Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial.

BACKGROUND: A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. METHODS: PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). FINDINGS: Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). INTERPRETATION: Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. FUNDING: Regeneron Pharmaceuticals and Bayer.

Efficacy and Safety of Faricimab for Macular Edema due to Retinal Vein Occlusion: 24-Week Results from the BALATON and COMINO Trials.

PURPOSE: To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion. DESIGN: Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192). PARTICIPANTS: Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO. METHODS: Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug. RESULTS: Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs. +17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs. +17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 µm [95.03% CI, -316.4 to -306.4 µm] and -304.4 µm [95.03% CI, -309.3 to -299.4 µm]) and COMINO (-461.6 µm [95.03% CI, -471.4 to -451.9 µm] and -448.8 µm [95.03% CI, -458.6 to -439.0 µm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively). CONCLUSIONS: These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials.

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 µm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration.

OBJECTIVE: To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). DESIGN: Twenty-four-month, open-label, multicenter, phase IV extension study. PARTICIPANTS: Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. METHODS: Ranibizumab 0.5 mg administered at the investigator's discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigator's opinion). MAIN OUTCOME MEASURES: Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections. RESULTS: Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline. CONCLUSIONS: The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigator's discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

BALATON and COMINO: Phase III Randomized Clinical Trials of Faricimab for Retinal Vein Occlusion: Study Design and Rationale.

Purpose: Dual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO). Design: Two identically designed global, randomized, double-masked, active comparator-controlled studies. Participants: Anti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO. Methods: Patients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend-based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA). Main Outcome Measures: Primary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0-24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24-72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed. Results: In total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers). Conclusions: Using a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical Characteristics and Outcomes of Eyes with Intraocular Inflammation after Brolucizumab: Post Hoc Analysis of HAWK and HARRIER.

PURPOSE: This analysis of the pivotal phase 3 HAWK and HARRIER trials aimed to provide insights on the timing of presentation, management, and outcomes of intraocular inflammation (IOI)-related adverse events (AEs), as reported by investigators in these trials. DESIGN: Post hoc analysis of investigator-reported IOI-related AEs in HAWK and HARRIER. PARTICIPANTS: Of 1088 brolucizumab-treated eyes (3 or 6 mg), 49 eyes demonstrated at least 1 IOI-related AE and were included in this analysis. METHODS: Reports of IOI-related AEs were analyzed and descriptive statistics were provided for outcome measures. MAIN OUTCOME MEASURES: Incidence and description of eyes with IOI-related AEs, timing of presentation, management, clinical outcomes, and brolucizumab treatment after the first IOI-related AE. RESULTS: Seventy IOI-related AEs were reported in 49 eyes. Before the onset of first IOI-related AE, eyes received a mean ± standard deviation (SD) of 3.9 ± 2.2 brolucizumab injections. Median time to first IOI-related AE from the last administered brolucizumab injection was 18.0 days (interquartile range, 4.0-29.0 days). Of the 70 AEs, 61 (87.1%) were treated, most with topical corticosteroids; systemic and intraocular corticosteroids were used for 3 AEs each. Overall, inflammation resolved completely in 39 eyes (79.6%), resolved with sequelae in 5 eyes (10.2%), and did not resolve in 5 eyes (10.2%) by end-of-study (EOS). Overall, the mean ± SD best-corrected visual acuity (BCVA) change from baseline to EOS, before AE to the lowest BCVA in 3 months after AE, and from before AE to EOS were -0.84 ± 20.6 , -16.31 ± 17.6, and -0.22 ± 18.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, respectively. Of the 36 eyes (73.5%) that continued with brolucizumab therapy after the first IOI-related AE, 24 completed the trials and 12 discontinued; mean ± SD BCVA change in these eyes was 2.6 ± 17.6, 7.8 ± 13.2, and -7.7 ± 21.3 ETDRS letters, respectively, from baseline to EOS. The remaining 13 eyes (26.5%) were not treated with brolucizumab after first IOI-related AE and showed a mean ± SD BCVA change of -10.4 ± 25.5 ETDRS letters from baseline to EOS. CONCLUSIONS: Findings of this analysis highlight the need for continued vigilance and monitoring for any signs of IOI-related events in patients receiving brolucizumab.

Expert Opinion on Management of Intraocular Inflammation, Retinal Vasculitis, and Vascular Occlusion after Brolucizumab Treatment.

