evidence from experimental, preclinical studies and pilot clinical trials that the use of adjunctive steroid medication, in particular triamcinolone acetonide (TA), can reduce the incidence of PVR and improve outcomes of surgery for OGT. Objective The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) study aimed to investigate the clinical effectiveness of adjunctive TA given at the time of vitreoretinal surgery for OGT. This included analysis of the economic and quality of life benefits of the adjunctive treatment. From an NHS perspective, to explore the incremental cost-effectiveness of TA and to explore the cost per quality-adjusted life-year (QALY) of adjunctive TA in vitreoretinal surgery for OGT to determine whether this falls below the National Institute of Health and Care Excellence threshold of £20,000–30,000 per QALY. Methods A phase 3 multicentre double-masked randomised controlled clinical trial randomising patients undergoing vitrectomy following OGT to either adjunctive TA (4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon’s) or standard care. Inclusion criteria were as follows: 1.adult subjects (aged 18 years or over at the time of enrolment) 2.full thickness, open globe ocular trauma undergoing vitrectomy 3.ability to give written informed consent 4.willingness to accept randomisation and attend follow-up for six months. Patients were recruited prior to vitrectomy surgery and randomised at the completion of surgery. The primary outcome was to determine whether adjunctive intraocular and periocular steroid (TA) improves visual acuity (VA) at six months compared with standard treatment in eyes undergoing vitreoretinal surgery for OGT. This was defined as the proportion of patients with at least 10 letters of improvement in corrected VA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at six months. Secondary outcomes were to determine whether adjunctive intraocular and periocular steroid (TA) influences the development of scarring (PVR), RD (stable complete retinal and macular reattachment), intraocular pressure abnormalities and other complications in eyes undergoing surgery for OGT. In addition, to assess the effects of treatment on quality of life measured using the EuroQol Five Dimensions (EQ-5D) questionnaire and the Visual Function Questionnaire-25 (VFQ-25) tools. The study sample size was calculated from previously published work and two non-randomised trials carried out by the investigators. Based on previous studies, to detect a 19% increase in the proportion of patients with clinically meaningful improvement in VA [from 55% to 74%, corresponding to an odds ratio (OR) of 2.33], with an allowance for an estimated 7% dropout rate, the target sample size was 300 patients (150 per study arm). The main analysis followed the intention-to-treat principle and was conducted subgroup blind (i.e. as group A vs. group B) in accordance with the prespecified ASCOT statistical analysis plan. The primary analysis model consisted of a mixed logistic model with change in VA (

Background: In the United Kingdom, it is estimated that 5,000 patients sustain eye injuries or ocular trauma requiring hospital admission annually, of which 250 patients will be permanently blinded. This study explores the cost-effectiveness of Adjunctive Steroid Combination in Ocular Trauma (ASCOT) given during surgery versus standard treatment in vitreoretinal surgery in patients with open globe trauma. Methods: This economic evaluation was embedded alongside the ASCOT RCT (ClinicalTrials.gov Identifier: NCT02873026). We conducted a primary cost-effectiveness analysis from a National Health Service perspective using the proportion of patients who achieved a visual acuity of 10 or more letter improvement on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale as the measure of effect, in developing incremental cost-effectiveness ratios (ICERs). Secondary cost-utility analysis using the EuroQol 5 Dimension 5 Level (EQ-5D-5L) to generate a cost per quality-adjusted life-year (QALY), and a cost-effectiveness analysis using vision-specific quality of life (QoL) was conducted. Sensitivity analyses were also applied to investigate parameter uncertainties. Results: The sample size of the ASCOT intervention arm and standard care arm of this study was 130 and 129, respectively. The intervention cost per patient was estimated at £132. The proportion of participants with an ETDRS of 10 or more letter improvement was 0.47 for the ASCOT group with a mean cost of £5,526 per patient, while the standard care group had an effect of 0.43 with a mean cost of £5,099 per patient. The ICER value of the primary outcome was £12,178 per 10 or more letter improvement on the ETDRS score. The secondary result in terms of cost per QALYs gained had a probability of 44% being cost-effective at a willingness-to-pay threshold of £30,000/QALY gained. Conclusions: Though there is no formally accepted cost-effectiveness willingness-to-pay threshold for 10-letter or more improvement, the ASCOT intervention for open globe trauma is a low-cost intervention. The ASCOT intervention is not cost-effective when compared to the standard care in this group and setting. The proportion of patients in the ASCOT intervention arm with 10 or more letter improvement produced some positive results but this is outweighed by the costs. [ABSTRACT FROM AUTHOR]

