Anti-vascular endothelial growth factor for diabetic macular oedema.

BACKGROUND: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO, or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities is used to try to improve vision in people with DMO. OBJECTIVES: To investigate the effects in preserving and improving vision and acceptability, including the safety, compliance with therapy and quality of life, of antiangiogenic therapy with anti-VEGF modalities for the treatment of DMO. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment or no treatment in people with DMO. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. The risk ratios (RR) for visual loss and visual gain of three or more lines of logMAR visual acuity were estimated at one year of follow-up (plus or minus six months) after treatment initiation. MAIN RESULTS: Eighteen studies provided data on four comparisons of interest in this review. Participants in the trials had central DMO and moderate vision loss.Compared with grid laser photocoagulation, people treated with antiangiogenic therapy were more likely to gain 3 or more lines of vision at one year (RR 3.6, 95% confidence interval (CI) 2.7 to 4.8, 10 studies, 1333 cases, high quality evidence) and less likely to lose 3 or more lines of vision (RR 0.11, 95% CI 0.05 to 0.24, 7 studies, 1086 cases, high quality evidence). In meta-analyses, no significant subgroup difference was demonstrated between bevacizumab, ranibizumab and aflibercept for the two primary outcomes, but there was little power to detect a difference. The quality of the evidence was judged to be high, because the effect was large, precisely measured and did not vary across studies, although some studies were at high or unclear risk of bias for one or more domains. Regarding absolute benefit, we estimated that 8 out of 100 participants with DMO may gain 3 or more lines of visual acuity using photocoagulation whereas 28 would do so with antiangiogenic therapy, meaning that 100 participants need to be treated with antiangiogenic therapy to allow 20 more people (95% CI 13 to 29) to markedly improve their vision after one year. People treated with anti-VEGF on average had 1.6 lines better vision (95% CI 1.4 to 1.8) after one year compared to laser photocoagulation (9 studies, 1292 cases, high quality evidence). To achieve this result, seven to nine injections were delivered in the first year and three or four in the second, in larger studies adopting either as needed regimens with monthly monitoring or fixed regimens.In other analyses antiangiogenic therapy was more effective than sham (3 studies on 497 analysed participants, high quality evidence) and ranibizumab associated with laser was more effective than laser alone (4 studies on 919 participants, high quality evidence).Ocular severe adverse events, such as endophthalmitis, were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation did not show a significant difference regarding serious systemic adverse events (15 studies, 441 events in 2985 participants, RR 0.98, 95% CI 0.83 to 1.17), arterial thromboembolic events (14 studies, 129 events in 3034 participants, RR 0.89, 95% CI 0.63 to 1.25) and overall mortality (63 events in 3562 participants, RR 0.88, 95% CI 0.52 to 1.47). We judged the quality of the evidence on adverse effects as moderate due to partial reporting of safety data and the exclusion of participants with previous cardiovascular events in some studies. AUTHORS' CONCLUSIONS: There is high quality evidence that antiangiogenic drugs provide a benefit compared to current therapeutic options for DMO, that is grid laser photocoagulation, in clinical trial populations at one or two years. Future research should investigate differences between drugs, effectiveness under real-world monitoring and treatment conditions, and safety in high-risk populations, particularly regarding cardiovascular risk

Treatment as required versus regular monthly treatment in the management of neovascular age-related macular degeneration: a systematic review and meta-analysis