PURPOSE: Recent reports have described a spectrum of uncommon findings of intraocular inflammation (IOI), retinal vasculitis, or retinal vascular occlusion in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal injection (IVI) of brolucizumab. We present guidance on the clinical presentation of this spectrum and propose recommendations for management of these events. DESIGN: PubMed literature review and expert opinion panel. PARTICIPANTS: A working group of international medical experts and Novartis medical personnel. METHODS: The working group deliberated on the clinical presentations and used a 3-pronged approach to develop management recommendations based on (1) critical appraisal of scientific literature; (2) clinical insights from the HAWK and HARRIER trials, postmarketing reports, and assessments from an independent Safety Review Committee (SRC); and (3) their clinical experience. MAIN OUTCOME MEASURES: Management recommendations for a spectrum of ocular inflammatory events after treatment with brolucizumab or other anti-vascular endothelial growth factors (VEGFs). RESULTS: Based on insights gained from the available information and the expertise of the contributors, recommendations were proposed for ocular examinations, imaging modalities, and treatment strategies for management of this spectrum of events. Patients should be educated to promptly report any relevant or persistent symptoms after IVI to facilitate timely intervention. Patients diagnosed with IOI should be evaluated for concomitant retinal vasculitis or retinal vascular occlusive events. Clinical examination can be augmented with multimodal imaging techniques, including widefield imaging, fluorescein angiography (with peripheral sweeps), and OCT. Once confirmed, the ongoing brolucizumab treatment should be suspended and intensive treatment with potent corticosteroids (topical, subtenon, intravitreal, or systemic) is recommended, which may be supplemented with other treatment strategies depending on the severity. Based on the clinical outcome of these events, individualized treatment with locally available standard of care should be considered for the underlying nAMD. CONCLUSIONS: These recommendations emphasize the need for early diagnosis, prompt and timely intervention, intensive treatment, and frequent monitoring to minimize the risk of progression of these events. The proposed recommendations may facilitate a consistent management approach of this spectrum of ocular inflammatory events should they arise in nAMD after treatment with brolucizumab or other anti-VEGFs.

Boundary detection errors on optical coherence tomography images in patients with diabetic retinopathy.

BACKGROUND AND OBJECTIVE: To study the incidence of boundary detection errors produced by optical coherence tomography measurements in patients with diabetic retinopathy. PATIENTS AND METHODS: One hundred sixteen eyes with diabetic retinopathy of 64 consecutive patients with diabetes mellitus were included in this retrospective study. The StratusOCT instrument (Carl Zeiss Meditec, Dublin, CA) with the macular thickness map protocol was used for the examinations. After data acquisition, each scan was analyzed using the retinal thickness (single eye) protocol to evaluate whether there was any misdetection of the retinal boundaries. RESULTS: Boundary detection errors were found in 35.3% of eyes. The majority of artifacts were those caused by hard exudates (41.5%), followed by cystoid macular edema (31.7%) and proliferation (17.0%). CONCLUSION: Occurrence of artifacts with optical coherence tomography measurements in cases of diabetic retinopathy is not a rare phenomenon and verification of quantitative measurements is strongly recommended.

Central corneal thickness measurements with optical coherence tomography and ultrasound pachymetry in healthy subjects and in patients after photorefractive keratectomy.

PURPOSE: To compare central corneal thickness measurements made using two different methods, optical coherence tomography (OCT) and ultrasound pachymetry, applied both in normal eyes and in eyes on which photorefractive keratectomy (PRK) had been performed. A second objective was to assess the intrasession variability of OCT measurements. METHODS: In this prospective study, central corneal thickness was measured in 20 normal subjects (normal group) and in 20 PRK patients using the StratusOCT instrument model 3000 (Carl Zeiss Meditec), and also with an ultrasound pachymeter. Five OCT measurements were performed using the Fast Macular Thickness protocol. Corneal thickness data were obtained with the Scan Profile analysis protocol. The OCT measurement results were compared with the mean value of three ultrasound pachymetry measurements for the same eye. RESULTS: The pachymetry-OCT correlation coefficients were 0.96 and 0.97 in the normal and PRK groups, respectively (p=0.14). Neither linear regression nor Bland-Altmann analysis revealed any significant systematic measurement error. Intrasession standard deviations in the normal and PRK groups were 4.9 microm and 3.8 microm, respectively. CONCLUSIONS: Noncontact central corneal thickness measurements made using the StratusOCT instrument are accurate and reproducible, both in normal subjects and in post-PRK patients. The instrument system does not need any modifications to correctly detect and measure the center of the cornea.

[Photodynamic therapy in age-related macular degeneration]. / Fotodinámiás kezelés idoskori maculadegenerációban.

INTRODUCTION: Exudative form of age-related macular degeneration is the leading cause of legal blindness in elderly. PURPOSE: The purpose of this study is to report 3.5 years experience with photodynamic therapy in this disorder. PATIENTS AND METHODS: Patient files of all patients underwent photodynamic therapy with verteporfin in Department of Ophthalmology, Semmelweis University, Budapest in a 3.5 years period were reviewed. Changes in visual acuity were considered as main outcome variable compared to natural history data. RESULTS: From April, 2000 to September 2003, 302 patients were treated using photodynamic therapy with verteporfin for exudative form of age-related macular degeneration. The mean change of visual acuity were 2.6 and 2,7 lines at 12 and 24 months, respectively, while according to the natural history data 4.2 and 4.5 could have been expected. After 2 years, 83% of the patients had visual acuity better than or equal to 20/200 (this is the level of legal blindness), while only 33% was expected according to natural history data. Visual acuity of 20/80 or better (practical ambulatory vision) was found in 39% of the treated eyes (12% in natural history data). There was no severe adverse event. CONCLUSIONS: Photodynamic therapy was found to reduce the risk of severe visual loss. The authors' results confirm the data from the international trials. To achieve good results, good patient compliance and continuous access to the treatment are indispensible.

