Philip Hykin

A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT Study): 12-Month Data: Report 2

PURPOSE To report the findings at 1 year of a study comparing repeated intravitreal bevacizumab (ivB) and modified Early Treatment of Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant diabetic macular edema (CSME). DESIGN Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial. PARTICIPANTS A total of 80 eyes of 80 patients with center-involving CSME and at least 1 prior MLT. METHODS Subjects were randomized to either ivB (6 weekly; minimum of 3 injections and maximum of 9 injections in the first 12 months) or MLT (4 monthly; minimum of 1 treatment and maximum of 4 treatments in the first 12 months). MAIN OUTCOME MEASURES The primary end point was the difference in ETDRS best-corrected visual acuity (BCVA) at 12 months between the bevacizumab and laser arms. RESULTS The baseline mean ETDRS BCVA was 55.7+/-9.7 (range 34-69) in the bevacizumab group and 54.6+/-8.6 (range 36-68) in the laser arm. The mean ETDRS BCVA at 12 months was 61.3+/-10.4 (range 34-79) in the bevacizumab group and 50.0+/-16.6 (range 8-76) in the laser arm (P = 0.0006). Furthermore, the bevacizumab group gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (P = 0.0002). The odds of gaining > or =10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95% confidence interval, 1.3-19.7; P = 0.019). At 12 months, central macular thickness decreased from 507+/-145 microm (range 281-900 microm) at baseline to 378+/-134 microm (range 167-699 microm) (P<0.001) in the ivB group, whereas it decreased to a lesser extent in the laser group, from 481+/-121 microm (range 279-844 microm) to 413+/-135 microm (range 170-708 microm) (P = 0.02). The median number of injections was 9 (interquartile range [IQR] 8-9) in the ivB group, and the median number of laser treatments was 3 (IQR 2-4) in the MLT group. CONCLUSIONS The study provides evidence to support the use of bevacizumab in patients with center-involving CSME without advanced macular ischemia.

Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study.

Objectives To evaluate the efficacy and safety of intravitreous bevacizumab injections for the treatment of neovascular age related macular degeneration. Design Prospective, double masked, multicentre, randomised controlled trial. Setting Three ophthalmology centres in the United Kingdom. Participants 131 patients (mean age 81) with wet age related macular degeneration randomised 1:1 to intervention or control. Interventions Intravitreous bevacizumab (1.25 mg, three loading injections at six week intervals followed by further treatment if required at six week intervals) or standard treatment available at the start of the trial (photodynamic treatment with verteporfin for predominantly classic type neovascular age related macular degeneration, or intravitreal pegaptanib or sham treatment for occult or minimally classic type neovascular age related macular degeneration). Main outcome measures Primary outcome: proportion of patients gaining ≥15 letters of visual acuity at one year (54 weeks). Secondary outcomes: proportion of patients with stable vision and mean change in visual acuity. Results Of the 131 patients enrolled in the trial, five patients did not complete the study because of adverse events, loss to follow-up, or death. In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P<0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P<0.001). Mean visual acuity increased by 7.0 letters in the bevacizumab group with a median of seven injections compared with a decrease of 9.4 letters in the standard care group (P<0.001), and the initial improvement at week 18 (plus 6.6 letters) was sustained to week 54. Among 65 patients treated with bevacizumab, there were no cases of endophthalmitis or serious uveitis related to the intervention. All end points with respect to visual acuity in the study eye at 54 weeks favoured bevacizumab treatment over standard care. Conclusions Bevacizumab 1.25 mg intavitreous injections given as part of a six weekly variable retreatment regimen is superior to standard care (pegaptanib sodium, verteporfin, sham), with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 54 weeks. Trial registration number Current controlled trials ISRCTN83325075

Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration

Background/aims Real-life anti-vascular endothelial growth factor (VEGF) therapy use in patients with wet age-related macular degeneration (wAMD) was assessed in a retrospective, observational study in Canada, France, Germany, Ireland, Italy, the Netherlands, UK and Venezuela. Methods Medical records of patients with wAMD, who started ranibizumab treatment between 1 January 2009 and 31 August 2009, were evaluated. Data were collected until the end of treatment and/or monitoring or until 31 August 2011. Results 2227 patients who received ≥1 anti-VEGF injection with a baseline visual acuity assessment and ≥1 postbaseline visual acuity assessment for the treated eye were evaluated. Visual acuity improved until about day 120; thereafter, visual acuity gains were not maintained. Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively. Patients received a mean of 5.0 and 2.2 injections in the first and second year, respectively. There were substantial differences in visual outcomes and injection frequency between countries. More frequent visits and injections were associated with greater improvements in visual acuity. Conclusions In clinical practice, fewer injections are administered than in clinical trials. Anti-VEGF treatment resulted in an initial improvement in visual acuity; however, this was not maintained over time. Trial registration number NCT01447043.