Background: To investigate whether treatment as required ‘pro re nata’ (PRN) versus regular monthly treatment regimens lead to differences in outcomes in neovascular age-related macular degeneration (nAMD). Regular monthly administration of vascular endothelial growth factor (VEGF) inhibitors is an established gold standard treatment, but this approach is costly. Replacement of monthly by PRN treatment can only be justified if there is no difference in patient relevant outcomes. Methods: Systematic review and meta-analysis. The intervention was PRN treatment and the comparator was monthly treatment with VEGF-inhibitors. Four bibliographic databases were searched for randomised controlled trials comparing both treatment regimens directly (head-to-head studies). The last literature search was conducted in December 2014. Risk of bias assessment was performed after the Cochrane Handbook for Systematic Reviews of Interventions. Findings: We included 3 head-to-head studies (6 reports) involving more than 2000 patients. After 2 years, the weighted mean difference in best corrected visual acuity (BCVA) was 1.9 (95% CI 0.5 to 3.3) ETDRS letters in favour of monthly treatment. Systemic adverse events were higher in PRN treated patients, but these differences were not statistically significant. After 2 years, the total number of intravitreal injections required by the patients in the PRN arms were 8.4 (95% CI 7.9 to 8.9) fewer than those having monthly treatment. The studies were considered to have a moderate risk of bias. Conclusions: PRN treatment resulted in minor but statistically significant decrease in mean BCVA which may not be clinically meaningful. There is a small increase in risk of systemic adverse events for PRN treated patients. Overall, the results indicate that an individualized treatment approach with anti-VEGF using visual acuity and OCT-guided re-treatment criteria may be appropriate for most patients with nAMD

Descemet stripping automated endothelial keratoplasty in Fuchs' corneal endothelial dystrophy: Anterior segment optical coherence tomography and in vivo confocal microscopy analysis

Background: To evaluate the in vivo corneal changes using in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) in patients with Fuchs' dystrophy who underwent Descemet stripping automated endothelial keratoplasty (DSAEK) and the relationship between these changes and the postoperative visual recovery up to 1-year follow-up. Methods: Before DSAEK and 1 day, 3, 6 and 12 months after surgery 31 patients (39 pseudophakic eyes) underwent a complete ophthalmological evaluation including best corrected visual acuity (BCVA), IVCM (subepithelial haze, interface haze, graft thickness) and AS-OCT (graft thickness). Results: Graft thickness measurements by AS-OCT were strongly correlated to those obtained using IVCM at every follow-up stage (intraclass correlation coefficientâ\u88\u88=â\u88\u880.95 to 0.97 between 3 and 12 months, Pâ\u88\u88<â\u88\u880.001 for all coefficients). No correlation between BCVA and graft thickness measured by AS-OCT at any follow-up stage was found, while at 3 and 6 postoperative months the correlations between BCVA and preoperative subepithelial haze (râ\u88\u88=â\u88\u880.61, Pâ\u88\u88<â\u88\u880.001 and râ\u88\u88=â\u88\u880.46, Pâ\u88\u88=â\u88\u880.002), interface haze (râ\u88\u88=â\u88\u880.51, Pâ\u88\u88<â\u88\u880.001 and râ\u88\u88=â\u88\u880.46, Pâ\u88\u88=â\u88\u880.003), postoperative subepithelial haze (râ\u88\u88=â\u88\u880.43, Pâ\u88\u88=â\u88\u880.004 and râ\u88\u88=â\u88\u880.39, Pâ\u88\u88=â\u88\u880.001) were significant. Conclusions: The study confirmed corneal subepithelial haze and interface haze as important factors limiting visual acuity after DSAEK, while graft thickness was not related to BCVA

Anti-vascular endothelial growth factor for diabetic macular oedema: A network meta-analysis

