Simon P. Harding

Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial.

PURPOSE To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD). DESIGN Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560). PARTICIPANTS People >50 years of age with untreated nAMD in the study eye who read ≥ 25 letters on the Early Treatment Diabetic Retinopathy Study chart. METHODS We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review. MAIN OUTCOME MEASURES The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs. RESULTS Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001). CONCLUSIONS The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosures may be found after the references.

Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study) A 12-month, randomized, controlled, double-masked, multicenter phase II study

OBJECTIVE The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center. RESEARCH DESIGN AND METHODS This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age >18 years, type 1 or 2 diabetes, central retinal thickness [CRT] ≥300 μm, and best corrected visual acuity [BCVA] of 73–39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham (n = 49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n = 151, patients receiving ≥1 injection). RESULTS At month 12, mean ± SD BCVA improved from baseline by 10.3 ± 9.1 letters with ranibizumab and declined by 1.4 ± 14.2 letters with sham (P < 0.0001). Mean CRT reduction was 194.2 ± 135.1 μm with ranibizumab and 48.4 ± 153.4 μm with sham (P < 0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P < 0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab. CONCLUSIONS Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial

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.

Sensitivity and specificity of photography and direct ophthalmoscopy in screening for sight threatening eye disease: the Liverpool diabetic eye study

Abstrac Objective: To evaluate different methods for community based screening for sight threatening diabetic eye disease. Design: Prospective study. Setting: Mobile screening unit visiting inner city community clinics; hospital assessment clinic (tertiary centre). Subjects: 395 diabetic patients registered with four general practices in an inner city location. Interventions: Community based photography with mydriasis and direct ophthalmoscopy through dilated pupils by an experienced ophthalmologist, both compared with reference standard of slit lamp biomicroscopy by a consultant specialist in medical retinal disease. Main outcome measures: Sensitivity and specificity of screening method and prevalence of sight threatening diabetic eye disease (moderate preproliferative retinopathy, circinate maculopathy, exudate within 1 disc diameter of fixation, other diabetes related eye disease). Results: 358 subjects underwent photography, 326 attended hospital clinic for ophthalmoscopy, and six were ungradable on photographs and biomicroscopy, leaving 320 for analysis. Of these 295 (91%) attended clinic within four months of photography. Sensitivity of detection of eye disease by photography was 89% (95% confidence interval 80% to 98%), significantly better than for direct ophthalmoscopy (65% (51% to 79%)). Analysis of patients with false negative results indicated possible improvement of photographic sensitivity to 93% by addition of stereoscopic macular pair photographs. Specificity of detection of sight threatening eye disease was 86% (82% to 90%) for photography and 97% (95% to 99%) for direct ophthalmoscopy. Conclusions: Since high sensitivity is essential for an effective screening programme, a photographic method should be considered as preferred option in national, community based screening programmes. Even in the hands of an experienced ophthalmologist, direct ophthalmoscopy is limited by weaknesses inherent to the instrument.

Incidence of sight-threatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: a cohort study.

BACKGROUND Incidence data on which to base targets and protocols for screening for sight-threatening diabetic retinopathy are few. We aimed to investigate yearly and cumulative incidence of any retinopathy, maculopathy, and sight-threatening diabetic retinopathy in patients with type 2 diabetes in an established systematic programme and to calculate optimum screening intervals according to retinopathy grade at baseline. METHODS We investigated all patients with type 2 diabetes registered with enrolled general practices (except those who were attending an ophthalmologist) who had retinopathy data available at baseline and at least one further screening event. To screen patients, we used non-stereoscopic three-field mydriatic photography and modified Wisconsin grading. Sight-threatening diabetic retinopathy was defined as moderate preproliferative retinopathy or worse, or clinically significant maculopathy in either or both eyes. FINDINGS Results were obtained from 20 570 screening events. Yearly incidence of sight-threatening diabetic retinopathy in patients without retinopathy at baseline was 0.3% (95% CI 0.1-0.5) in the first year, rising to 1.8% (1.2-2.5) in the fifth year; cumulative incidence at 5 years was 3.9% (2.8-5.0). Rates of progression to sight-threatening diabetic retinopathy in year 1 by baseline status were: background 5.0% (3.5-6.5), and mild preproliferative 15% (10.2-19.8). For a 95% probability of remaining free of sight-threatening diabetic retinopathy, mean screening intervals by baseline status were: no retinopathy 5.4 years (95% CI 4.7-6.3), background 1.0 years (0.7-1.3), and mild preproliferative 0.3 years (0.2-0.5). INTERPRETATION A 3-year screening interval could be safely adopted for patients with no retinopathy, but yearly or more frequent screening is needed for patients with higher grades of retinopathy.