Pars plana vitrectomy with and without peeling of the inner limiting membrane for diabetic macular edema

Purpose: A prospective, comparative, nonrandomized study to evaluate the efficacy of pars plana vitrectomy (PPV) with and without inner limiting membrane (ILM) peeling for persistent diffuse clinically significant macular edema. Methods: Eighteen patients with persistent diffuse clinically significant macular edema despite laser photocoagulation were recruited for the study. Clinical assessment included determination of best-corrected visual acuity, fundus fluorescein angiography, optical coherence tomography, and perifoveal cone function testing. Eight patients underwent PPV with elevation and removal of the posterior hyaloid alone, and 10 patients underwent vitrectomy and ILM peeling. The follow-up was 12 months. Results: Patients with ILM peeling had improvement in foveal thickness (P = 0.07) and significant improvement in the macular volume (P = 0.039) 12 months after surgery but did not have significant improvement in Early Treatment Diabetic Retinopathy Study vision or perifoveal cone function. There was no significant difference in outcome parameters between the no peeling group and the ILM peeling group. Conclusions: In this prospective, comparative study of PPV with and without ILM peeling for diffuse clinically significant macular edema, structural improvement was seen but with limited visual improvement after ILM peeling.

The natural history and management of recurrent corneal erosion: a prospective randomised trial

One hundred and seventeen patients with a history of recurrent corneal erosion were recruited at initial hospital presentation. Seventy-five cases had a history of shallow corneal injury, 23 had epithelial basement membrane dystrophy (EBMD), 8 had both and 11 had neither. Mean age at presentation was 38 years and follow-up ranged from 6 to 16 months (mean 10.6 months). Sixty-one patients presented with a first acute corneal erosion, 21 with a subsequent acute corneal erosion and 35 with chronic symptoms. Patients with EBMD or a trauma-related focal epithelial basement membrane abnormality were more likely to present with chronic recurrent symptoms than trauma-related cases with no abnormality on examination. Both EBMD and trauma-related cases typically recurred in the lower half of the cornea, frequently in the midline (z = 7.3, p < 0.0001), suggesting an intrinsic or acquired abnormality of the epithelial basement membrane at this site. Only four of 82 acute episodes did not resolve by 5 days with simple patching, cycloplegia and topical antibiotic ointment. In the vast majority of patients presenting with an acute erosion, simple management measures only are required. Of 117 cases started on prophylactic ointment at night, further therapy due to prophylaxis failure was required in only 5. EBMD was a risk factor for failure (relative risk 10.77). There was no difference in efficacy between once daily prophylactic paraffin and hypertonic saline ointments (p = 0.17), suggesting they both have only a lubricant action.

Phacoemulsification versus extracapsular cataract extraction in patients with diabetes

OBJECTIVE To compare phacoemulsification with extracapsular cataract surgery in patients with diabetes and to identify determinants of postoperative visual acuity. DESIGN Prospective, randomized, paired-eye trial. PARTICIPANTS Forty-six patients with diabetes and bilateral cataract. INTERVENTION Patients were allocated to phacoemulsification surgery with silicone intraocular lens to one randomly determined eye, and extracapsular cataract surgery with 7-mm polymethylmethacrylate intraocular lens to the other. MAIN OUTCOME MEASURES Logarithm of minimum angle of resolution visual acuity (logMAR VA), incidence of clinically significant macular edema (CSME), retinopathy progression, indices of anterior segment inflammation, and incidence of capsulotomy. RESULTS Compared with eyes undergoing phacoemulsification, eyes managed with extracapsular surgery had more anterior chamber cells (P = 0.0004) and flare (P = 0.007) 1 week after surgery and a higher incidence of posterior synechiae (P = 0.04) and intraocular lens deposits (P < 0.0005) in the first postoperative year. The need for posterior capsulotomy was greater in eyes undergoing extracapsular surgery (16 of 46 vs. 5 of 46, P = 0.01). No difference in incidence of postoperative CSME, progression of retinopathy, or development of high-risk proliferative retinopathy was identified between techniques (P = 1.0, 0.8, and 0.2). Median 1-year logMAR VA was worse in eyes undergoing extracapsular surgery (0.08 vs. 0.06, P = 0.02), especially in those with retinopathy (0.14 vs. 0.08, respectively; P = 0.01). The presence or absence of CSME at the time of surgery was the most significant determinant of 1-year logMAR VA in regression models for both extracapsular (P = 0.0004, R2 = 0.45) and phacoemulsification groups (P < 0.00005, R2 = 0.46). CONCLUSIONS Phacoemulsification is associated with better postoperative VA, less postoperative inflammation, and less need for capsulotomy than extracapsular cataract surgery in patients with diabetes. However, with both techniques, the principal determinant of postoperative VA appears to be the presence or absence of CSME at the time of surgery. Early intervention, reducing the risk that unrecognized CSME is present at the time of surgery, may be more critical to outcome than choice of surgical technique.

Visual acuity following extracapsular cataract extraction in diabetes: a meta-analysis.