BACKGROUND: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities can reduce oedema and thereby improve vision and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. OBJECTIVES: The 2014 update of this review found high-quality evidence of benefit with antiangiogenic therapy with anti-VEGF modalities, compared to laser photocoagulation, for the treatment of DMO.The objective of this updated review is to compare the effectiveness and safety of the different anti-VEGF drugs in preserving and improving vision and quality of life using network meta-analysis methods. SEARCH METHODS: We searched various electronic databases on 26 April 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham or no treatment in people with DMO. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for pair-wise meta-analysis and we augmented this evidence using network meta-analysis methods. We focused on the relative efficacy and safety of the three most commonly used drugs as interventions of direct interest for practice: aflibercept and ranibizumab, used on-label; and off-label bevacizumab.We collected data on three efficacy outcomes (gain of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters; mean change in best-corrected visual acuity (BCVA); mean change in central retinal thickness (CRT)), three safety outcomes (all severe systemic adverse events (SSAEs); all-cause death; arterial thromboembolic events) and quality of life.We used Stata 'network' meta-analysis package for all analyses. We investigated the risk of bias of mixed comparisons based on the variance contribution of each study, having assigned an overall risk of bias to each study. MAIN RESULTS: Twenty-four studies included 6007 participants with DMO and moderate vision loss, of which two studies randomised 265 eyes of 230 participants and one was a cross-over study on 56 participants (62 eyes) that was treated as a parallel-arm trial. Data were collected on drugs of direct interest from three studies on aflibercept (975 eyes), eight studies on bevacizumab (515 eyes), and 14 studies on ranibizumab (1518 eyes). As treatments of indirect interest or legacy treatment we included three studies on pegaptanib (541 eyes), five studies on ranibizumab plus prompt laser (557 eyes), one study on ranibizumab plus deferred laser (188 eyes), 13 studies on laser photocoagulation (936 eyes) and six studies on sham treatment (793 eyes).Aflibercept, bevacizumab and ranibizumab were all more effective than laser for improving vision by 3 or more lines after one year (high-certainty evidence). Approximately one in 10 people improve vision with laser, and about three in 10 people improve with anti-VEGF treatment: risk ratio (RR) versus laser 3.66 (95% confidence interval (CI) 2.79 to 4.79) for aflibercept; RR 2.47 (95% CI 1.81 to 3.37) for bevacizumab; RR 2.76 (95% CI 2.12 to 3.59) for ranibizumab. On average there was no change in visual acuity (VA) with laser after one year, compared with a gain of 1 or 2 lines with anti-VEGF treatment: laser versus aflibercept mean difference (MD) -0.20 (95% CI -0.22 to -0.17) logMAR; versus bevacizumab MD -0.12 (95% CI -0.15 to -0.09) logMAR; versus ranibizumab MD -0.12 (95% CI -0.14 to -0.10) logMAR. The certainty of the evidence was high for the comparison of aflibercept and ranibizumab with laser and moderate for bevacizumab comparison with laser due to inconsistency between the indirect and direct evidence.People receiving ranibizumab were less likely to gain 3 or more lines of VA at one year compared with aflibercept: RR 0.75 (95% CI 0.60 to 0.94), moderate-certainty evidence. For every 1000 people treated with aflibercept, 92 fewer would gain 3 or more lines of VA at one year if treated with ranibizumab (22 to 148 fewer). On average people receiving ranibizumab had worse VA at one year (MD 0.08 logMAR units, 95% CI 0.05 to 0.11), moderate-certainty evidence; and higher CRT (MD 39 µm, 95% CI 2 µm to 76 µm; low-certainty evidence). Ranibizumab and bevacizumab were comparable with respect to aflibercept and did not differ in terms of VA: RR of gain of 3 or more lines of VA at one year 1.11 (95% CI 0.87 to 1.43), moderate-certainty evidence, and difference in change in VA was 0.00 (95% CI -0.02 to 0.03) logMAR, moderate-certainty evidence. CRT reduction favoured ranibizumab by -29 µm (95% CI -58 µm to -1 µm, low-certainty evidence). There was no evidence of overall statistical inconsistency in our analyses.The previous version of this review found moderate-certainty evidence of good safety of antiangiogenic drugs versus control. This update used data at the longest available follow-up (one or two years) and found that aflibercept, ranibizumab and bevacizumab do not differ regarding systemic serious adverse events (SSAEs) (moderate- or high-certainty evidence). However, risk of bias was variable, loop inconsistency could be found and estimates were not precise enough on relative safety regarding less frequent events such as arterial thromboembolic events or death (low- or very low-certainty evidence).Two-year data were available and reported in only four RCTs in this review. Most industry-sponsored studies were open-label after one year. One large publicly-funded study compared the three drugs at two years and found no difference. AUTHORS' CONCLUSIONS: Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. There is moderate-certainty evidence that aflibercept confers some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms. Relative effects among anti-VEGF drugs at two years are less well known, since most studies were short term. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death

Utilities and QALYs in health economic evaluations: glossary and introduction

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Distinctive Mechanisms and Patterns of Exudative Versus Tractional Intraretinal Cystoid Spaces as Seen With Multimodal Imaging.