The diameters of the human retinal branch vessels do not change in darkness.

PURPOSE: To examine whether the diameters of retinal branch vessels of the human eye change during dark and light adaptation. METHODS: Images (S-VHS recordings) were obtained of the peripapillary region in 11 eyes of 11 healthy young adults (seven women, four men; mean age, 26.4 years). The images were made under a sequence of different illumination conditions (light, 30 minutes of darkness, light) with a scanning laser ophthalmoscope (SLO), using near-infrared illumination (785 nm). The recordings were then analyzed with a retinal vessel analyzer (RVA), and the caliber changes of one branch artery and one vein were measured in each eye. RESULTS: For arteries, the changes of diameter under different illumination conditions showed no clear trend, and comparisons between the different time sections revealed no statistically significant changes (P = 0.933; repeated measures ANOVA). There was a slight dilation (average, 0.9%; range, -3.9% to +5.1%) in darkness, and a return to baseline (range, -2.9% to + 2.9%) on restoring normal illumination. Veins during darkness showed a small but fairly consistent constriction (average, 1.5%; range -5.4% to +3.9%; significant P = 0.05), again returning to baseline (range, -2.1% to +2.6%) in normal light. CONCLUSIONS: The small changes of retinal branch vessel diameters under different light conditions probably have little influence on the possible changes of retinal blood flow in healthy subjects.

Effect of calcium dobesilate on progression of early diabetic retinopathy: a randomised double-blind study.

BACKGROUND: The study was carried out to confirm the effect of calcium dobesilate (CaD) compared to placebo (PLA) on the blood-retinal barrier (BRB) permeability in early diabetic retinopathy (DR). METHODS: Adults with type II diabetes and early diabetic retinopathy (below level 47 of ETDRS grading and PVPR between 20 and 50x10(-6)/ min, plasma-free fluorescein) were included in this double-blind placebo-controlled study. Treatment was 2 g daily for 24 months. The primary parameter, posterior vitreous penetration ratio (PVPR), was measured every 6 months by fluorophotometry. Secondary parameters were fundus photography, fluorescein angiography and safety assessments. Metabolic control was performed every 3 months. RESULTS: A total of 194 patients started the treatment (98 CaD, 96 PLA) and 137 completed the 24-month study (69 CaD, 68 PLA). Both treatment groups were comparable at baseline, with ETDRS level 10 in about 59% of patients. Mean PVPR change from baseline after 24 months was significantly (P=0.002) lower in the CaD group [-3.87 (SD 12.03)] than in the PLA group [+2.03 (SD 12.86)], corresponding to a 13.2% decrease in the CaD group and a 7.3% increase in the PLA group. PVPR evolution was also analysed by HbA1c classes (<7%, between 7 and 9%, > or =9%) and results confirmed the superiority of CaD independently of the diabetes control level. A highly significant difference [CaD: -3.38 (SD 13.44) versus PLA: +3.50 (SD 13.70)] was also obtained in a subgroup of patients without anti-hypertensive and/or lipid-lowering agents (P=0.002 at 24 months). A further analysis of the secondary parameters showed significant changes in favour of CaD in the evolution from baseline to the last visit of haemorrhages (P=0.029), DR level (P=0.0006) and microaneurysms (P=0.013). Regarding safety, only 2.5% (n=5 patients/ events) of all adverse events reported were assessed as possibly or probably related to the test drug, while all serious adverse events were reported as unlikely. There was no statistical difference between groups. CONCLUSION: Calcium dobesilate 2 g daily for 2 years shows a significantly better activity than placebo on prevention of BRB disruption, independently of diabetes control. Tolerance was very good.

Presentation delay in patients affected with exudative age-related macular degeneration.

BACKGROUND: Presentation delay (i.e. duration of visual symptoms before initial presentation) is an established critical parameter for visual prognosis in patients with exudative age-related macular degeneration (ARMD) considering the natural history of the disease and the limitations of current treatments. The purpose of this study was to determine the duration of presentation delay and its evolution in two periods 4 years apart. METHODS: Presentation delay in 1598 patients affected with exudative ARMD was retrospectively reviewed during two similar 8-month periods in 1994 and 1998 in a tertiary referral center. RESULTS: The proportions of patients examined either within 1 month, between 1 and 3 months, and between 3 and 6 months after onset of symptoms, respectively, increased between 1994 and 1998 from 23% to 33%, from 27% to 32.5%, and from 14% to 18.5%. The proportions of patients examined between 6 and 12 months and after 12 months decreased from 16% to 12% and from 20% to 4%, respectively. Furthermore, the proportion of patients presenting with a first eye involvement during the first month following the onset of symptoms rose from 42% in 1994 to 52% in 1998. All these differences were statistically significant. CONCLUSION: This first specific review of presentation delay in exudative ARMD showed a significant decrease in this parameter between 1994 and 1998 that should be taken into account when assessing the overall evolution of visual outcome. Further studies are warranted to ascertain that these findings reflect a global improvement in the management of macular diseases.