Although pre-operative retinopathy severity appears to be a major factor in determining the visual outcome of diabetic extracapsular cataract extraction, its precise relationship to post-operative visual acuity is ill defined. A meta-analysis was therefore carried out, and studies were included if pre-operative maculopathy and retinopathy status was sufficiently defined to permit discrimination of visual outcome between subgroups. Weighted mean proportions of eyes achieving a postoperative visual acuity ≥6/12 were as follows: no retinopathy, 87%; non-proliferative retinopathy with no maculopathy, 80%; quiescent proliferative retinopathy with no maculopathy, 57%; non-proliferative retinopathy with maculopathy, 41%; quiescent proliferative retinopathy with maculopathy, 11%; active proliferative retinopathy, 0. Differences in visual outcome between groups were significant (χ2 = 119.9, p<0.0005), attributable mostly to the trend across groups (χ2 for trend = 115.4, p<0.0005). Logistic regression indicated that maculopathy was a more potent predictor of post-operative visual acuity ≤6/12 (odds ratio 6.4, 95% CI 4.13-9.94, p<0.0005) than quiescent proliferative retinopathy (odds ratio 3.33, 95% CI 2.04-5.42, p<0.0005). The severity of retinopathy and maculopathy prior to cataract surgery in diabetics are the major determinants of post-operative visual acuity. Further study of the relationship between pre-operative retinopathy severity and the incidence of post-operative complications, progression of retinopathy and maculopathy is required to optimise the management of cataract in diabetes.

Posterior capsule opacification following diabetic extracapsular cataract extraction

Review was performed of extracapsular cataract extraction with posterior chamber lens implantation in 90 diabetic patients and 263 non-diabetic patients. There was a higher incidence of posterior capsular opacification as judged by the requirement for Nd:YAG posterior capsulotomy in patients with non-proliferative (12/35, 34%) or quiescent proliferative diabetic retinopathy (8/18, 44%) than in non-diabetic patients (48/263, 18%) (Mantel-Haenszel p= 0.04). Although subgroup analysis showed a higher incidence of posterior capsule opacification in diabetics with non-proliferative or quiescent proliferative retinopathy than in diabetics without retinopathy, this was not statistically significant (Mantel-Haenszel p= 0.19 and p= 0.07, respectively). Following cataract surgery in diabetics with retinopathy, frequent review and prompt management of posterior capsular opacification is recommended, to maintain adequate fundus visualisation at a time when deterioration of retinopathy is likely.

Angiopoietin concentrations in diabetic retinopathy

Background/aim: Angiopoietin 1 and 2 interact with vascular endothelial growth factor (VEGF) to promote angiogenesis in animal and in vitro models. Although VEGF concentrations are elevated, there is little information regarding angiopoietin concentration in the vitreous of patients with diabetic retinopathy. Methods: Angiopoietin concentrations were measured by luminescence immunoassay in vitreous samples from 17 patients with non-proliferative diabetic retinopathy (NPDR) and clinically significant diabetic macular oedema (CSMO), 10 patients with proliferative diabetic retinopathy (PDR), and five patients with macular hole (controls) obtained at pars plana vitrectomy. Results: Angiopoietin 1 concentrations were low in patients with macular hole (median 17 pg/ml) while in NPDR with CSMO they were 2002 pg/ml (range 289–5820 pg/ml) and in PDR 186 pg/ml (range 26–2292 pg/ml). Angiopoietin 2 concentrations in NPDR with CSMO were a median of 4000 pg/ml (range 1341–14 329 pg/ml). For both macular hole and PDR patients angiopoietin 2 was below the limit of detection. Conclusions: Angiopoietin 2 concentration was twice that of angiopoietin 1 in NPDR with CSMO. Angiopoietin 2 is the natural antagonist of angiopoietin 1 which is thought to act as an anti-permeability agent. The predominance of angiopoietin 2 may allow VEGF induced retinal vascular permeability in patients with CSMO. The relatively low concentration of both angiopoietin 1 and 2 in patients with proliferative diabetic retinopathy may reflect the established nature of the neovascularisation in cases proceeding to vitrectomy.

Diabetic retinopathy: pathogenesis, clinical grading, management and future developments.

Decades of research into the pathophysiology and management of diabetic retinopathy have revolutionized our understanding of the disease process. Diabetic retinopathy is now more accurately defined as a neurovascular rather than a microvascular disease as neurodegenerative disease precedes and coexists with microvascular changes. However, the complexities of the pathways involved in different stages of disease severity continue to remain a challenging issue for drug discovery. Currently, laser photocoagulation is the mainstay of treatment for proliferative diabetic retinopathy, but is gradually being superseded for diabetic macular oedema. However, it is destructive and at best results in a gradual but modest improvement in vision in the long term. So, diabetic retinopathy remains the most prevalent cause of visual impairment in the working‐age population despite established screening programmes, early diagnosis and treatment of the condition. The recent discovery of inhibitors of vascular endothelial growth factor is revolutionizing the management of diabetic retinopathy, particularly diabetic macular oedema. However, not all patients respond to anti‐vascular endothelial growth factor agents, reinforcing the fact that diabetic retinopathy is a multifactorial disease. Studies are still required to improve our understanding of how retinal structure correlates with visual function. It is hoped that these will lead to better characterization of the disease phenotype based on treatment responses to different agents and allow an algorithm to be developed that will guide the management of diabetic retinopathy and diabetic macular oedema at different stages of severity.