Background/aims To investigate the clinical effectiveness of adjunctive triamcinolone acetonide (TA) given at the time of vitreoretinal surgery following open globe trauma (OGT). Methods A phase 3, multicentre, double-masked randomised controlled trial of patients undergoing vitrectomy following OGT comparing adjunctive TA (intravitreal and subtenons) against standard care (2014-2020). The primary outcome was the proportion of patients with at least 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letter improvement in corrected visual acuity (VA) at 6 months. Secondary outcomes included: change in ETDRS, retinal detachment (RD) secondary to PVR, retinal reattachment, macular reattachment, tractional RD, number of operations, hypotony, elevated intraocular pressure and quality of life. Results 280 patients were randomised over 75 months, of which 259 completed the study. 46.9% (n=61/130) of patients in the treatment group had a 10-letter improvement in VA compared with 43.4% (n=56/129) of the control group (difference 3.5% (95% CI -8.6% to 15.6%), OR=1.03 (95% CI 0.61 to 1.75), p=0.908)). Secondary outcome measures also failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal and macular reattachment, outcomes were worse in the treatment group compared with controls, respectively, 51.6% (n=65/126) vs 64.2% (n=79/123), OR=0.59 (95% CI 0.36 to 0.99), and 54.0% (n=68/126) vs 66.7% (n=82/123), OR=0.59 (95% CI 0.35 to 0.98), for TA vs control. Conclusion The use of combined intraocular and sub-Tenons capsule TA is not recommended as an adjunct to vitrectomy surgery following OGT. [ABSTRACT FROM AUTHOR]

Abstract Background We conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma. Methods Randomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate. Results Fifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72). Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33). No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any cardiotoxicity (clinical and subclinical) showed moderate to high statistical heterogeneity for four of five pooled analyses; criteria for any cardiotoxic event differed between studies. Nonetheless the pattern of results was similar to those for clinical or subclinical cardiotoxicity described above. Conclusions Evidence is not sufficiently robust to support clear evidence-based recommendations on different anthracycline treatment regimens, or for routine use of cardiac protective agents or liposomal formulations. There is a need to improve cardiac monitoring in oncology trials.

Background: The Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT) is a trial to determine the clinical efficacy and safety of omalizumab for children with severe atopic eczema. This article describes the detailed statistical analysis plan for the ADAPT as an update to the published protocol and is submitted prior to knowing all outcomes.Method and Design: The ADAPT is a randomised, double-blind, placebo-controlled trial with a primary objective to determine whether anti-IgE reduces eczema severity as assessed by the validated eczema score (objective SCORAD) after 24 weeks of treatment in children with severe eczema. This articles outline the overall analysis principles including considerations on sample definition in each analysis, missing data, and adjusted covariates. Comparability and representativeness of the randomised groups, primary and sensitivity analyses of the primary and secondary outcomes as well as subgroup analysis are described.Results: This prespecified statistical analysis plan has been developed to comply with international guidelines which will increase the transparency of the data analysis for the ADAPT.Trial Registration: ISRCTN, identifier: ISRCTN15090567 . Registered on 3 December 2014; EU Clinical Trials Register, EudraCT Number: 2010-020841-29 . Registered on 14 May 2010. The first participant was enrolled on 15 January 2015. [ABSTRACT FROM AUTHOR]

Background: We conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma. Methods: Randomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate. Results: Fifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72). Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33). No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any cardiotoxicity (clinical and subclinical) showed moderate to high statistical heterogeneity for four of five pooled analyses; criteria for any cardiotoxic event differed between studies. Nonetheless the pattern of results was similar to those for clinical or subclinical cardiotoxicity described above. Conclusions: Evidence is not sufficiently robust to support clear evidence-based recommendations on different anthracycline treatment regimens, or for routine use of cardiac protective agents or liposomal formulations. There is a need to improve cardiac monitoring in oncology trials. [ABSTRACT FROM AUTHOR]