PurposeTo determine clear-cut distinctions between tractional and exudative intraretinal cystoid spaces subtypes.DesignRetrospective, multicenter, observational case series.MethodsA cohort of patients diagnosed with intraretinal cystoid spaces and imaged with optical coherence tomography (OCT), fluorescein angiography (FA), blue fundus autofluorescence (BFAF), en face OCT, and OCT angiography (OCT-A) was included in the study. All images were qualitatively and quantitatively evaluated.ResultsIn this study were included 72 eyes of 69 patients. Exudative intraretinal cystoid spaces (36/72 eyes, 50%) displayed a "petaloid" morphology as seen with en face OCT, FA, and BFAF. Tractional intraretinal cystoid spaces (24/72 eyes, 33.3%), displayed a radial "spoke-wheel" en face OCT pattern. There was no leakage with FA and BFAF did not reveal specific patterns. Eyes with full-thickness macular hole (FTMH, 12/72 eyes, 16.7%) displayed a "sunflower" en face OCT appearance. FTMH showed OCT, OCT-A, and BFAF features of both exudative and tractional cystoid spaces, but without any FA leakage. Inner nuclear layer (INL) thickness was significantly lower in tractional cystoid spaces (P &lt; .001). There were a greater number of INL cystoid spaces in both the exudative and FTMH subgroups (P = .001). The surface area of INL cystoid spaces was significantly lower in the tractional subgroup (P &lt; .001). There was a significant reduction of the microvascular density in eyes with exudative vs tractional (P = .002) and FTMH (P &lt; .001) subgroups.ConclusionsExudative and tractional intraretinal cystoid spaces displayed characteristic multimodal imaging features and they may represent 2 different pathologic conditions with equally different clinical implications

Intravitreal infliximab clearance in a rabbit model: different sampling methods and assay techniques.

PURPOSE. To investigate the clearance of intravitreal infliximab with the use of different sampling techniques and immunoassay methods in rabbits. METHODS. Infliximab (1.6 mg) was intravitreally injected into both eyes of 47 rabbits. Two approaches were used to collect the vitreous: the classic method and a microsampling technique. Whereas the classic method consists of collection of the whole vitreous after enucleation, the microsampling technique consisted of the aspiration of small (10‐15 L) samples with a 200-L syringe. Samples were taken from 30 minutes to 40 days using both methods and were then compared. Infliximab concentration was estimated with competitive ELISA, dot blot analysis, and Western blot analysis. RESULTS. The vitreous half-life of infliximab was estimated to be 6.5 0.6 days. The data indicated monoexponential decay reaching its conclusion after approximately 40 days. This decay was preceded by 4-day-long diffusion in the vitreous. Microsampling proved to be effective in the vitreous collection, giving statistically comparable signals ( 4%, P 0.68) with respect to the classic procedure. ELISA proved to be the best analytical technique—especially if coupled with microsamplings—because of its lower detection limit, precision, and reduced amount of sample needed. No differences were observed between half-life values obtained by ELISA and dot blot analysis (P 0.081) and Western blot analysis (P 0.614). CONCLUSIONS. The findings of this study added to the knowledge of infliximab clearance in the vitreous and confirmed the validity of a microsampling technique that was compared with the classic one. ELISA was found to be the best analytical technique when using microsampling. (Invest Ophthalmol Vis Sci. 2009;50:5328‐5335) DOI:10.1167/iovs.09-356