Genotyping and functional analysis of a polymorphic (CCTTT)(n) repeat of NOS2A in diabetic retinopathy

Accumulating evidence shows that the severity and rapidity of onset of diabetic retinopathy are influenced by genetic factors. Expression of the nitric oxide synthases is altered in the retinal vascu‐lature in the early stages of diabetic retinopathy. We analyzed the allele distribution of a polymorphic pentanucleotide repeat within the 5′ upstream promoter region of the NOS2A gene in samples of diabetic patients. In diabetic patients from Northern Ireland, the 14‐repeat allele of the NOS2A marker was significantly associated with the absence of diabetic retinopathy. Carriers of this repeat had 0.21‐fold the relative risk of developing diabetic retinopathy than noncarriers of this allele. They also had significantly fewer renal and cardiovascular complications. The ability of differing numbers of (CCTTT)n pentanucleotide repeats to induce transcription of the NOS2A gene was analyzed using a luciferase reporter gene assay in transfected colonic carcinoma cells. Interleukin 1β (IL‐1β) induction was most effective in constructs carrying the 14‐repeat allele. When cells were incubated in 25 mM glucose to mimic the diabetic state, IL‐1 β induction was inhibited in all cases, but to a significantly lesser extent with the 14‐repeat allele. These unique properties of the 14‐repeat allele may confer selective advantages in diabetic individuals, which may delay or prevent microvascular complications of diabetes.—Warpeha, K. M., Xu, W., Liu, L., Charles, I. G., Patterson, C. C., Ah‐Fat, F., Harding, S., Hart, P. M., Chakravarthy, U., Hughes, A. E. Functional analysis of the polymorphic (CCTTT)n locus of NOS2A in diabetic retinopathy. FASEB J. 13, 1825–1832 (1999)

Natural history of herpes zoster ophthalmicus: predictors of postherpetic neuralgia and ocular involvement.

Seventy-one patients presenting with acute herpes zoster ophthalmicus were followed up for six months for a prospective analysis of the natural history of the disease. Acute and chronic ocular complications, nasociliary nerve involvement, age, sex, rash, and pain were assessed, and the results are presented. Acute pain was measured by a visual analogue scale. Postherpetic neuralgia (PHN) was more likely in patients over 80 and in those who scored their pain highly at presentation. Duration of rash was longer in patients who developed PHN. No other associations between the parameters studied were found. Nasociliary nerve involvement was associated with subsequent ocular disease.

Cost effectiveness analysis of screening for sight threatening diabetic eye disease

Abstract Objective: To measure the cost effectiveness of systematic photographic screening for sight threatening diabetic eye disease compared with existing practice. Design: Cost effectiveness analysis Setting: Liverpool. Subjects: A target population of 5000 diabetic patients invited for screening. Main outcome measures: Cost effectiveness (cost per true positive) of systematic and opportunistic programmes; incremental cost effectiveness of replacing opportunistic with systematic screening. Results: Baseline prevalence of sight threatening eye disease was 14.1%. The cost effectiveness of the systematic programme was £209 (sensitivity 89%, specificity 86%, compliance 80%, annual cost £104 996) and of the opportunistic programme was £289 (combined sensitivity 63%, specificity 92%, compliance 78%, annual cost £99 981). The incremental cost effectiveness of completely replacing the opportunistic programme was £32. Absolute values of cost effectiveness were highly sensitive to varying prevalence, sensitivity and specificity, compliance, and programme size. Conclusion: Replacing existing programmes with systematic screening for diabetic eye disease is justified.

Perfusion Abnormalities in Children with Cerebral Malaria and Malarial Retinopathy

BACKGROUND In patients with cerebral malaria (CM), retinal angiography allows the study of infected central nervous system microvasculature in vivo. We aimed to examine retinal perfusion in children with CM by use of fluorescein angiography to investigate the pathophysiology of CM. METHODS We performed fluorescein angiography on children with CM admitted to Queen Elizabeth Central Hospital, Malawi. We related angiograms to funduscopic findings. RESULTS Fluorescein angiography was performed for 34 patients with CM, and impaired perfusion was identified in 28 (82%). Areas of capillary nonperfusion (CNP) were seen in 26 patients (76%). Multiple, scattered areas of CNP were typical and topographically matched to retinal whitening. Larger retinal vessels were occluded in 9 patients (26%) who had associated ischemia. These vessels appeared white on ophthalmoscopy. Intravascular abnormalities were seen in 9 patients (26%), including filling defects and mottling of the blood column. Limited fluorescein leakage occurred in 15 patients (44%) and was not related to angiographic intravascular abnormalities or visible vessel discoloration. CONCLUSIONS Impaired perfusion occurs in the retinal microvasculature of most children with CM. This is evidence for hypoxia and ischemia as important components in the pathogenesis of CM. Vessel occlusion and filling defects are likely to be due to sequestration of infected erythrocytes. Interventions which improve perfusion or limit hypoxic injury may be beneficial in CM.

Oral acyclovir in herpes zoster ophthalmicus

46 patients with acute herpes zoster ophthalmicus of less than 72 hours duration were recruited into a placebo controlled trial to assess the efficacy of oral acyclovir, 800mg 5 times daily, in preventing or modifying ocular complications and pain.Fewer acyclovir recipients developed intraocular complications and these were less severe but neither difference was statistically significant. However, active ocular disease was significantly less common in the acyclovir group (p=0.01) at 6 months. Pain was significantly less severe in the acyclovir group between 2 and 6 months. The proportion of patients with pain scores greater than 0 was significantly lower in the acyclovir group between 2 and 3 months.Oral acyclovir appears to modify the disease process in herpes zoster ophthalmicus, to reduce the severity and incidence of postherpetic pain and especially to protect against long-term ocular complications.